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Inhibition of Aurora A Kinase in Combination with Chemotherapy Induces Synthetic Lethality and Overcomes Chemoresistance in Myc-Overexpressing Lymphoma

Inhibition of Aurora A Kinase in Combination with Chemotherapy Induces Synthetic Lethality and... Background Aberrant Myc expression plays a critical role in various tumors, including non-Hodgkin lymphoma (NHL). Myc-positive lymphoma is clinically aggressive, more resistant to chemotherapy, and associated with high mortality. Objective The current study aimed to show inhibition of aurora A kinase (AURKA) may overcome resistance to chemo- therapy and improve outcomes in Myc-overexpressing lymphoma. Methods Myc-overexpressing lymphoma cell lines were evaluated by trypan blue, annexin V/propidium iodide staining, and western blotting for cytotoxicity, cell cycle, apoptosis, and Myc-associated protein expression, respectively, in the presence of cyclophosphamide with or without MLN8237, an AURKA inhibitor. Immunofluorescence for apoptosis-inducing factor (AIF) and acridine orange staining were used to analyze levels of autophagy. EµMyc genetically modified mouse model and xenograft models bearing Myc-overexpressing lymphoma cells were used to determine the efficacy of cyclophosphamide, MLN8237, or the combination in chemosensitive and chemoresistant tumors. Results In our in vitro experiments using chemoresistant lymphoma cells, MLN8237 and cyclophosphamide showed syn- ergistic effects. Mice bearing lymphoma xenograft had rapid disease progression with median survival of ~ 35 days when treated with cyclophosphamide alone. In contrast, the combination of cyclophosphamide and MLN8237 induced complete tumor regression in all mice, which led to improvement in survival compared with the single agent http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Targeted Oncology Springer Journals

Inhibition of Aurora A Kinase in Combination with Chemotherapy Induces Synthetic Lethality and Overcomes Chemoresistance in Myc-Overexpressing Lymphoma

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References (53)

Publisher
Springer Journals
Copyright
Copyright © 2019 by Springer Nature Switzerland AG
Subject
Medicine & Public Health; Oncology; Biomedicine, general
ISSN
1776-2596
eISSN
1776-260X
DOI
10.1007/s11523-019-00662-4
Publisher site
See Article on Publisher Site

Abstract

Background Aberrant Myc expression plays a critical role in various tumors, including non-Hodgkin lymphoma (NHL). Myc-positive lymphoma is clinically aggressive, more resistant to chemotherapy, and associated with high mortality. Objective The current study aimed to show inhibition of aurora A kinase (AURKA) may overcome resistance to chemo- therapy and improve outcomes in Myc-overexpressing lymphoma. Methods Myc-overexpressing lymphoma cell lines were evaluated by trypan blue, annexin V/propidium iodide staining, and western blotting for cytotoxicity, cell cycle, apoptosis, and Myc-associated protein expression, respectively, in the presence of cyclophosphamide with or without MLN8237, an AURKA inhibitor. Immunofluorescence for apoptosis-inducing factor (AIF) and acridine orange staining were used to analyze levels of autophagy. EµMyc genetically modified mouse model and xenograft models bearing Myc-overexpressing lymphoma cells were used to determine the efficacy of cyclophosphamide, MLN8237, or the combination in chemosensitive and chemoresistant tumors. Results In our in vitro experiments using chemoresistant lymphoma cells, MLN8237 and cyclophosphamide showed syn- ergistic effects. Mice bearing lymphoma xenograft had rapid disease progression with median survival of ~ 35 days when treated with cyclophosphamide alone. In contrast, the combination of cyclophosphamide and MLN8237 induced complete tumor regression in all mice, which led to improvement in survival compared with the single agent

Journal

Targeted Oncology – Springer Journals

Published: Aug 19, 2019

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