The combination of nelfinavir and cisplatin drives lytic cell death through a caspase-8/caspase-3/GSDME axis in platinum-resistant ovarian cancer cells

NFV synergized with CDDP to reduce the viability of platinum-resistant ovarian cancer cells and promoted a regulated lytic cell death phenotype involving apoptotic and pyroptotic features. Combination treatment induced caspase-8 and caspase-3 activation, with downstream gasdermin E (GSDME) processing. Inhibition of caspase-3 significantly attenuated cell death, while caspase-8 inhibition rescued viability and prevented Bid cleavage, caspase-3 activation, and GSDME cleavage.

These effects occurred in the context of enhanced endoplasmic reticulum stress, increased DNA damage with reduced DNA repair, and impaired Akt-driven survival signaling. Together, these findings establish that NFV synergizes with CDDP in platinum-resistant ovarian cancer cells by promoting a caspase-8-dependent apoptotic-to-secondary pyroptotic response, supporting further investigation of NFV as a candidate drug for repurposing to enhance platinum-based therapy.