Quinacrine promotes autophagic cell death and chemosensitivity in ovarian cancer and attenuates tumor growth

A promising new strategy for cancer therapy is to target the autophagic pathway. In the current study, we demonstrate that the antimalarial drug Quinacrine (QC) reduces cell viability and promotes chemotherapy-induced cell death in an autophagy-dependent manner more extensively in chemoresistant cel...

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Autores principales: Khurana, Ashwani, Roy, Debarshi, Kalogera, Eleftheria, Mondal, Susmita, Wen, Xuyang, He, Xiaoping, Dowdy, Sean, Shridhar, Viji
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742182/
https://www.ncbi.nlm.nih.gov/pubmed/26497553
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author Khurana, Ashwani
Roy, Debarshi
Kalogera, Eleftheria
Mondal, Susmita
Wen, Xuyang
He, Xiaoping
Dowdy, Sean
Shridhar, Viji
author_facet Khurana, Ashwani
Roy, Debarshi
Kalogera, Eleftheria
Mondal, Susmita
Wen, Xuyang
He, Xiaoping
Dowdy, Sean
Shridhar, Viji
author_sort Khurana, Ashwani
collection PubMed
description A promising new strategy for cancer therapy is to target the autophagic pathway. In the current study, we demonstrate that the antimalarial drug Quinacrine (QC) reduces cell viability and promotes chemotherapy-induced cell death in an autophagy-dependent manner more extensively in chemoresistant cells compared to their isogenic chemosensitive control cells as quantified by the Chou-Talalay methodology. Our preliminary data, in vitro and in vivo, indicate that QC induces autophagy by downregulating p62/SQSTM1 to sensitize chemoresistant cells to autophagic- and caspase-mediated cell death in a p53-independent manner. QC promotes autophagosome accumulation and enhances autophagic flux by clearance of p62 in chemoresistant ovarain cancer (OvCa) cell lines to a greater extent compared to their chemosensitive controls. Notably, p62 levels were elevated in chemoresistant OvCa cell lines and knockdown of p62 in these cells resulted in a greater response to QC treatment. Bafilomycin A, an autophagy inhibitor, restored p62 levels and reversed QC-mediated cell death and thus chemosensitization. Importantly, our in vivo data shows that QC alone and in combination with carboplatin suppresses tumor growth and ascites in the highly chemoresistant HeyA8MDR OvCa model compared to carboplatin treatment alone. Collectively, our preclinical data suggest that QC in combination with carboplatin can be an effective treatment for patients with chemoresistant OvCa.
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spelling pubmed-47421822016-04-04 Quinacrine promotes autophagic cell death and chemosensitivity in ovarian cancer and attenuates tumor growth Khurana, Ashwani Roy, Debarshi Kalogera, Eleftheria Mondal, Susmita Wen, Xuyang He, Xiaoping Dowdy, Sean Shridhar, Viji Oncotarget Research Paper A promising new strategy for cancer therapy is to target the autophagic pathway. In the current study, we demonstrate that the antimalarial drug Quinacrine (QC) reduces cell viability and promotes chemotherapy-induced cell death in an autophagy-dependent manner more extensively in chemoresistant cells compared to their isogenic chemosensitive control cells as quantified by the Chou-Talalay methodology. Our preliminary data, in vitro and in vivo, indicate that QC induces autophagy by downregulating p62/SQSTM1 to sensitize chemoresistant cells to autophagic- and caspase-mediated cell death in a p53-independent manner. QC promotes autophagosome accumulation and enhances autophagic flux by clearance of p62 in chemoresistant ovarain cancer (OvCa) cell lines to a greater extent compared to their chemosensitive controls. Notably, p62 levels were elevated in chemoresistant OvCa cell lines and knockdown of p62 in these cells resulted in a greater response to QC treatment. Bafilomycin A, an autophagy inhibitor, restored p62 levels and reversed QC-mediated cell death and thus chemosensitization. Importantly, our in vivo data shows that QC alone and in combination with carboplatin suppresses tumor growth and ascites in the highly chemoresistant HeyA8MDR OvCa model compared to carboplatin treatment alone. Collectively, our preclinical data suggest that QC in combination with carboplatin can be an effective treatment for patients with chemoresistant OvCa. Impact Journals LLC 2015-10-16 /pmc/articles/PMC4742182/ /pubmed/26497553 Text en Copyright: © 2015 Khurana et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Khurana, Ashwani
Roy, Debarshi
Kalogera, Eleftheria
Mondal, Susmita
Wen, Xuyang
He, Xiaoping
Dowdy, Sean
Shridhar, Viji
Quinacrine promotes autophagic cell death and chemosensitivity in ovarian cancer and attenuates tumor growth
title Quinacrine promotes autophagic cell death and chemosensitivity in ovarian cancer and attenuates tumor growth
title_full Quinacrine promotes autophagic cell death and chemosensitivity in ovarian cancer and attenuates tumor growth
title_fullStr Quinacrine promotes autophagic cell death and chemosensitivity in ovarian cancer and attenuates tumor growth
title_full_unstemmed Quinacrine promotes autophagic cell death and chemosensitivity in ovarian cancer and attenuates tumor growth
title_short Quinacrine promotes autophagic cell death and chemosensitivity in ovarian cancer and attenuates tumor growth
title_sort quinacrine promotes autophagic cell death and chemosensitivity in ovarian cancer and attenuates tumor growth
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742182/
https://www.ncbi.nlm.nih.gov/pubmed/26497553
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