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

// Ashwani Khurana 1, * , Debarshi Roy 1, * , Eleftheria Kalogera 2, * , Susmita Mondal 1 , Xuyang Wen 1 , Xiaoping He 1 , Sean Dowdy 2 , Viji Shridhar 1 1 Department of Experimental Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA 2 Department of Obstetrics and Gynecology, Mayo Clinic College of Medicine, Rochester, MN, USA * These authors have contributed equally to this work Correspondence to: Viji Shridhar, e-mail: shridhar.vijayalakshmi@mayo.edu Keywords: quinacrine, ovarian cancer, autophagy, apoptosis and tumorigenesis Received: August 25, 2015      Accepted: October 05, 2015      Published: October 16, 2015 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.