Glycogen phosphorylase inhibition alongside taxol chemotherapy synergistically elicits ferroptotic cell death in clear cell ovarian and kidney cancers

Abstract

ABSTRACTBackgroundClear cell carcinomas (CCCs) are a distinct histopathological subtype defined by a clear cytoplasm comprised of glycogen and lipids and characterised by poor prognosis and widespread chemoresistance. In the present work we investigate glycogen metabolism as a targetable modality for these cancers.Methods and ResultsAdopting the indole carboxamide site pan-glycogen phosphorylase inhibitor CP91149 against clear cell ovarian and renal cancer cell line models, we note antiproliferative and antimigratory effects, as well as energetic stress reflected by reduced ATP pools and increased superoxide-derived reactive oxygen species. Following this, using the agent alongside standard of care chemotherapies for clear cell ovarian (ccOC) and renal cell carcinoma (ccRCC), we note specific synergy with microtubule disrupting chemotherapy paclitaxel, a phenomenon retained in ccOC lines made stably resistant to paclitaxel. Rescue experiments, as well as phenotypic assays suggest that combination-treated cells undergo ferroptotic cell death. We postulate this synergistic efficacy to arise from subjecting the already hypersensitive clear cell cancers to the mitochondrial stress elicited by taxol chemotherapy alongside the oxidative stress augured by glycogen phosphorylase inhibition.ConclusionsGiven that CCCs are widely chemoresistant, the present work potentially presents a novel therapeutic avenue for this shared histotype.