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

Ashwani Khurana,Xuyang Wen,Susmita Mondal,Debarshi Roy,Viji Shridhar,Sean Dowdy,Xiaoping He,Eleftheria Kalogera

doi:10.18632/oncotarget.5632

Abstract

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.

Highlights

Ovarian cancer remains a leading cause of death among women with gynecological cancers despite significant advances in the systemic as well as surgical cancer treatment modalities [1]
Quinacrine inhibits cell growth and induces cell death in ovarian cancer cells Isogenic pairs of OvCA cell lines [OV2008 and C13 cells derived from OV2008 [37]; HEYA8 and HEYA8MDR [38, 39] cells] were evaluated for the effect of QC on cell growth by colony formation and MTT assays
Our findings suggest that QCmediated induction of autophagy preceded the induction of apoptosis as the effects on the autophagic proteins LC3B and p62 were observed at earlier time points

Summary

Introduction

Ovarian cancer remains a leading cause of death among women with gynecological cancers despite significant advances in the systemic as well as surgical cancer treatment modalities [1]. The majority of these therapeutic compounds induce apoptosis through type I programmed cell death (PCD), compounds inducing type II PCD have been shown to be effective as anti-cancer agents [3]. Extensive autophagic activity leads eventually to cell death which, differs from the homeostatic autophagy associated with normal cellular organelle turnover [4]. Various strategies have been investigated to explore the potential of autophagy as a putative anticancer modality including development of www.impactjournals.com/oncotarget chemical inhibitors of autophagy as well as genetic silencing of key autophagy proteins [7]. Several studies have shown that inhibiting autophagy using anti-malarial compounds such as chloroquine (CQ) and hydroxychloroquine while combining these compounds with frontline therapeutic agents such as cisplatin and taxol results in significant inhibition of tumor growth [8, 9]. High beclin 1 and LC3 levels in ovarian tumors have been associated with improved overall survival [15, 16]

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