Combined disulfiram and MK-8776 treatment reveals cell line–dependent antitumor activity in different 3D ovarian cancer subtypes

Vollständiger Abstract

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Abstract Disulfiram (DSF) is an FDA-approved drug with pleiotropic anticancer activity, including induction of cellular stress and effects on stemness-associated phenotypes in ovarian cancer. Here, we investigated whether DSF enhances the antitumor efficacy of the CHK1 inhibitor MK-8776 in ovarian cancer models, with emphasis on 3D spheroids that better reflect tumor architecture than conventional monolayer culture. Initial 2D screening confirmed cytotoxic activity of both agents, whereas the models used for subsequent 3D analyses were selected according to their capacity to form stable spheroids. In spheroids, DSF/MK-8776 reduced viability more effectively than monotherapy and showed limited toxicity in peripheral blood mononuclear cells. The response was strongly cell line–dependent. In TOV-21G, the combination was associated with reinforced late apoptotic execution together with increased pCHK1 and γH2AX and reduced RAD51. OVCAR-8 displayed a time-dependent increase in cell death, consistent with progression from an early ROS (reactive oxygen species)-associated state to loss of membrane integrity. ALDH-related stem-like responses were also divergent, with ALDH enrichment in TOV-21G but depletion of the ALDH positive compartment in OVCAR-8. Together, these data identify DSF/CHK1 inhibition as a promising but highly context-dependent strategy in ovarian cancer.