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Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment

Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment Citation: Cell Death and Disease (2013) 4, e838; doi:10.1038/cddis.2013.350 OPEN & 2013 Macmillan Publishers Limited All rights reserved 2041-4889/13 www.nature.com/cddis Review Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment 1,5 2,5 1,5 2 1 2 1 1 1 3 ,1,4 ,2,4 ,1,4 X Sui , R Chen , Z Wang , Z Huang , N Kong , M Zhang , W Han , F Lou , J Yang , Q Zhang , X Wang* , C He* and H Pan* Induction of cell death and inhibition of cell survival are the main principles of cancer therapy. Resistance to chemotherapeutic agents is a major problem in oncology, which limits the effectiveness of anticancer drugs. A variety of factors contribute to drug resistance, including host factors, specific genetic or epigenetic alterations in the cancer cells and so on. Although various mechanisms by which cancer cells become resistant to anticancer drugs in the microenvironment have been well elucidated, how to circumvent this resistance to improve anticancer efficacy remains to be defined. Autophagy, an important homeostatic cellular recycling mechanism, is now emerging as a crucial player in response to metabolic and therapeutic stresses, which attempts to maintain/restore metabolic homeostasis through the catabolic lysis of excessive or unnecessary proteins and injured or aged organelles. Recently, several studies have shown that autophagy constitutes a potential target for cancer therapy and the induction of autophagy in response to therapeutics can be viewed as having a prodeath or a prosurvival role, which contributes to the anticancer efficacy of these drugs as well as drug resistance. Thus, understanding the novel function of autophagy may allow us to develop a promising therapeutic strategy to enhance the effects of chemotherapy and improve clinical outcomes in the treatment of cancer patients. Cell Death and Disease (2013) 4, e838; doi:10.1038/cddis.2013.350; published online 10 October 2013 Subject Category: Cancer Facts Open Questions Whether we should try to enhance or inhibit autophagy in The induction of autophagy in response to metabolic and cancer treatment? therapeutic stresses can have a prodeath or a prosurvival Chloroquine and its derivative: just act as autophagy role, which contributes to the anticancer efficacy of these inhibitors? drugs as well as drug resistance. Autophagy is shown to precede apoptosis or act in parallel Anticancer drugs induce different effects of autophagy on with this cellular process in addition to be an alternative cell survival in different cancer types. mechanism to cell death when apoptosis is inhibited. Autophagy as a prosurvival and resistance mechanism Therefore, the autophagy induction may exert other against chemotherapy treatment. possibilities, which should be considered in the design of Autophagy-mediated cell death mechanism contributes to new treatments for the malignancies. efficacy of anticancer drugs. Targeting autophagy will hopefully provide a promising therapeutic strategy to circumvent resistance and enhance Resistance to anticancer drugs is a common clinical issue in the effects of anticancer therapies for cancer patients. the treatment of patients with cancer. Drug resistance, 1 2 Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China; Department of Colorectal Surgery, Sir Run Run Shaw Hospital, 3 4 Zhejiang University, Hangzhou, China; Department of Gastrointestinal Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, China and Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China *Corresponding authors: X Wang, Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang 310016, China. Tel: +86 571 8600 6926; Fax: +86 571 8600 6926; E-mail: wangxzju@163.com or C He, Department of Colorectal Surgery, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang 310016, China. Tel: +86 571 8600 6929; Fax: +86 571 8600 6929; E-mail: drhechao@yahoo.com.cn or H Pan, Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang 310016, China. Tel: +86 0571 8600 6926; Fax: +86 0571 8600 6926; E-mail: drpanhm@aliyun.com These authors contributed equally to this work. Keywords: autophagy; chemotherapy resistance; cancer; therapy Abbreviations: PI3K, phosphatidylinositol 3-kinase; mTOR, mammalian target of rapamycin; AMPK, AMP-activated protein kinase; ER, endoplasmic reticulum; eIF2a, eukaryotic initiation factor 2a; HDAC, histone deacetylase; DDR, DNA damage response; CQ, chloroquine; HCQ, hydroxychloroquine; EPI, epirubicin; 5-FU, 5-fluorouracil; MAPK, mitogen-activated protein kinase; GBM, glioblastoma; TMZ, temozolomide; MTD, maximum tolerated dose; HCC, hepatocellular carcinoma; MCL, mantle cell lymphoma; DAMP, damage-associated molecular pattern; B-CLL, B-chronic lymphocytic leukemia; EGF, epidermal growth factor; EGFR-TKI, epidermal growth factor receptor tyrosine kinase inhibitor; TPT, topotecan; PDAC, pancreatic adenocarcinoma; HDIL-2, high-dose interleukin-2; NAC1, nucleus accumbens-1; 3-MA, 3-methyladenine; MPNST, malignant peripheral nerve sheath tumor; BITC, benzyl isothiocyanate; LMP, lysosomal membrane permeabilization; MMP, mitochondrial membrane potential; SAHA, suberoylanilide hydroxamic acid; BL, Burkitt’s lymphoma Received 08.5.13; revised 25.8.13; accepted 27.8.13; Edited by GM Fimia Autophagy and chemotherapy resistance X Sui et al Drug efflux and metabolism Angiogenesis Mutation or loss Tumor of molecular heterogeneity targets Induction of Inactivation autophagy of apoptosis Increased repair of Compartmentalization damage Figure 1 A summary of the approaches by which cancer cells become resistant to chemotherapy and various kinds of genotoxic or metabolic stresses intrinsic or acquired, can be attributed to a wide variety of autophagy is also shown to promote cell death following mechanisms including tumor cell heterogeneity, drug efflux treatment with specific chemotherapeutic agents, either by and metabolism and tumor microenvironment stress-induced enhancing the induction of apoptosis or mediating ‘autophagic genetic or epigenetic alterations as a cellular response to cell death’. 1,2 drug exposure (Figure 1). Among these mechanisms, the Although the molecular mechanisms whereby autophagy response or adaptation of cancer cell itself to anticancer mediates its effects on both normal and cancer cells are far drug-induced tumor microenvironment stresses is a vital from complete, various signaling pathways have been cause for chemotherapy resistance. implicated in the upregulation or downregulation of auto- 10,11 Autophagy is an evolutionarily conserved catabolic process phagy. The phosphatidylinositol 3-kinase/mammalian in which portions of cytosol and organelles are sequestered target of rapamycin (PI3K/mTOR) and AMP-activated protein into a double-membrane vesicle and delivered to the kinase (AMPK) signaling pathways have emerged as the 3–6 lysosome for bulk degradation. In this review, the term central conduit in the regulation of autophagy (Figure 2). ‘autophagy’ refers to macroautophagy. The role of autophagy mTOR can be activated by growth factors signal through the in regulating cancer cell death or survival remains controversial. class I PI3K/Akt pathway, and inhibited by AMPK and 12,13 Current evidence supports the idea that constitutive p53. Once activated, mTOR exerts a negative effect on autophagy can act as a cellular housekeeper to eliminate autophagy by phosphorylating a complex of autophagy damaged organelles and recycle macromolecules, thus proteins (ULK1/2), which inhibits the downstream autophagy 14,15 protecting against cancer, particularly during malignant cascade. In contrast, AMPK can suppress mTORC1 transformation and carcinogenesis. In established tumors, signaling to stimulate autophagy through TSC1/2 phosphor- 16,17 autophagy can function as a prosurvival pathway in response ylation. Several of the known tumor-suppressor genes to metabolic stresses such as nutrient deprivation, hypoxia, (p53, PTEN, TSC1/TSC2) and tumor-associated genes 10,15 absence of growth factors and the presence of chemotherapy (p21, AKT) also respectively stimulate or inhibit autophagy. or some targeted therapies that might mediate resistance to Autophagy is also induced by a variety of metabolic 7–9 anticancer therapies. In this review we will summarize the stresses such as endoplasmic reticulum (ER) stress, hypoxia, possible role of autophagy as a novel target for anticancer oxidative stress, expression of aggregate-prone proteins, therapies and discuss the attractive prospect of manipulating glucose deprivation and so on. ER stress stimulates this control as a revolutionary strategy for cancer therapy. autophagy through the PERK/eukaryotic initiation factor 2a (eIF2a) and IRE1/JNK1 pathways. PERK/eIF2a phosphoryla- tion has been shown to be essential for the transcription of key The Regulation of Autophagy in Cancer During autophagy-associated genes during ER stress and may Response to Multiple Stresses mediate the polyglutamine-induced LC3 conversion. The Autophagy is essential for not only cell survival but also activation of IRE1/JNK promotes phosphorylation of Bcl-2 and organism survival in response to microenvironmental stresses. p53, resulting in interfering with Bcl-2 binding to Beclin 1 and When cancer cells are subjected to stressful conditions, autophagic cell death in cancer cells. Depletion of nutrients autophagy is rapidly upregulated to maintain metabolic or energy induces autophagy by activating the AMPK homeostasis and ensure that cell growth is appropriate to its pathway or promoting upregulate transcription of certain 16,17 changing environmental conditions through reduced growth autophagy genes. The MEK/ERK signaling activation and increased catabolic lysis of excessive or unnecessary and Rag inactivation contribute to amino acid depletion- 7,21 proteins and organelles. However, persistent or excessive induced autophagy. Many anticancer drugs including Cell Death and Disease Autophagy and chemotherapy resistance XSui et al Activation arrow Growth factors Anticancer drugs depletion Inhibition arrow Essential amino IRS1 PI3K PTEN acid depletion RAS Epigenetic alterations PDK1 PKB/AKT ER stress Rag Raf Glucose/Energy depletion TSC1/TSC2 MEK PERK IRE LKB1 ERK JNK Rheb eIF2a Raptor p53 AMPK ATF4 mTOR p21 Beclin 1 autophagy Hypoxia stress HIF BNIP3 Beclin 1 Cell survival or death Figure 2 Interrelations between autophagy-related signaling and cell growth control in response to stress. Autophagy can be activated in response to multiple stresses during cancer progression, including nutrient deprivation, endoplasmic reticulum stress, hypoxia, glucose/energy depletion, chemotherapy and other diverse stresses. The AMPK/mTOR pathway functions as a central conduit for autophagic signaling pathways to promote cell survival or death Cancer cells novel targeted therapies stimulate autophagy by inhibiting the Cancer cells PI3K/Akt/mTOR axis or altering genetic/epigenetic phenotype of cancer cells, which provides a survival advantage for 22–24 struggling tumor cells. The histone deacetylase (HDAC) inhibitors are recently involved in the control of DNA damage Chemotherapeutic agents response (DDR) and autophagy. SD118-xanthocillin X (1), a novel marine agent extracted from Penicillium commune, induces autophagy through the inhibition of the MEK/ERK pathway. Overall, autophagy is a cell biological process that Autophagic Autophagic flux involves diverse signals that have overlapping functions in flux autophagy and the control of other cellular stress responses. Stress Cytotoxicity restoration Autophagy in Response to Chemotherapy Similar to its potential to either induce cell death or promote cell survival, a growing body of evidence implicates a paradoxical role of autophagy following anticancer A major protective mechanism: Autophagic the acquired resistance phenotype treatments, with response increasing or diminishing their cell death anticancer activity. On the one hand, autophagy is activated Figure 3 Dual role of autophagy for therapeutic purposes in cancer. On one as a protective mechanism to mediate the acquired resistance hand, autophagy is activated as a protective mechanism to mediate the acquired phenotype of some cancer cells during chemotherapy. resistance phenotype of some cancer cells during chemotherapy. On the other Thus, the inhibition of autophagy can re-sensitize previously hand, autophagy may also function as a death executioner to induce autophagic cell resistant cancer cells and augment cytotoxicity of chemo- death, a form of physiological cell death that is contradictory to apoptosis therapeutic agents. On the other hand, autophagy may also play as a death executioner to induce autophagic cell death, a Autophagy as a Prosurvival and Resistance Mechanism form of physiological cell death which is contradictory to type Against Chemotherapy Treatment I programmed cell death (apoptosis) (Figure 3). Based on current genetic and pharmacological studies, it appears that Recent studies have demonstrated that tumor resistance to anticancer drugs induce different effects of autophagy on cell anticancer therapies including radiation therapy, chemotherapy survival in different cancer types (Table 1). Here we delineate and targeted therapies can be enhanced through upregulation 26,27 the possible role of autophagy as a novel target for anticancer of autophagy in different tumor cell lines. Moreover, therapy. increasing evidence suggests that autophagy inhibition Cell Death and Disease Autophagy and chemotherapy resistance X Sui et al Table 1 Autophagy in response to chemotherapy in different types of cancers Class Target Type of cancer Autophagy Method used to evaluate References role autophagy Autophagy inducers Aurora kinase A mTOR Breast Prosurvival siRNA (LC3, Atg5) CQ Bafilomycin A Suberoylanilide HDAC inhibitor CML Prosurvival 3-MA hydroxamic acid Bafilomycin A (SAHA) Breast Prodeath 3-MA Epirubicin (EPI) Anthracyclines Breast Prosurvival siRNA (Beclin 1, Atg7) Bafilomycin A 37,40–42 5-Fluorouracil Thymidylate synthase Colorectal Prosurvival siRNA (Atg7) 3-MA inhibitor Prodeath 3-MA Atorvastatin AMPK Digestive Prosurvival siRNA (Atg5) malignancies Bafilomycin A Irinotecan MAPK14/p38a Colorectal Prosurvival siRNA (Atg5, Atg7) Bafilomycin A 3-MA Cisplatin Genotoxic stress Esophageal Prosurvival 3-MA Oxaliplatin Genotoxic stress Hepatocellular Prosurvival siRNA (Atg5) carcinoma CQ 3-MA Bevacizumab Angiogenesis inhibitor Hepatocellular Prosurvival CQ 3-MA carcinoma Sorafenib ER stress Hepatocellular Prosurvival CQ carcinoma Genotoxic stress Prodeath siRNA (Beclin 1) High-mobility group DAMP molecule CML Prosurvival box 1 protein (HMGB1) 55,58 Gefitinib or Erlotinib EGFR tyrosine kinase Lung Prosurvival siRNA (Atg5, Atg7) inhibitor CQ 3-MA Topotecan Genotoxic stress Lung Prosurvival CQ RAGE Genotoxic or metabolic Pancreatic Prosurvival stress NVP-BEZ235 PI3K/AKT/mTOR inhibitor Renal Prosurvival Urothelial Prodeath CQ Ursolic acid Genotoxic stress Prostate Prosurvival siRNA (Atg5, Beclin 1) 3-MA Cervical Prodeath siRNA (Atg5) Wortmannin Imatinib Tyrosine kinase inhibitor Glioma Prosurvival Bafilomycin A RTA 203 Prodeath siRNA (Atg5, Beclin 1) 3-MA FK-16 Fragment of LL-37 Colon Prodeath siRNA (Bax, Bcl-2) Temozolomide Genotoxic stress Glioblastoma Prodeath mTOR inhibitor RAD001 Mono-Pt Genotoxic stress Ovarian Prodeath siRNA (Atg7, Beclin 1) 3-MA CQ Bafilomycin A Cannabinoids ER stress Glioma Prodeath siRNA (Atg1) AMPK Pancreatic Prodeath 3-MA CQ Hepatocellular Prodeath siRNA (Atg5) 3-MA carcinoma Autophagy inhibitors CQ Lysosomotropic agent Breast Prosurvival 43–45 HCQ Esophageal Prosurvival Hepatocellular Prosurvival carcinoma 56,57 Lung Prosurvival Pancreatic Prosurvival augments cytotoxicity in combination with several anticancer chloroquine (CQ) and its derivative hydroxychloroquine 28–30 drugs in preclinical models. Several pharmacological (HCQ) that suppress autophagy by blocking autophagosome 31,32 compounds and strategies have been reported to inhibit fusion and degradation. Both CQ and HCQ have been autophagy in vitro and in vivo. investigated in preclinical studies or clinical trials. In comparison with CQ, HCQ can be safely dose escalated in cancer patients. Currently, more than 30 phase I/II cancer clinical Antimalarial Drugs trials (http://clinicaltrials.gov/) involving CQ or HCQ are open The only autophagy inhibitors whose effectiveness in vivo and around the world and many of them have evidence of safety in clinical trials have been approved by the FDA are preliminary antitumor activity (Table 2). Cell Death and Disease Autophagy and chemotherapy resistance XSui et al Table 2 Active clinical trials combining the autophagy inhibitor HCQ with anticancer therapies Identifier Cancer type Drugs Phase Title NCT00969306 NSCLC CQ þ cisplatin Etoposide I/II Cisplatin, etoposide and escalating CQ in extensive disease SCLC NCT00809237 NSCLC HCQ þ gefitinib I/II Hydroxychloroquine and gefitinib to treat lung cancer NCT01649947 NSCLC HCQ þ paclitaxel and II Modulation of autophagy in patients with advanced/recurrent carboplatin non-small-cell lung cancer – phase II NCT00977470 Advanced NSCLC and HCQ þ erlotinib II Erlotinib with or without hydroxychloroquine in chemonaive (EGFR) mutations advanced NSCLC and (EGFR) mutations NCT00933803 Advanced or recurrent HCQ þ carboplatin, paclitaxel, Carboplatin, paclitaxel, bevacizumab and HCQ in advanced NSCLC bevacizuma or recurrent NSCLC NCT01292408 Breast cancer HCQ II Autophagy inhibition using hydroxychloroquine in breast cancer patients NCT00765765 Breast cancer HCQ þ ixabepilone I/II Ixabepilone and HCQ in metastatic breast cancer NCT01023477 DCIS CQ þ tamoxifen I/II Neoadjuvant tamoxifen, tamoxifen þ CQ, or CQ in DCIS NCT01510119 Renal cell carcinoma HCQ and RAD001(p.o. 10 mg/ I/II Autophagy inhibition to augment mTOR inhibition: a phase I/ day) II trial of RAD001 and hydroxychloroquine in patients with previously treated renal cell carcinoma NCT01144169 Renal cell carcinoma HCQ þ high dose interleukin-2 I Study of hydroxychloroquine before surgery in patients with and other systemic therapies primary renal cell carcinoma NCT01550367 Renal cell carcinoma HCQ þ IL-2 I/II Study of hydroxychloroquine and aldesleukin in renal cell carcinoma patients (RCC) NCT00726596 Prostate cancer HCQ II Hydroxychloroquine in treating patients with rising PSA levels after local therapy for prostate cancer NCT01128296 Pancreatic cancer HCQ þ gemcitabine I/II Study of presurgery gemcitabine þ hydroxychloroquine (GcHc) in stage IIb or III adenocarcinoma of the pancreas NCT01273805 Pancreatic cancer HCQ II Hydroxychloroquine in previously treated patients with metastatic pancreatic cancer NCT01506973 Pancreatic cancer HCQ þ gemcitabine/abraxane I/II A phase I/II/pharmacodynamic study of hydroxychloroquine in combination with gemcitabine/abraxane to inhibit autop- hagy in pancreatic cancer NCT01128296 Pancreatic cancer HCQ þ gemcitabine I/II Study of Pre-surgery Gemcitabine þ hydroxychloroquine (GcHc) in stage IIb or III adenocarcinoma of the pancreas NCT01494155 Pancreatic cancer HCQ þ capecitabine þ photon II Short-course radiation therapy with proton beam capecita- radiation bine and hydroxychloroquine for resectable pancreatic cancer NCT01206530 Colorectal cancer HCQ þ FOLFOX/ I/II FOLFOX/Bevacizumab/Hydroxychloroquine (HCQ) in col- bevacizumab orectal cancer NCT01006369 Metastatic colorectal HCQ þ capecitabine, oxalipla- II Hydroxychloroquine, capecitabine, oxaliplatin, and bevaci- cancer tin, and bevacizumab zumab in treating patients with metastatic colorectal cancer NCT00224978 Glioblastoma CQ III Adjuvant CQ versus placebo in glioblastoma NCT00486603 Glioblastoma HCQ þ temozolomide I/II Adjuvant radiation, temozolomide and HCQ in newly resected GBM NCT00962845 Melanoma HCQ No Hydroxychloroquine in patients with stage III or Stage IV phase melanoma that can be removed by surgery specified NCT00568880 Multiple myeloma HCQ þ bortezomib I/II Hydroxychloroquine and bortezomib in treating patients with relapsed or refractory multiple myeloma NCT01480154 Advanced solid tumors or HCQ þ MTD of Akt inhibitor I Phase I study of Akt inhibitor MK2206 and hydroxychlor- prostate or renal cancer MK2206 (MK-2206) oquine in patients with advanced solid tumors or prostate or renal cancer NCT00909831 Metastatic solid tumors HCQ þ temsirolimus I Hydroxychloroquine and temsirolimus in treating patients with metastatic solid tumors that have not responded to treatment NCT00813423 Advanced solid tumors HCQ þ sunitinib I Sunitinib and Hydroxychloroquine in treating patients with advanced solid tumors that have not responded to chemotherapy NCT01023737 Advanced solid tumors HCQ þ vorinostat I Vorinostat and HCQ in advanced solid tumors NCT01417403 Solid tumors undergoing HCQ I Hydroxychloroquine in treating patients with solid tumors radiation therapy for bone undergoing radiation therapy for bone metastases metastases NCT01266057 Advanced cancer HCQ þ the highest tolerable I Sirolimus or vorinostat and hydroxychloroquine in advanced dose of sirolimus or vorinostat cancer NCT00714181 Metastatic or unresect- HCQ þ temozolomide I Hydroxychloroquine and temozolomide in treating patients able solid tumors with metastatic or unresectable solid tumors NCT01227135 CML HCQ þ imatinib II Imatinib mesylate with or without hydroxychloroquine in treating patients with chronic myeloid leukemia NCT01634893 Ovarian cancer HCQ þ sorafenib I Oral hydroxychloroquine plus oral sorafenib to treat epithelial ovarian cancer FIGO stage III or stage IV, or extraovarian peritoneal carcinoma, or fallopian tube carcinoma failing or ineligible for first-line therapy NSCLC, non-small-cell lung cancer; CML, chronic myeloid leukemia; EGFR, epidermal growth factor receptor; MTD, maximum tolerated dose; HCQ, hydroxychloroquine Cell Death and Disease Autophagy and chemotherapy resistance X Sui et al Breast cancer. The role of autophagy in breast cancer is an lower than controls. Another phase I/II trial concerning area of active investigation. There is evidence to suggest that dose-limiting toxicities of HCQ with temozolomide (TMZ) epirubicin (EPI) may induce autophagy in human breast cancer and radiation for GBM patients was conducted. The MCF-7 cells, resulting in protecting MCF-7 cells from EPI- information about the antitumor activity of this combination induced apoptosis. Autophagy is also regarded as a key is underway. mechanism of antiestrogen resistance, and blocking autophago- some can significantly reduce the emergence of antiestrogen- Hepatocellular carcinoma. The combination of autophagy resistant breast cancer cells. A phase II clinical trial inhibitor and chemotherapy or molecular-targeted therapies (NCT01292408) is investigating the effects of autophagy has been regarded as a promising therapeutic strategy in the inhibition via HCQ on breast cancer patients. The current treatment of hepatocellular carcinoma (HCC). Autophagy is reports indicate that CQ or HCQ is often used in combination functionally activated in HCC cell lines after oxaliplatin with chemotherapeutic drugs to enhance the efficacy of treatment, and suppression of autophagy enhances oxali- tumor cell killing; however, its sensitizing effects can also platin-induced cell death. Autophagy also contributes to occur independently of autophagy inhibition, which should HCC cell survival, and the combined treatment of an be considered in the ongoing clinical trials where CQ or HCQ autophagy inhibitor and bevacizumab markedly inhibits the 36 49 are used in the treatment of breast cancer. growth of HCC. Moreover, the combination of sorafenib with CQ can generate more ER stress-induced cell death in Colorectal cancer. So far, 5-fluorouracil (5-FU), together HCC both in vivo and in vitro. Therefore, autophagy with other drugs such as oxaliplatin, remains a widely used inhibition may be a promising therapeutic strategy to chemotherapeutic drug in the treatment of a variety of enhance the effects of chemotherapy and improve clinical colorectal carcinomas. Previous researches have demon- outcomes in the treatment of HCC. strated that inhibition of autophagy augments anticancer effects of chemotherapy or some targeted therapies in Leukemia and MCL. Recently, it is reported that high- 37,38 colorectal cancer. Recently, it has been shown that mobility group box 1 (HMGB1), a damage-associated mitogen-activated protein kinase 14 (MAPK14)/p38a is molecular pattern (DAMP) molecule, contributes to chemo- involved in resistance of colon cancer cells to 5-FU and therapy resistance though the upregulation of autophagy in 51,52 irinotecan, which triggers survival-promoting autophagy to leukemia. Autophagy inhibitor HCQ is also shown to protect tumor cells against the cytotoxic effects of these decrease cell viability of B-chronic lymphocytic leukemia 39,40 53 drugs. Furthermore, autophagy inhibitor CQ significantly (B-CLL) in a dose- and time-dependent manner. The enhances the 5-FU-induced inhibition of tumor growth both resistance to Akt/mTOR inhibitors such as everolimus 41,42 in vitro and in vivo. In addition, the combination of (RAD001) is a significant clinical problem in relapsed mantle FOLFOX/bevacizumab with HCQ is currently being cell lymphoma (MCL) patients. Fortunately, pretreatment investigated. with HCQ can efficiently overcome this resistance, resulting in the activation of the mitochondrial apoptotic pathway. Esophageal cancer. The role of autophagy in response to These data illustrate a strategy of blocking activation of chemotherapy and radiotherapy has been investigated in adaptive autophagy pathway to improve treatment outcomes human esophageal squamous carcinoma cells. Autophagy in leukemia and MCL. might play a role as a self-protective mechanism in chemotherapeutic drug-treated esophageal cancer cells, Lung cancer. Epidermal growth factor receptor tyrosine and its inhibition has the potential to improve the efficacy of kinase inhibitors (EGFR-TKIs) have been widely used in 43–45 chemotherapeutic agents such as cisplatin and 5-FU. patients with non-small-cell lung cancer (NSCL). Unfortu- However, the effect of adding HCQ to conventional therapy nately, the efficacy of these drugs is limited because of for esophageal cancer patients remains unclear. natural or acquired resistance. We report that autophagy can be activated by gefitinib or erlotinib in lung cancer cells, Glioblastoma. Malignant cell clones resistant to chemo- which contributes to the acquired drug resistance of EGFR- therapy is a key reason for treatment failure in patients with TKIs. Furthermore, the antimalaria drug CQ has been (GBM). When treated with bevacizumab alone, human GBM shown to enhance chemotherapy and radiation sensitivity in xenografts show increased autophagic flux and hypoxia- several preclinical models. CQ can not only potentiate the associated growth, which indicates that hypoxia-mediated cytotoxicity of topotecan (TPT), but also substantially autophagy promotes tumor cell survival and resistance to increase the effects of PI3K/mTOR inhibitor NVP-BEZ235 antiangiogenic therapy. However, in treatment by combining on induction of apoptosis, inhibition of colony formation and 56,57 with the autophagy inhibitor CQ, tumor growth is disrupted, suppression of xenografts in nude mice. A phase I study which elucidates a novel mechanism of overcoming resis- in advanced NSCL patients with prior clinical benefit from tance to antiangiogenic therapy for GMB. A randomized, EGFR-TKIs suggests that HCQ with or without erlotinib is double-blind, placebo-controlled trial examines the effect of safe, and the recommended phase II dose for HCQ with adding CQ to conventional therapy for GBM. As a result, a erlotinib 150 mg is 1000 mg daily. Although no difference in median overall survival is 24 months for CQ-treated patients survival was elaborated, this study explored the safety of and 11 months for placebo-treated patients. Although it is adding HCQ to erlotinib. To assess the efficacy of the not statistically different because of the small sample size, combination of HCQ with conventional chemotherapeutics, the rate of death of patients receiving CQ is prominently several clinical trials have been launched. Cell Death and Disease Autophagy and chemotherapy resistance XSui et al Table 3 The strategies for autophagy inhibition Strategies Target The effect on autophagy Pharmacological approaches Chloroquine Lysosomal pH Inhibit autophagosome fusion with lysosomes and autophagosome degradation Hydroxychloroquine Lysosomal pH Inhibit autophagosome fusion with lysosomes and autophagosome degradation Monensin Change endocytic and lysosomal pH Inhibit the initiation/expansion stage of autophagy Bafilomycin A 1 Class III PI3K inhibitor Inhibit the initiation/expansion stage of autophagy 3-Methyladenine Class III PI3K inhibitor Inhibit the initiation/expansion stage of autophagy Wortmannin Class III PI3K inhibitor Inhibit the initiation/expansion stage of autophagy LY294002 Class III PI3K inhibitor Inhibit the initiation/expansion stage of autophagy Pyrvinium Class III PI3K inhibitor Inhibit the initiation/expansion stage of autophagy Genetic silencing of autophagy regulatory genes Inhibit the initiation/expansion stage of autophagy Pancreatic adenocarcinoma. The cytoprotective role of Other Compounds and Strategies autophagy in response to chemotherapy has been confirmed In addition to antimalarial drugs, inhibition of autophagy by in the treatment of pancreatic cancer cells. In agreement either pharmacological approaches or via genetic silencing of with this, Mirzoeva et al. showed that autophagy suppres- autophagy regulatory genes such as Beclin 1, ATG6, ATG5, sion with CQ promotes antitumor activity of PI3K/mTOR ATG7 or ATG12 (Table 3) also results in sensitization to a inhibitor for the treatment of pancreatic adenocarcinoma variety of therapeutic agents. Different autophagy inhibitors (PDAC) in vitro and in vivo. In addition to CQ, the efficacy block the autophagic process at different stages. For and side effects of adding HCQ to conventional therapy are example, antimalarial drugs or bafilomycin A1 can inhibit being investigated through several clinical trials. autophagosome fusion with lysosomes and autophagosome degradation in the final stage of autophagy. Class III PI3K Prostate cancer and renal cell carcinoma. Several recent inhibitors (3-methyladenine (3-MA), LY294002 and Wortmannin) studies have indicated that autophagy functions as a survival or knockdown of autophagy regulatory genes are involved mechanism to promote chemoresistance in prostate and 70–73 in the initiation/expansion stage of autophagy. So far, 61,62 renal cancer cells. Autophagy activation protects against different autophagy inhibitors or genetic knockout of ER stress-induced cell death, whereas inhibition of auto- autophagy regulatory genes have been developed and used phagy significantly suppresses PC-3 prostate tumor growth 74–78 in the study of autophagy in cancer chemotherapy. in vivo. Moreover, inhibition of autophagy by either HCQ or Beclin-1/Atg5 small interfering RNA enhances ABT-737 The Molecular Mechanisms of Protective cytotoxicity and ursolic acid-induced apoptosis in prostate Autophagy-Mediated Chemoresistance 64,65 cancer cells. Administration of high-dose interleukin-2 (HDIL-2) has durable complete and partial responses in Although many anticancer therapeutic strategies can induce patients with metastatic renal cell carcinoma. However, autophagic cell death, a majority of pertinent studies have HDIL-2 treatment is often limited by side effects, because of been conducted to indicate that autophagy is a protective a cytokine-induced systemic autophagic syndrome. Liang mechanism associated with increased resistance to chemo- et al. found that the combination of IL-2 with CQ increases therapy. Induction of autophagy has emerged as a drug antitumor effects and decreases toxicity when compared with resistance mechanism that promotes cancer cell survival. IL-2 treatment alone, which provide a novel clinical strategy to There are a number of different mechanisms through which enhance the efficacy of HDIL-2 immunotherapy for patients the autophagy-related functions of promoting the survival of with renal cell carcinoma. So far, two active trials (NCT tumor cells under the treatment of anticancer drugs (Figure 4). 01144169 and NCT 01550367) are investigating the efficacy of adding HCQ to IL-2. EGFR signaling. Epidermal growth factor is a key regula- tory factor for cell survival. Through its binding to cell surface Ovarian cancer. Ovarian cancer has poor prognosis and is receptors, EGF can induce the activation of three signaling frequently resistant to chemotherapy. In this issue, it has pathways which are important to the initiation and progres- been presented that autophagy may be a factor in drug sion of cancers, Ras/MAPK, PI3K/Akt and JAK/STATs. In resistance and poor survival in clear cell ovarian cancer the previous study, we confirmed biochemically and morpho- patients. Nucleus accumbens-1 (NAC1) can mediate resis- logically that autophagy can be activated by gefitinib or tance to cisplatin in ovarian cancer cell lines because of erlotinib, which was accompanied by the inhibition of the activation of autophagy. FTY720, a sphingosine analog, may PI3K/Akt/mTOR signaling pathway. Furthermore, blockage of enhance autophagic flux when treated as a new chemo- autophagy by the pharmacological inhibitors or gene silence therapeutic agent for ovarian cancer, and blockade of greatly enhanced cytotoxicity of gefitinib or erlotinib. autophagy aggravates necrotic ovarian cancer cell death in PD168393, an EGFR-TKI, may induce autophagy as a responsetoFTY720. Now, the effect of combining HCQ with cytostatic but not a cytotoxic response in malignant peripheral sorafenib is being assessed in FIGO stage III or stage IV nerve sheath tumor (MPNST) cells that was accompanied by ovarian cancer, or extraovarian peritoneal carcinoma, or suppression of Akt and mTOR activation; moreover, suppres- fallopian tube carcinoma failing or ineligible for first-line therapy. sion of autophagy by CQ increased caspase activation. Cell Death and Disease Autophagy and chemotherapy resistance X Sui et al Autophagy activation PI3K/ AMPK/ MAPK14/ AKT/ AKT/ EGFR p53 VEGF miRNA ERK K-Ras β-catenin p38α mTOR mTOR Chemotherapy resistance or insensitivity Cytotoxicity Figure 4 The molecular mechanisms of autophagy activation in response to chemotherapeutic agents. The activation of autophagy either leads to cancer cell chemoresistance via EGFR signaling, PI3K/AKT/ mTOR pathways, p53, VEGF, MAPK14/p38a signaling and microRNA or potentiates autophagic cell death through AMPK/ AKT1/mTOR axis, which depends on the tumor types and treatment characteristic These results indicate that EGFR-TKIs can induce autophagy was activated and triggered survival-promoting autophagy to promote tumor cell survival in response to targeted to protect tumor cells against the cytotoxic effects of chemotherapies, and suppression of autophagy can augment irinotecan. Furthermore, p38MAPK activation is considered the growth inhibitory effect of these drugs through inhibition of a key determinant in the cellular response to 5-FU by the PI3K/Akt/mTOR signaling pathway. controlling the balance between apoptosis and autophagy. PI3K/AKT/mTOR pathways. In addition to EGFR, the MicroRNAs. MicroRNAs (miRNAs) are a class of small, aberrant expression of PI3K/AKT/mTOR is also known to be noncoding, endogenously encoded, single-stranded RNAs a key regulator of authophagy. Genetic and pharmacologic that regulate gene expression at the post-transcriptional autophagy blockade via PI3K/mTOR inhibition may reverse level. Recently, a number of miRNAs have been reported to apoptotic resistance and result in significant cell apoptosis. be deeply involved in resistance or sensitization to chemo- NVP-BEZ235 (BEZ235) is a novel, orally bioavailable dual 86,87 therapy. miR-30a, a member of miR-30 family, is a PI3K/mTOR inhibitor that has exerted a positive effect on potent inhibitor of autophagy by selectively downregulating autophagy. A recent study suggests that NVP-BEZ235 could Beclin 1 and Atg5 expression. Targeting miR-30a promotes induce apoptosis and autophagy; moreover, the combination autophagy in response to imatinib treatment and enhances treatment of NVP with autophagy inhibitors lead to enhanced imatinib resistance against CML including primary stem and 62,82 RCC cell apoptosis. Benzyl isothiocyanate (BITC), a dietary 88,89 progenitor cells. Moreover, the blockade of autophagy by chemopreventive agent, is also found to induce protective miR-30a expression or 3-MA significantly increased cis- autophagy in human prostate cancer cells via inhibition of 90 DDP-induced apoptosis in cancer cells. Downregulation of mTOR signaling pathway, and inhibition of autophagy using miR-199a-5p is observed in most HCC tissues of patients. 3-MA increased BITC-induced apoptosis. Taken together, More importantly, downregulation of miR-199a-5p increases targeting PI3K/AKT/mTOR-autophagy pathways displays a cisplatin resistance by activating autophagy in HCC well-recognized contribution to overcome chemotherapy resis- 91 cells. Cisplatin-induced ATM-dependent phosphorylated tance and sensitize the tumor cells to anticancer therapy. (p)-DNp63a also plays an important role in chemoresistance. Further research shows that the p-DNp63a-induced miR-885- p53, VEGF and MAPK14/p38a signaling. As a well-known 3p might contribute to regulation of apoptosis and/or auto- tumor-suppressor gene, p53 is also involved in autophagic phagy in squamous cell carcinoma cells upon cisplatin regulation. In a mouse model of c-Myc-driven lymphoma, exposure. Although the relationship between miRNA, inhibition of autophagy with either CQ or ATG5 shRNA autophagy and anticancer therapy resistance is quite compli- promotes tumor cell death by p53 activation. Stanton cated, and has not been well elucidated, miRNA may underlie et al. show that the VEGF-C/NRP-2 axis is involved in the key aspects of chemotherapy resistance. activation of autophagy, and VEGF-C or NRP-2 depletion contributes to cytotoxic drug-mediated cell death. In addition, Chloroquine and Its Derivative: Just Act as Autophagy the recent studies have provided strong evidence that Inhibitors? the MAPK14/p38 signaling is involved in cancer cell resistance to chemotherapy treatment. Paillas et al. investi- CQ and its derivative are currently the only autophagy gated the relationship between MAPK14/p38, autophagy and inhibitors available for clinical treatment of patients. In resistance to irinotecan and found that MAPK14/p38 ongoing cancer treatment clinical trials, HCQ is often used in Cell Death and Disease Autophagy and chemotherapy resistance XSui et al combination with chemotherapeutic drugs, radiotherapy, maprotiline and fluoxetine induce autophagic cell death in drug- some targeted therapies and immunotherapy. The treatment resistant Burkitt’s lymphoma (BL), which supports a new of CQ or HCQ can inhibit autophagy-related survival function mechanistic role for maprotiline and fluoxetine as novel and exert their anticancer action. However, emerging data proautophagic agents in the treatment of resistant BL. These indicate that the ability of CQ and its derivative to inhibit the data indicate that autophagic cell death can be induced as an final degradative step of autophagy may not be the only alternative cell death mechanism when cells fail to undergo mechanism by which they exert anticancer action; CQ and apoptosis. HCQ may also affect other pathways such as lysosomal In addition, induction of autophagic cell death is also an membrane permeabilization. alternative approach to kill tumor cells without resistance to Recently, Maycotte et al. reported that CQ could sensitize anticancer drugs. Ursolic acid promotes cancer cell death by breast cancer cells to chemotherapy independent of autophagy inducing Atg5-dependent autophagy. FK-16, derived from inhibition, as sensitization was not mimicked by Atg12, Beclin 1 the anticancer peptide LL-37, induces caspase-independent knockdown or bafilomycin A1 treatment, and occurred even in apoptosis and autophagic cell death in colon cancer cells. the absence of Atg12. In further studies, CQ and HCQ are The mTOR inhibitor RAD001 potentiates autophagic cell shown to function as lysosomotropic agents to promote death induced by temozolomide in a GBM cell line. Novel lysosomal membrane permeabilization (LMP), resulting in signs monofunctional platinum (II) complex Mono-Pt induces of apoptosis. The research from Enzenmu¨ller et al. shows that apoptosis-independent autophagic cell death in human PI3K/mTOR inhibitor PI103 enhances the lysosomal compart- ovarian carcinoma cells, distinct from cisplatin. Sorafenib ment by increasing its volume and function, whereas CQ and SC-59, which is a novel sorafenib derivative, induce destabilizes lysosomal membranes. Together, CQ overcomes autophagic cell death in hepatocellular carcinoma cells resistance of lung carcinoma cells to PI103-induced apoptosis in a dose- and time-dependent manner. Recently, canna- by cooperating with PI103 to trigger lysosome-mediated binoids have been shown to exert their anticancer activity in apoptosis. An additional report suggests that induction of glioma, pancreatic cancer and hepatocellular carcinoma 105–108 lysosome-mediated apoptosis rather than inhibition of autophagy via stimulation of autophagy-mediated cell death. is critical for the CQ-mediated sensitization to BEZ235-induced Moreover, the combination of cannabinoids and TMZ strongly apoptosis, as lysosomal enzyme inhibitors significantly decrease activates autophagy-mediated cancer cell death, resulting BEZ235- and CQ-induced drop of mitochondrial membrane in a strong antitumoral action in both TMZ-sensitive and 94 109 potential (MMP) and caspase-dependent apoptosis. Similar TMZ-resistant tumors. These studies present new insights to the potential of CQ, HCQ can also induce LMP and Bax/ into our understanding of the relationship between autophagy Bak-dependent MMP to trigger caspase activation. and anticancer efficacy and provide a potential therapeutic Taken together, these data indicate that the success of clinical strategy for the management of some of these tumors. trials using CQ or HCQ combined with other anticancer agents Several genes and signal pathways contribute to autophagic might not be due to CQ or HCQ effects on autophagy induced by cell death in cancer cells (Figure 4). The AMPK/AKT1/mTOR chemotherapeutic drugs, as the effect may be mediated by axis is critical for regulation of autophagic cell death. mechanisms other than its inhibition of autophagy. Thus, a better Tanshinone IIA induces autophagic cell death via activation knowledge of the molecular mechanisms and cellular targets of of AMPK/ERK and inhibition of mTOR and p70 S6K in CQ or HCQ should be considered in the ongoing clinical trials KBM-5 leukemia cells. Cannabinoids can trigger autophagic where CQ or HCQ are used as autophagy inhibitors. cell death in an ER stress and Akt/mTORC1-dependent 105–108 manner. 4-Hydroxytamoxifen induces autophagic death through K-Ras degradation. Diarylquinoline compounds Autophagy-Mediated Cell Death Mechanism Contributes induce a autophagic cell death by inhibiting the Akt pathway to Efficacy of Anticancer Drugs and increasing reactive oxygen species in human nasophar- Despite its a clear prosurvival role, autophagy has also been yngeal carcinoma cells. b-Catenin is also involved in activation viewed as having a prodeath role under certain circumstances of autophagic cell death. These results further strengthen the and following treatment with a specific set of chemotherapeutic connection between autophagy and anticancer efficacy. agents, either by enhancing the induction of apoptosis or Recently, autophagy has been shown to precede apoptosis mediating ‘autophagic cell death’. or act in parallel with this cellular process in addition to being Increasing evidence supports that autophagy may mediate an alternative mechanism to cell death when apoptosis is inhibited. It has been acknowledged that autophagy precedes cell death in cancer cells which are apoptosis defective or hard 96 114,115 caspase-dependent apoptosis. Several studies demon- to induce. Xiong et al. found that autophagic cell death could strate that autophagy precedes apoptosis and acts as a be induced in PUMA- or Bax-deficient human colon cancer 116–118 cells after the treatment with 5-FU, consequently followed by protective mechanism in cancer cells. Therefore, the decreased cancer proliferation. Suberoylanilide hydroxamic autophagy induction may exert other possibilities, which acid (SAHA), a prototype of the newly developed HDAC should be considered in the design of new treatments for inhibitor, induces autophagic cell death in tamoxifen-resistant these malignancies. MCF-7 breast cancer cells and significantly reduces the tumor growth in vitro and in vivo. NVP-BEZ235 is demonstrated Conclusions and Perspectives to inhibit cisplatin-resistant urothelial cancer cell proliferation by activating autophagic flux and cell cycle arrest, but Autophagy is a lysosomal degradation process usually not inducing apoptotic cell death. The antidepressants activated in response to adverse microenvironmental stresses. Cell Death and Disease Autophagy and chemotherapy resistance X Sui et al Autophagy itself fulfils a dual role, having tumor-promoting and 1. Ringborg U, Platz A. Chemotherapy resistance mechanisms. 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Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment

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Life Sciences; Life Sciences, general; Biochemistry, general; Cell Biology; Immunology; Cell Culture; Antibodies
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Abstract

Citation: Cell Death and Disease (2013) 4, e838; doi:10.1038/cddis.2013.350 OPEN & 2013 Macmillan Publishers Limited All rights reserved 2041-4889/13 www.nature.com/cddis Review Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment 1,5 2,5 1,5 2 1 2 1 1 1 3 ,1,4 ,2,4 ,1,4 X Sui , R Chen , Z Wang , Z Huang , N Kong , M Zhang , W Han , F Lou , J Yang , Q Zhang , X Wang* , C He* and H Pan* Induction of cell death and inhibition of cell survival are the main principles of cancer therapy. Resistance to chemotherapeutic agents is a major problem in oncology, which limits the effectiveness of anticancer drugs. A variety of factors contribute to drug resistance, including host factors, specific genetic or epigenetic alterations in the cancer cells and so on. Although various mechanisms by which cancer cells become resistant to anticancer drugs in the microenvironment have been well elucidated, how to circumvent this resistance to improve anticancer efficacy remains to be defined. Autophagy, an important homeostatic cellular recycling mechanism, is now emerging as a crucial player in response to metabolic and therapeutic stresses, which attempts to maintain/restore metabolic homeostasis through the catabolic lysis of excessive or unnecessary proteins and injured or aged organelles. Recently, several studies have shown that autophagy constitutes a potential target for cancer therapy and the induction of autophagy in response to therapeutics can be viewed as having a prodeath or a prosurvival role, which contributes to the anticancer efficacy of these drugs as well as drug resistance. Thus, understanding the novel function of autophagy may allow us to develop a promising therapeutic strategy to enhance the effects of chemotherapy and improve clinical outcomes in the treatment of cancer patients. Cell Death and Disease (2013) 4, e838; doi:10.1038/cddis.2013.350; published online 10 October 2013 Subject Category: Cancer Facts Open Questions Whether we should try to enhance or inhibit autophagy in The induction of autophagy in response to metabolic and cancer treatment? therapeutic stresses can have a prodeath or a prosurvival Chloroquine and its derivative: just act as autophagy role, which contributes to the anticancer efficacy of these inhibitors? drugs as well as drug resistance. Autophagy is shown to precede apoptosis or act in parallel Anticancer drugs induce different effects of autophagy on with this cellular process in addition to be an alternative cell survival in different cancer types. mechanism to cell death when apoptosis is inhibited. Autophagy as a prosurvival and resistance mechanism Therefore, the autophagy induction may exert other against chemotherapy treatment. possibilities, which should be considered in the design of Autophagy-mediated cell death mechanism contributes to new treatments for the malignancies. efficacy of anticancer drugs. Targeting autophagy will hopefully provide a promising therapeutic strategy to circumvent resistance and enhance Resistance to anticancer drugs is a common clinical issue in the effects of anticancer therapies for cancer patients. the treatment of patients with cancer. Drug resistance, 1 2 Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China; Department of Colorectal Surgery, Sir Run Run Shaw Hospital, 3 4 Zhejiang University, Hangzhou, China; Department of Gastrointestinal Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, China and Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China *Corresponding authors: X Wang, Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang 310016, China. Tel: +86 571 8600 6926; Fax: +86 571 8600 6926; E-mail: wangxzju@163.com or C He, Department of Colorectal Surgery, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang 310016, China. Tel: +86 571 8600 6929; Fax: +86 571 8600 6929; E-mail: drhechao@yahoo.com.cn or H Pan, Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang 310016, China. Tel: +86 0571 8600 6926; Fax: +86 0571 8600 6926; E-mail: drpanhm@aliyun.com These authors contributed equally to this work. Keywords: autophagy; chemotherapy resistance; cancer; therapy Abbreviations: PI3K, phosphatidylinositol 3-kinase; mTOR, mammalian target of rapamycin; AMPK, AMP-activated protein kinase; ER, endoplasmic reticulum; eIF2a, eukaryotic initiation factor 2a; HDAC, histone deacetylase; DDR, DNA damage response; CQ, chloroquine; HCQ, hydroxychloroquine; EPI, epirubicin; 5-FU, 5-fluorouracil; MAPK, mitogen-activated protein kinase; GBM, glioblastoma; TMZ, temozolomide; MTD, maximum tolerated dose; HCC, hepatocellular carcinoma; MCL, mantle cell lymphoma; DAMP, damage-associated molecular pattern; B-CLL, B-chronic lymphocytic leukemia; EGF, epidermal growth factor; EGFR-TKI, epidermal growth factor receptor tyrosine kinase inhibitor; TPT, topotecan; PDAC, pancreatic adenocarcinoma; HDIL-2, high-dose interleukin-2; NAC1, nucleus accumbens-1; 3-MA, 3-methyladenine; MPNST, malignant peripheral nerve sheath tumor; BITC, benzyl isothiocyanate; LMP, lysosomal membrane permeabilization; MMP, mitochondrial membrane potential; SAHA, suberoylanilide hydroxamic acid; BL, Burkitt’s lymphoma Received 08.5.13; revised 25.8.13; accepted 27.8.13; Edited by GM Fimia Autophagy and chemotherapy resistance X Sui et al Drug efflux and metabolism Angiogenesis Mutation or loss Tumor of molecular heterogeneity targets Induction of Inactivation autophagy of apoptosis Increased repair of Compartmentalization damage Figure 1 A summary of the approaches by which cancer cells become resistant to chemotherapy and various kinds of genotoxic or metabolic stresses intrinsic or acquired, can be attributed to a wide variety of autophagy is also shown to promote cell death following mechanisms including tumor cell heterogeneity, drug efflux treatment with specific chemotherapeutic agents, either by and metabolism and tumor microenvironment stress-induced enhancing the induction of apoptosis or mediating ‘autophagic genetic or epigenetic alterations as a cellular response to cell death’. 1,2 drug exposure (Figure 1). Among these mechanisms, the Although the molecular mechanisms whereby autophagy response or adaptation of cancer cell itself to anticancer mediates its effects on both normal and cancer cells are far drug-induced tumor microenvironment stresses is a vital from complete, various signaling pathways have been cause for chemotherapy resistance. implicated in the upregulation or downregulation of auto- 10,11 Autophagy is an evolutionarily conserved catabolic process phagy. The phosphatidylinositol 3-kinase/mammalian in which portions of cytosol and organelles are sequestered target of rapamycin (PI3K/mTOR) and AMP-activated protein into a double-membrane vesicle and delivered to the kinase (AMPK) signaling pathways have emerged as the 3–6 lysosome for bulk degradation. In this review, the term central conduit in the regulation of autophagy (Figure 2). ‘autophagy’ refers to macroautophagy. The role of autophagy mTOR can be activated by growth factors signal through the in regulating cancer cell death or survival remains controversial. class I PI3K/Akt pathway, and inhibited by AMPK and 12,13 Current evidence supports the idea that constitutive p53. Once activated, mTOR exerts a negative effect on autophagy can act as a cellular housekeeper to eliminate autophagy by phosphorylating a complex of autophagy damaged organelles and recycle macromolecules, thus proteins (ULK1/2), which inhibits the downstream autophagy 14,15 protecting against cancer, particularly during malignant cascade. In contrast, AMPK can suppress mTORC1 transformation and carcinogenesis. In established tumors, signaling to stimulate autophagy through TSC1/2 phosphor- 16,17 autophagy can function as a prosurvival pathway in response ylation. Several of the known tumor-suppressor genes to metabolic stresses such as nutrient deprivation, hypoxia, (p53, PTEN, TSC1/TSC2) and tumor-associated genes 10,15 absence of growth factors and the presence of chemotherapy (p21, AKT) also respectively stimulate or inhibit autophagy. or some targeted therapies that might mediate resistance to Autophagy is also induced by a variety of metabolic 7–9 anticancer therapies. In this review we will summarize the stresses such as endoplasmic reticulum (ER) stress, hypoxia, possible role of autophagy as a novel target for anticancer oxidative stress, expression of aggregate-prone proteins, therapies and discuss the attractive prospect of manipulating glucose deprivation and so on. ER stress stimulates this control as a revolutionary strategy for cancer therapy. autophagy through the PERK/eukaryotic initiation factor 2a (eIF2a) and IRE1/JNK1 pathways. PERK/eIF2a phosphoryla- tion has been shown to be essential for the transcription of key The Regulation of Autophagy in Cancer During autophagy-associated genes during ER stress and may Response to Multiple Stresses mediate the polyglutamine-induced LC3 conversion. The Autophagy is essential for not only cell survival but also activation of IRE1/JNK promotes phosphorylation of Bcl-2 and organism survival in response to microenvironmental stresses. p53, resulting in interfering with Bcl-2 binding to Beclin 1 and When cancer cells are subjected to stressful conditions, autophagic cell death in cancer cells. Depletion of nutrients autophagy is rapidly upregulated to maintain metabolic or energy induces autophagy by activating the AMPK homeostasis and ensure that cell growth is appropriate to its pathway or promoting upregulate transcription of certain 16,17 changing environmental conditions through reduced growth autophagy genes. The MEK/ERK signaling activation and increased catabolic lysis of excessive or unnecessary and Rag inactivation contribute to amino acid depletion- 7,21 proteins and organelles. However, persistent or excessive induced autophagy. Many anticancer drugs including Cell Death and Disease Autophagy and chemotherapy resistance XSui et al Activation arrow Growth factors Anticancer drugs depletion Inhibition arrow Essential amino IRS1 PI3K PTEN acid depletion RAS Epigenetic alterations PDK1 PKB/AKT ER stress Rag Raf Glucose/Energy depletion TSC1/TSC2 MEK PERK IRE LKB1 ERK JNK Rheb eIF2a Raptor p53 AMPK ATF4 mTOR p21 Beclin 1 autophagy Hypoxia stress HIF BNIP3 Beclin 1 Cell survival or death Figure 2 Interrelations between autophagy-related signaling and cell growth control in response to stress. Autophagy can be activated in response to multiple stresses during cancer progression, including nutrient deprivation, endoplasmic reticulum stress, hypoxia, glucose/energy depletion, chemotherapy and other diverse stresses. The AMPK/mTOR pathway functions as a central conduit for autophagic signaling pathways to promote cell survival or death Cancer cells novel targeted therapies stimulate autophagy by inhibiting the Cancer cells PI3K/Akt/mTOR axis or altering genetic/epigenetic phenotype of cancer cells, which provides a survival advantage for 22–24 struggling tumor cells. The histone deacetylase (HDAC) inhibitors are recently involved in the control of DNA damage Chemotherapeutic agents response (DDR) and autophagy. SD118-xanthocillin X (1), a novel marine agent extracted from Penicillium commune, induces autophagy through the inhibition of the MEK/ERK pathway. Overall, autophagy is a cell biological process that Autophagic Autophagic flux involves diverse signals that have overlapping functions in flux autophagy and the control of other cellular stress responses. Stress Cytotoxicity restoration Autophagy in Response to Chemotherapy Similar to its potential to either induce cell death or promote cell survival, a growing body of evidence implicates a paradoxical role of autophagy following anticancer A major protective mechanism: Autophagic the acquired resistance phenotype treatments, with response increasing or diminishing their cell death anticancer activity. On the one hand, autophagy is activated Figure 3 Dual role of autophagy for therapeutic purposes in cancer. On one as a protective mechanism to mediate the acquired resistance hand, autophagy is activated as a protective mechanism to mediate the acquired phenotype of some cancer cells during chemotherapy. resistance phenotype of some cancer cells during chemotherapy. On the other Thus, the inhibition of autophagy can re-sensitize previously hand, autophagy may also function as a death executioner to induce autophagic cell resistant cancer cells and augment cytotoxicity of chemo- death, a form of physiological cell death that is contradictory to apoptosis therapeutic agents. On the other hand, autophagy may also play as a death executioner to induce autophagic cell death, a Autophagy as a Prosurvival and Resistance Mechanism form of physiological cell death which is contradictory to type Against Chemotherapy Treatment I programmed cell death (apoptosis) (Figure 3). Based on current genetic and pharmacological studies, it appears that Recent studies have demonstrated that tumor resistance to anticancer drugs induce different effects of autophagy on cell anticancer therapies including radiation therapy, chemotherapy survival in different cancer types (Table 1). Here we delineate and targeted therapies can be enhanced through upregulation 26,27 the possible role of autophagy as a novel target for anticancer of autophagy in different tumor cell lines. Moreover, therapy. increasing evidence suggests that autophagy inhibition Cell Death and Disease Autophagy and chemotherapy resistance X Sui et al Table 1 Autophagy in response to chemotherapy in different types of cancers Class Target Type of cancer Autophagy Method used to evaluate References role autophagy Autophagy inducers Aurora kinase A mTOR Breast Prosurvival siRNA (LC3, Atg5) CQ Bafilomycin A Suberoylanilide HDAC inhibitor CML Prosurvival 3-MA hydroxamic acid Bafilomycin A (SAHA) Breast Prodeath 3-MA Epirubicin (EPI) Anthracyclines Breast Prosurvival siRNA (Beclin 1, Atg7) Bafilomycin A 37,40–42 5-Fluorouracil Thymidylate synthase Colorectal Prosurvival siRNA (Atg7) 3-MA inhibitor Prodeath 3-MA Atorvastatin AMPK Digestive Prosurvival siRNA (Atg5) malignancies Bafilomycin A Irinotecan MAPK14/p38a Colorectal Prosurvival siRNA (Atg5, Atg7) Bafilomycin A 3-MA Cisplatin Genotoxic stress Esophageal Prosurvival 3-MA Oxaliplatin Genotoxic stress Hepatocellular Prosurvival siRNA (Atg5) carcinoma CQ 3-MA Bevacizumab Angiogenesis inhibitor Hepatocellular Prosurvival CQ 3-MA carcinoma Sorafenib ER stress Hepatocellular Prosurvival CQ carcinoma Genotoxic stress Prodeath siRNA (Beclin 1) High-mobility group DAMP molecule CML Prosurvival box 1 protein (HMGB1) 55,58 Gefitinib or Erlotinib EGFR tyrosine kinase Lung Prosurvival siRNA (Atg5, Atg7) inhibitor CQ 3-MA Topotecan Genotoxic stress Lung Prosurvival CQ RAGE Genotoxic or metabolic Pancreatic Prosurvival stress NVP-BEZ235 PI3K/AKT/mTOR inhibitor Renal Prosurvival Urothelial Prodeath CQ Ursolic acid Genotoxic stress Prostate Prosurvival siRNA (Atg5, Beclin 1) 3-MA Cervical Prodeath siRNA (Atg5) Wortmannin Imatinib Tyrosine kinase inhibitor Glioma Prosurvival Bafilomycin A RTA 203 Prodeath siRNA (Atg5, Beclin 1) 3-MA FK-16 Fragment of LL-37 Colon Prodeath siRNA (Bax, Bcl-2) Temozolomide Genotoxic stress Glioblastoma Prodeath mTOR inhibitor RAD001 Mono-Pt Genotoxic stress Ovarian Prodeath siRNA (Atg7, Beclin 1) 3-MA CQ Bafilomycin A Cannabinoids ER stress Glioma Prodeath siRNA (Atg1) AMPK Pancreatic Prodeath 3-MA CQ Hepatocellular Prodeath siRNA (Atg5) 3-MA carcinoma Autophagy inhibitors CQ Lysosomotropic agent Breast Prosurvival 43–45 HCQ Esophageal Prosurvival Hepatocellular Prosurvival carcinoma 56,57 Lung Prosurvival Pancreatic Prosurvival augments cytotoxicity in combination with several anticancer chloroquine (CQ) and its derivative hydroxychloroquine 28–30 drugs in preclinical models. Several pharmacological (HCQ) that suppress autophagy by blocking autophagosome 31,32 compounds and strategies have been reported to inhibit fusion and degradation. Both CQ and HCQ have been autophagy in vitro and in vivo. investigated in preclinical studies or clinical trials. In comparison with CQ, HCQ can be safely dose escalated in cancer patients. Currently, more than 30 phase I/II cancer clinical Antimalarial Drugs trials (http://clinicaltrials.gov/) involving CQ or HCQ are open The only autophagy inhibitors whose effectiveness in vivo and around the world and many of them have evidence of safety in clinical trials have been approved by the FDA are preliminary antitumor activity (Table 2). Cell Death and Disease Autophagy and chemotherapy resistance XSui et al Table 2 Active clinical trials combining the autophagy inhibitor HCQ with anticancer therapies Identifier Cancer type Drugs Phase Title NCT00969306 NSCLC CQ þ cisplatin Etoposide I/II Cisplatin, etoposide and escalating CQ in extensive disease SCLC NCT00809237 NSCLC HCQ þ gefitinib I/II Hydroxychloroquine and gefitinib to treat lung cancer NCT01649947 NSCLC HCQ þ paclitaxel and II Modulation of autophagy in patients with advanced/recurrent carboplatin non-small-cell lung cancer – phase II NCT00977470 Advanced NSCLC and HCQ þ erlotinib II Erlotinib with or without hydroxychloroquine in chemonaive (EGFR) mutations advanced NSCLC and (EGFR) mutations NCT00933803 Advanced or recurrent HCQ þ carboplatin, paclitaxel, Carboplatin, paclitaxel, bevacizumab and HCQ in advanced NSCLC bevacizuma or recurrent NSCLC NCT01292408 Breast cancer HCQ II Autophagy inhibition using hydroxychloroquine in breast cancer patients NCT00765765 Breast cancer HCQ þ ixabepilone I/II Ixabepilone and HCQ in metastatic breast cancer NCT01023477 DCIS CQ þ tamoxifen I/II Neoadjuvant tamoxifen, tamoxifen þ CQ, or CQ in DCIS NCT01510119 Renal cell carcinoma HCQ and RAD001(p.o. 10 mg/ I/II Autophagy inhibition to augment mTOR inhibition: a phase I/ day) II trial of RAD001 and hydroxychloroquine in patients with previously treated renal cell carcinoma NCT01144169 Renal cell carcinoma HCQ þ high dose interleukin-2 I Study of hydroxychloroquine before surgery in patients with and other systemic therapies primary renal cell carcinoma NCT01550367 Renal cell carcinoma HCQ þ IL-2 I/II Study of hydroxychloroquine and aldesleukin in renal cell carcinoma patients (RCC) NCT00726596 Prostate cancer HCQ II Hydroxychloroquine in treating patients with rising PSA levels after local therapy for prostate cancer NCT01128296 Pancreatic cancer HCQ þ gemcitabine I/II Study of presurgery gemcitabine þ hydroxychloroquine (GcHc) in stage IIb or III adenocarcinoma of the pancreas NCT01273805 Pancreatic cancer HCQ II Hydroxychloroquine in previously treated patients with metastatic pancreatic cancer NCT01506973 Pancreatic cancer HCQ þ gemcitabine/abraxane I/II A phase I/II/pharmacodynamic study of hydroxychloroquine in combination with gemcitabine/abraxane to inhibit autop- hagy in pancreatic cancer NCT01128296 Pancreatic cancer HCQ þ gemcitabine I/II Study of Pre-surgery Gemcitabine þ hydroxychloroquine (GcHc) in stage IIb or III adenocarcinoma of the pancreas NCT01494155 Pancreatic cancer HCQ þ capecitabine þ photon II Short-course radiation therapy with proton beam capecita- radiation bine and hydroxychloroquine for resectable pancreatic cancer NCT01206530 Colorectal cancer HCQ þ FOLFOX/ I/II FOLFOX/Bevacizumab/Hydroxychloroquine (HCQ) in col- bevacizumab orectal cancer NCT01006369 Metastatic colorectal HCQ þ capecitabine, oxalipla- II Hydroxychloroquine, capecitabine, oxaliplatin, and bevaci- cancer tin, and bevacizumab zumab in treating patients with metastatic colorectal cancer NCT00224978 Glioblastoma CQ III Adjuvant CQ versus placebo in glioblastoma NCT00486603 Glioblastoma HCQ þ temozolomide I/II Adjuvant radiation, temozolomide and HCQ in newly resected GBM NCT00962845 Melanoma HCQ No Hydroxychloroquine in patients with stage III or Stage IV phase melanoma that can be removed by surgery specified NCT00568880 Multiple myeloma HCQ þ bortezomib I/II Hydroxychloroquine and bortezomib in treating patients with relapsed or refractory multiple myeloma NCT01480154 Advanced solid tumors or HCQ þ MTD of Akt inhibitor I Phase I study of Akt inhibitor MK2206 and hydroxychlor- prostate or renal cancer MK2206 (MK-2206) oquine in patients with advanced solid tumors or prostate or renal cancer NCT00909831 Metastatic solid tumors HCQ þ temsirolimus I Hydroxychloroquine and temsirolimus in treating patients with metastatic solid tumors that have not responded to treatment NCT00813423 Advanced solid tumors HCQ þ sunitinib I Sunitinib and Hydroxychloroquine in treating patients with advanced solid tumors that have not responded to chemotherapy NCT01023737 Advanced solid tumors HCQ þ vorinostat I Vorinostat and HCQ in advanced solid tumors NCT01417403 Solid tumors undergoing HCQ I Hydroxychloroquine in treating patients with solid tumors radiation therapy for bone undergoing radiation therapy for bone metastases metastases NCT01266057 Advanced cancer HCQ þ the highest tolerable I Sirolimus or vorinostat and hydroxychloroquine in advanced dose of sirolimus or vorinostat cancer NCT00714181 Metastatic or unresect- HCQ þ temozolomide I Hydroxychloroquine and temozolomide in treating patients able solid tumors with metastatic or unresectable solid tumors NCT01227135 CML HCQ þ imatinib II Imatinib mesylate with or without hydroxychloroquine in treating patients with chronic myeloid leukemia NCT01634893 Ovarian cancer HCQ þ sorafenib I Oral hydroxychloroquine plus oral sorafenib to treat epithelial ovarian cancer FIGO stage III or stage IV, or extraovarian peritoneal carcinoma, or fallopian tube carcinoma failing or ineligible for first-line therapy NSCLC, non-small-cell lung cancer; CML, chronic myeloid leukemia; EGFR, epidermal growth factor receptor; MTD, maximum tolerated dose; HCQ, hydroxychloroquine Cell Death and Disease Autophagy and chemotherapy resistance X Sui et al Breast cancer. The role of autophagy in breast cancer is an lower than controls. Another phase I/II trial concerning area of active investigation. There is evidence to suggest that dose-limiting toxicities of HCQ with temozolomide (TMZ) epirubicin (EPI) may induce autophagy in human breast cancer and radiation for GBM patients was conducted. The MCF-7 cells, resulting in protecting MCF-7 cells from EPI- information about the antitumor activity of this combination induced apoptosis. Autophagy is also regarded as a key is underway. mechanism of antiestrogen resistance, and blocking autophago- some can significantly reduce the emergence of antiestrogen- Hepatocellular carcinoma. The combination of autophagy resistant breast cancer cells. A phase II clinical trial inhibitor and chemotherapy or molecular-targeted therapies (NCT01292408) is investigating the effects of autophagy has been regarded as a promising therapeutic strategy in the inhibition via HCQ on breast cancer patients. The current treatment of hepatocellular carcinoma (HCC). Autophagy is reports indicate that CQ or HCQ is often used in combination functionally activated in HCC cell lines after oxaliplatin with chemotherapeutic drugs to enhance the efficacy of treatment, and suppression of autophagy enhances oxali- tumor cell killing; however, its sensitizing effects can also platin-induced cell death. Autophagy also contributes to occur independently of autophagy inhibition, which should HCC cell survival, and the combined treatment of an be considered in the ongoing clinical trials where CQ or HCQ autophagy inhibitor and bevacizumab markedly inhibits the 36 49 are used in the treatment of breast cancer. growth of HCC. Moreover, the combination of sorafenib with CQ can generate more ER stress-induced cell death in Colorectal cancer. So far, 5-fluorouracil (5-FU), together HCC both in vivo and in vitro. Therefore, autophagy with other drugs such as oxaliplatin, remains a widely used inhibition may be a promising therapeutic strategy to chemotherapeutic drug in the treatment of a variety of enhance the effects of chemotherapy and improve clinical colorectal carcinomas. Previous researches have demon- outcomes in the treatment of HCC. strated that inhibition of autophagy augments anticancer effects of chemotherapy or some targeted therapies in Leukemia and MCL. Recently, it is reported that high- 37,38 colorectal cancer. Recently, it has been shown that mobility group box 1 (HMGB1), a damage-associated mitogen-activated protein kinase 14 (MAPK14)/p38a is molecular pattern (DAMP) molecule, contributes to chemo- involved in resistance of colon cancer cells to 5-FU and therapy resistance though the upregulation of autophagy in 51,52 irinotecan, which triggers survival-promoting autophagy to leukemia. Autophagy inhibitor HCQ is also shown to protect tumor cells against the cytotoxic effects of these decrease cell viability of B-chronic lymphocytic leukemia 39,40 53 drugs. Furthermore, autophagy inhibitor CQ significantly (B-CLL) in a dose- and time-dependent manner. The enhances the 5-FU-induced inhibition of tumor growth both resistance to Akt/mTOR inhibitors such as everolimus 41,42 in vitro and in vivo. In addition, the combination of (RAD001) is a significant clinical problem in relapsed mantle FOLFOX/bevacizumab with HCQ is currently being cell lymphoma (MCL) patients. Fortunately, pretreatment investigated. with HCQ can efficiently overcome this resistance, resulting in the activation of the mitochondrial apoptotic pathway. Esophageal cancer. The role of autophagy in response to These data illustrate a strategy of blocking activation of chemotherapy and radiotherapy has been investigated in adaptive autophagy pathway to improve treatment outcomes human esophageal squamous carcinoma cells. Autophagy in leukemia and MCL. might play a role as a self-protective mechanism in chemotherapeutic drug-treated esophageal cancer cells, Lung cancer. Epidermal growth factor receptor tyrosine and its inhibition has the potential to improve the efficacy of kinase inhibitors (EGFR-TKIs) have been widely used in 43–45 chemotherapeutic agents such as cisplatin and 5-FU. patients with non-small-cell lung cancer (NSCL). Unfortu- However, the effect of adding HCQ to conventional therapy nately, the efficacy of these drugs is limited because of for esophageal cancer patients remains unclear. natural or acquired resistance. We report that autophagy can be activated by gefitinib or erlotinib in lung cancer cells, Glioblastoma. Malignant cell clones resistant to chemo- which contributes to the acquired drug resistance of EGFR- therapy is a key reason for treatment failure in patients with TKIs. Furthermore, the antimalaria drug CQ has been (GBM). When treated with bevacizumab alone, human GBM shown to enhance chemotherapy and radiation sensitivity in xenografts show increased autophagic flux and hypoxia- several preclinical models. CQ can not only potentiate the associated growth, which indicates that hypoxia-mediated cytotoxicity of topotecan (TPT), but also substantially autophagy promotes tumor cell survival and resistance to increase the effects of PI3K/mTOR inhibitor NVP-BEZ235 antiangiogenic therapy. However, in treatment by combining on induction of apoptosis, inhibition of colony formation and 56,57 with the autophagy inhibitor CQ, tumor growth is disrupted, suppression of xenografts in nude mice. A phase I study which elucidates a novel mechanism of overcoming resis- in advanced NSCL patients with prior clinical benefit from tance to antiangiogenic therapy for GMB. A randomized, EGFR-TKIs suggests that HCQ with or without erlotinib is double-blind, placebo-controlled trial examines the effect of safe, and the recommended phase II dose for HCQ with adding CQ to conventional therapy for GBM. As a result, a erlotinib 150 mg is 1000 mg daily. Although no difference in median overall survival is 24 months for CQ-treated patients survival was elaborated, this study explored the safety of and 11 months for placebo-treated patients. Although it is adding HCQ to erlotinib. To assess the efficacy of the not statistically different because of the small sample size, combination of HCQ with conventional chemotherapeutics, the rate of death of patients receiving CQ is prominently several clinical trials have been launched. Cell Death and Disease Autophagy and chemotherapy resistance XSui et al Table 3 The strategies for autophagy inhibition Strategies Target The effect on autophagy Pharmacological approaches Chloroquine Lysosomal pH Inhibit autophagosome fusion with lysosomes and autophagosome degradation Hydroxychloroquine Lysosomal pH Inhibit autophagosome fusion with lysosomes and autophagosome degradation Monensin Change endocytic and lysosomal pH Inhibit the initiation/expansion stage of autophagy Bafilomycin A 1 Class III PI3K inhibitor Inhibit the initiation/expansion stage of autophagy 3-Methyladenine Class III PI3K inhibitor Inhibit the initiation/expansion stage of autophagy Wortmannin Class III PI3K inhibitor Inhibit the initiation/expansion stage of autophagy LY294002 Class III PI3K inhibitor Inhibit the initiation/expansion stage of autophagy Pyrvinium Class III PI3K inhibitor Inhibit the initiation/expansion stage of autophagy Genetic silencing of autophagy regulatory genes Inhibit the initiation/expansion stage of autophagy Pancreatic adenocarcinoma. The cytoprotective role of Other Compounds and Strategies autophagy in response to chemotherapy has been confirmed In addition to antimalarial drugs, inhibition of autophagy by in the treatment of pancreatic cancer cells. In agreement either pharmacological approaches or via genetic silencing of with this, Mirzoeva et al. showed that autophagy suppres- autophagy regulatory genes such as Beclin 1, ATG6, ATG5, sion with CQ promotes antitumor activity of PI3K/mTOR ATG7 or ATG12 (Table 3) also results in sensitization to a inhibitor for the treatment of pancreatic adenocarcinoma variety of therapeutic agents. Different autophagy inhibitors (PDAC) in vitro and in vivo. In addition to CQ, the efficacy block the autophagic process at different stages. For and side effects of adding HCQ to conventional therapy are example, antimalarial drugs or bafilomycin A1 can inhibit being investigated through several clinical trials. autophagosome fusion with lysosomes and autophagosome degradation in the final stage of autophagy. Class III PI3K Prostate cancer and renal cell carcinoma. Several recent inhibitors (3-methyladenine (3-MA), LY294002 and Wortmannin) studies have indicated that autophagy functions as a survival or knockdown of autophagy regulatory genes are involved mechanism to promote chemoresistance in prostate and 70–73 in the initiation/expansion stage of autophagy. So far, 61,62 renal cancer cells. Autophagy activation protects against different autophagy inhibitors or genetic knockout of ER stress-induced cell death, whereas inhibition of auto- autophagy regulatory genes have been developed and used phagy significantly suppresses PC-3 prostate tumor growth 74–78 in the study of autophagy in cancer chemotherapy. in vivo. Moreover, inhibition of autophagy by either HCQ or Beclin-1/Atg5 small interfering RNA enhances ABT-737 The Molecular Mechanisms of Protective cytotoxicity and ursolic acid-induced apoptosis in prostate Autophagy-Mediated Chemoresistance 64,65 cancer cells. Administration of high-dose interleukin-2 (HDIL-2) has durable complete and partial responses in Although many anticancer therapeutic strategies can induce patients with metastatic renal cell carcinoma. However, autophagic cell death, a majority of pertinent studies have HDIL-2 treatment is often limited by side effects, because of been conducted to indicate that autophagy is a protective a cytokine-induced systemic autophagic syndrome. Liang mechanism associated with increased resistance to chemo- et al. found that the combination of IL-2 with CQ increases therapy. Induction of autophagy has emerged as a drug antitumor effects and decreases toxicity when compared with resistance mechanism that promotes cancer cell survival. IL-2 treatment alone, which provide a novel clinical strategy to There are a number of different mechanisms through which enhance the efficacy of HDIL-2 immunotherapy for patients the autophagy-related functions of promoting the survival of with renal cell carcinoma. So far, two active trials (NCT tumor cells under the treatment of anticancer drugs (Figure 4). 01144169 and NCT 01550367) are investigating the efficacy of adding HCQ to IL-2. EGFR signaling. Epidermal growth factor is a key regula- tory factor for cell survival. Through its binding to cell surface Ovarian cancer. Ovarian cancer has poor prognosis and is receptors, EGF can induce the activation of three signaling frequently resistant to chemotherapy. In this issue, it has pathways which are important to the initiation and progres- been presented that autophagy may be a factor in drug sion of cancers, Ras/MAPK, PI3K/Akt and JAK/STATs. In resistance and poor survival in clear cell ovarian cancer the previous study, we confirmed biochemically and morpho- patients. Nucleus accumbens-1 (NAC1) can mediate resis- logically that autophagy can be activated by gefitinib or tance to cisplatin in ovarian cancer cell lines because of erlotinib, which was accompanied by the inhibition of the activation of autophagy. FTY720, a sphingosine analog, may PI3K/Akt/mTOR signaling pathway. Furthermore, blockage of enhance autophagic flux when treated as a new chemo- autophagy by the pharmacological inhibitors or gene silence therapeutic agent for ovarian cancer, and blockade of greatly enhanced cytotoxicity of gefitinib or erlotinib. autophagy aggravates necrotic ovarian cancer cell death in PD168393, an EGFR-TKI, may induce autophagy as a responsetoFTY720. Now, the effect of combining HCQ with cytostatic but not a cytotoxic response in malignant peripheral sorafenib is being assessed in FIGO stage III or stage IV nerve sheath tumor (MPNST) cells that was accompanied by ovarian cancer, or extraovarian peritoneal carcinoma, or suppression of Akt and mTOR activation; moreover, suppres- fallopian tube carcinoma failing or ineligible for first-line therapy. sion of autophagy by CQ increased caspase activation. Cell Death and Disease Autophagy and chemotherapy resistance X Sui et al Autophagy activation PI3K/ AMPK/ MAPK14/ AKT/ AKT/ EGFR p53 VEGF miRNA ERK K-Ras β-catenin p38α mTOR mTOR Chemotherapy resistance or insensitivity Cytotoxicity Figure 4 The molecular mechanisms of autophagy activation in response to chemotherapeutic agents. The activation of autophagy either leads to cancer cell chemoresistance via EGFR signaling, PI3K/AKT/ mTOR pathways, p53, VEGF, MAPK14/p38a signaling and microRNA or potentiates autophagic cell death through AMPK/ AKT1/mTOR axis, which depends on the tumor types and treatment characteristic These results indicate that EGFR-TKIs can induce autophagy was activated and triggered survival-promoting autophagy to promote tumor cell survival in response to targeted to protect tumor cells against the cytotoxic effects of chemotherapies, and suppression of autophagy can augment irinotecan. Furthermore, p38MAPK activation is considered the growth inhibitory effect of these drugs through inhibition of a key determinant in the cellular response to 5-FU by the PI3K/Akt/mTOR signaling pathway. controlling the balance between apoptosis and autophagy. PI3K/AKT/mTOR pathways. In addition to EGFR, the MicroRNAs. MicroRNAs (miRNAs) are a class of small, aberrant expression of PI3K/AKT/mTOR is also known to be noncoding, endogenously encoded, single-stranded RNAs a key regulator of authophagy. Genetic and pharmacologic that regulate gene expression at the post-transcriptional autophagy blockade via PI3K/mTOR inhibition may reverse level. Recently, a number of miRNAs have been reported to apoptotic resistance and result in significant cell apoptosis. be deeply involved in resistance or sensitization to chemo- NVP-BEZ235 (BEZ235) is a novel, orally bioavailable dual 86,87 therapy. miR-30a, a member of miR-30 family, is a PI3K/mTOR inhibitor that has exerted a positive effect on potent inhibitor of autophagy by selectively downregulating autophagy. A recent study suggests that NVP-BEZ235 could Beclin 1 and Atg5 expression. Targeting miR-30a promotes induce apoptosis and autophagy; moreover, the combination autophagy in response to imatinib treatment and enhances treatment of NVP with autophagy inhibitors lead to enhanced imatinib resistance against CML including primary stem and 62,82 RCC cell apoptosis. Benzyl isothiocyanate (BITC), a dietary 88,89 progenitor cells. Moreover, the blockade of autophagy by chemopreventive agent, is also found to induce protective miR-30a expression or 3-MA significantly increased cis- autophagy in human prostate cancer cells via inhibition of 90 DDP-induced apoptosis in cancer cells. Downregulation of mTOR signaling pathway, and inhibition of autophagy using miR-199a-5p is observed in most HCC tissues of patients. 3-MA increased BITC-induced apoptosis. Taken together, More importantly, downregulation of miR-199a-5p increases targeting PI3K/AKT/mTOR-autophagy pathways displays a cisplatin resistance by activating autophagy in HCC well-recognized contribution to overcome chemotherapy resis- 91 cells. Cisplatin-induced ATM-dependent phosphorylated tance and sensitize the tumor cells to anticancer therapy. (p)-DNp63a also plays an important role in chemoresistance. Further research shows that the p-DNp63a-induced miR-885- p53, VEGF and MAPK14/p38a signaling. As a well-known 3p might contribute to regulation of apoptosis and/or auto- tumor-suppressor gene, p53 is also involved in autophagic phagy in squamous cell carcinoma cells upon cisplatin regulation. In a mouse model of c-Myc-driven lymphoma, exposure. Although the relationship between miRNA, inhibition of autophagy with either CQ or ATG5 shRNA autophagy and anticancer therapy resistance is quite compli- promotes tumor cell death by p53 activation. Stanton cated, and has not been well elucidated, miRNA may underlie et al. show that the VEGF-C/NRP-2 axis is involved in the key aspects of chemotherapy resistance. activation of autophagy, and VEGF-C or NRP-2 depletion contributes to cytotoxic drug-mediated cell death. In addition, Chloroquine and Its Derivative: Just Act as Autophagy the recent studies have provided strong evidence that Inhibitors? the MAPK14/p38 signaling is involved in cancer cell resistance to chemotherapy treatment. Paillas et al. investi- CQ and its derivative are currently the only autophagy gated the relationship between MAPK14/p38, autophagy and inhibitors available for clinical treatment of patients. In resistance to irinotecan and found that MAPK14/p38 ongoing cancer treatment clinical trials, HCQ is often used in Cell Death and Disease Autophagy and chemotherapy resistance XSui et al combination with chemotherapeutic drugs, radiotherapy, maprotiline and fluoxetine induce autophagic cell death in drug- some targeted therapies and immunotherapy. The treatment resistant Burkitt’s lymphoma (BL), which supports a new of CQ or HCQ can inhibit autophagy-related survival function mechanistic role for maprotiline and fluoxetine as novel and exert their anticancer action. However, emerging data proautophagic agents in the treatment of resistant BL. These indicate that the ability of CQ and its derivative to inhibit the data indicate that autophagic cell death can be induced as an final degradative step of autophagy may not be the only alternative cell death mechanism when cells fail to undergo mechanism by which they exert anticancer action; CQ and apoptosis. HCQ may also affect other pathways such as lysosomal In addition, induction of autophagic cell death is also an membrane permeabilization. alternative approach to kill tumor cells without resistance to Recently, Maycotte et al. reported that CQ could sensitize anticancer drugs. Ursolic acid promotes cancer cell death by breast cancer cells to chemotherapy independent of autophagy inducing Atg5-dependent autophagy. FK-16, derived from inhibition, as sensitization was not mimicked by Atg12, Beclin 1 the anticancer peptide LL-37, induces caspase-independent knockdown or bafilomycin A1 treatment, and occurred even in apoptosis and autophagic cell death in colon cancer cells. the absence of Atg12. In further studies, CQ and HCQ are The mTOR inhibitor RAD001 potentiates autophagic cell shown to function as lysosomotropic agents to promote death induced by temozolomide in a GBM cell line. Novel lysosomal membrane permeabilization (LMP), resulting in signs monofunctional platinum (II) complex Mono-Pt induces of apoptosis. The research from Enzenmu¨ller et al. shows that apoptosis-independent autophagic cell death in human PI3K/mTOR inhibitor PI103 enhances the lysosomal compart- ovarian carcinoma cells, distinct from cisplatin. Sorafenib ment by increasing its volume and function, whereas CQ and SC-59, which is a novel sorafenib derivative, induce destabilizes lysosomal membranes. Together, CQ overcomes autophagic cell death in hepatocellular carcinoma cells resistance of lung carcinoma cells to PI103-induced apoptosis in a dose- and time-dependent manner. Recently, canna- by cooperating with PI103 to trigger lysosome-mediated binoids have been shown to exert their anticancer activity in apoptosis. An additional report suggests that induction of glioma, pancreatic cancer and hepatocellular carcinoma 105–108 lysosome-mediated apoptosis rather than inhibition of autophagy via stimulation of autophagy-mediated cell death. is critical for the CQ-mediated sensitization to BEZ235-induced Moreover, the combination of cannabinoids and TMZ strongly apoptosis, as lysosomal enzyme inhibitors significantly decrease activates autophagy-mediated cancer cell death, resulting BEZ235- and CQ-induced drop of mitochondrial membrane in a strong antitumoral action in both TMZ-sensitive and 94 109 potential (MMP) and caspase-dependent apoptosis. Similar TMZ-resistant tumors. These studies present new insights to the potential of CQ, HCQ can also induce LMP and Bax/ into our understanding of the relationship between autophagy Bak-dependent MMP to trigger caspase activation. and anticancer efficacy and provide a potential therapeutic Taken together, these data indicate that the success of clinical strategy for the management of some of these tumors. trials using CQ or HCQ combined with other anticancer agents Several genes and signal pathways contribute to autophagic might not be due to CQ or HCQ effects on autophagy induced by cell death in cancer cells (Figure 4). The AMPK/AKT1/mTOR chemotherapeutic drugs, as the effect may be mediated by axis is critical for regulation of autophagic cell death. mechanisms other than its inhibition of autophagy. Thus, a better Tanshinone IIA induces autophagic cell death via activation knowledge of the molecular mechanisms and cellular targets of of AMPK/ERK and inhibition of mTOR and p70 S6K in CQ or HCQ should be considered in the ongoing clinical trials KBM-5 leukemia cells. Cannabinoids can trigger autophagic where CQ or HCQ are used as autophagy inhibitors. cell death in an ER stress and Akt/mTORC1-dependent 105–108 manner. 4-Hydroxytamoxifen induces autophagic death through K-Ras degradation. Diarylquinoline compounds Autophagy-Mediated Cell Death Mechanism Contributes induce a autophagic cell death by inhibiting the Akt pathway to Efficacy of Anticancer Drugs and increasing reactive oxygen species in human nasophar- Despite its a clear prosurvival role, autophagy has also been yngeal carcinoma cells. b-Catenin is also involved in activation viewed as having a prodeath role under certain circumstances of autophagic cell death. These results further strengthen the and following treatment with a specific set of chemotherapeutic connection between autophagy and anticancer efficacy. agents, either by enhancing the induction of apoptosis or Recently, autophagy has been shown to precede apoptosis mediating ‘autophagic cell death’. or act in parallel with this cellular process in addition to being Increasing evidence supports that autophagy may mediate an alternative mechanism to cell death when apoptosis is inhibited. It has been acknowledged that autophagy precedes cell death in cancer cells which are apoptosis defective or hard 96 114,115 caspase-dependent apoptosis. Several studies demon- to induce. Xiong et al. found that autophagic cell death could strate that autophagy precedes apoptosis and acts as a be induced in PUMA- or Bax-deficient human colon cancer 116–118 cells after the treatment with 5-FU, consequently followed by protective mechanism in cancer cells. 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