Citations

Metabolic alterations are increasingly recognized as important novel anti‐cancer targets. Among several regulators of metabolic alterations, fructose 2,6 bisphosphate (F2,6BP) is a critical glycolytic regulator. Inhibition of the active form of PFKFB3ser461 using a novel inhibitor, PFK158 resulted in reduced glucose uptake, ATP production, lactate release as well as induction of apoptosis in gynecologic cancer cells. Moreover, we found that PFK158 synergizes with carboplatin (CBPt) and paclitaxel (PTX) in the chemoresistant cell lines, C13 and HeyA8MDR but not in their chemosensitive counterparts, OV2008 and HeyA8, respectively. We determined that PFK158‐induced autophagic flux leads to lipophagy resulting in the downregulation of cPLA2, a lipid droplet (LD) associated protein. Immunofluorescence and co‐immunoprecipitation revealed colocalization of p62/SQSTM1 with cPLA2 in HeyA8MDR cells uncovering a novel pathway for the breakdown of LDs promoted by PFK158. Interestingly, treating the cells with the autophagic inhibitor bafilomycin A reversed the PFK158‐mediated synergy and lipophagy in chemoresistant cells. Finally, in a highly metastatic PTX‐resistant in vivo ovarian mouse model, a combination of PFK158 with CBPt significantly reduced tumor weight and ascites and reduced LDs in tumor tissue as seen by immunofluorescence and transmission electron microscopy compared to untreated mice. Since the majority of cancer patients will eventually recur and develop chemoresistance, our results suggest that PFK158 in combination with standard chemotherapy may have a direct clinical role in the treatment of recurrent cancer.

Abstract Resistance to chemotherapy is a major hurdle that results in the increased mortality associated with ovarian cancer (OvCa). New therapeutics that synergize with cis-carboplatin/paclitaxel in recurrent tumors will have an enormous impact in prolonging the survival of OvCa patients. Due to the enormous cost of designing and testing new drugs, we have adopted the drug repurposing approach and tested the effect of the antimalarial drug quinacrine (QC) in sensitizing drug resistant OvCa cells to carboplatin induced cytotoxicity and determined that it is autophagy dependent. We have discovered that QC, an autophagy modulator exhibited distinct anti-cancer properties in OvCa cell lines in contrast to other anti-malarial/autophagy inhibitor drugs such as hydroxyquinacrine, bafilomycin A and 3-MA. It is well established that autophagy can be a survival mechanism under stress in cancer or a death promoting phenomenon that is cell type and contextual dependent. Here we demonstrate that QC acts to promote chemotherapy induced cell death specifically more in resistant cells in an autophagy dependent manner. Our preliminary data both in vitro and in vivo indicate that QC induced autophagy downregulates p62 and upregulates cathepsin L levels to sensitize the chemoresistant cells to autophagic and caspase mediated cell death in a p53 independent manner. These unexpected findings led us to explore the mechanistic basis of QC-induced upregulation of the cell cycle inhibitor p21 in cells bearing mutant p53. We uncovered that irrespective of p53 status, QC induces p21 expression in an autophagy-dependent p62-Skp2 mediated ubiquitin pathway resulting in cell cycle arrest and cell death. Since QC is already in PhaseI Clinical trial, these studies may spur new treatment strategies to improve OvCa patient outcome and patient care. Citation Format: Debarshi Roy, Ashwani Khurana, Eleftheria Kalogera, Xuyang Wen, Susmita Mondal, Viji Shridhar. Can we repurpose anti-malarial drug quinacrine to treat ovarian cancer? [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B74.