Delineating the Switch between Senescence and Apoptosis in Cervical Cancer Cells under Ciclopirox Treatment

SIMPLE SUMMARY: Novel treatment options for cervical cancer are urgently required. Ciclopirox (CPX), an iron chelator, has shown promising anti-tumorigenic potential in several preclinical tumor models, including cervical cancer cells. In these cells, CPX can induce apoptosis, a form of cell death, or senescence, an irreversible cellular growth arrest. These different phenotypic outcomes may influence therapy response. Here, we show that the decision of cervical cancer cells to induce apoptosis or senescence is strongly dependent on glucose availability: CPX induces apoptosis under limited glucose availability, whereas under increased glucose supply, CPX treatment results in senescence. Further, we link the pro-apoptotic and pro-senescent activities of CPX to its capacity to block oxidative phosphorylation and to chelate iron, respectively. In addition, we show that the combined treatment of CPX and glycolysis inhibitors blocks the proliferation of cervical cancer cells in a synergistic manner. Collectively, we provide novel insights into the anti-proliferative activities of CPX in cervical cancer cells, elucidate the cellular decision between apoptosis or senescence induction, and provide a rationale to combine CPX with glycolysis inhibitors. ABSTRACT: The iron-chelating drug ciclopirox (CPX) may possess therapeutic potential for cancer treatment, including cervical cancer. As is observed for other chemotherapeutic drugs, CPX can induce senescence or apoptosis in cervical cancer cells which could differently affect their therapy response. The present study aims to gain insights into the determinants which govern the switch between senescence and apoptosis in cervical cancer cells. We performed proteome analyses, proliferation studies by live-cell imaging and colony formation assays, senescence and apoptosis assays, and combination treatments of CPX with inhibitors of oxidative phosphorylation (OXPHOS) or glycolysis. We found that CPX downregulates OXPHOS factors and facilitates the induction of apoptosis under limited glucose availability, an effect which is shared by classical OXPHOS inhibitors. Under increased glucose availability, however, CPX-induced apoptosis is prevented and senescence is induced, an activity which is not exerted by classical OXPHOS inhibitors, but by other iron chelators. Moreover, we show that the combination of CPX with glycolysis inhibitors blocks cervical cancer proliferation in a synergistic manner. Collectively, our results reveal that the phenotypic response of cervical cancer cells towards CPX is strongly dependent on glucose availability, link the pro-apoptotic and pro-senescent activities of CPX to its bifunctionality as an OXPHOS inhibitor and iron chelator, respectively, and provide a rationale for combining CPX with glycolysis inhibitors.