Synergistic effects of the curcumin analog HO-3867 and olaparib in transforming fallopian tube epithelial cells.

Abstract

Ovarian cancer remains one of the most lethal gynecologic malignancies, largely due to high recurrence rates and treatment-related toxicities. Although PARP inhibitors like Olaparib have shown efficacy in BRCA-mutated cancers, their benefit is limited in broader patient populations. TP53 mutations, highly prevalent in ovarian cancer, promote tumor progression and resistance, making p53 a key therapeutic target. This study evaluated the anticancer potential of HO-3867, a curcumin analog known to restore mutant p53 function, alone and in combination with Olaparib. We used fallopian tube-derived ovarian cancer models harboring mutant or null TP53 and analyzed TP53 expression and mutation profiles using TCGA datasets. Molecular docking simulations and cellular thermal shift assays (CETSA) confirmed HO-3867 binding to the p53^Y220C mutant core domain. Cytotoxicity was assessed via SRB assays; flow cytometry and Western blotting were used to examine cell cycle progression, apoptosis, and DNA damage. HO-3867 treatment increased phospho-p53 (Ser15) and p21 expression, induced G1 phase arrest, and suppressed cell viability. Notably, co-treatment with Olaparib synergistically enhanced apoptosis, as indicated by increased caspase-3 and PARP1 cleavage and elevated γH2AX levels. These findings suggest that HO-3867 reactivates mutant p53 and potentiates Olaparib efficacy by promoting apoptosis and amplifying DNA damage, offering a promising therapeutic strategy for TP53-mutant ovarian cancer.