BACKGROUND:Multidrug resistance (MDR) remains a significant challenge in cancer chemotherapy, with no FDA-approved drugs currently available for its treatment. Natural chalcones, known for their diverse bioactivities, have emerged as potential therapeutic candidates.
PURPOSE:This study aimed to investigate the potential of 4,6-dimethoxy-2,5-quinodihydrochalcone (DODHC), a compound derived from Fissistigma latifolium, in overcoming MDR in cancer and to elucidate its underlying molecular mechanisms.
METHODS:The reversal effects of DODHC on MDR were evaluated using cytotoxicity assays. The molecular mechanisms were explored through apoptosis- and cell cycle-related assays, STAT3 ELISA, western blotting, docking simulations, and a zebrafish model. The impact of DODHC on P-glycoprotein (P-gp) activity was assessed using the Calcein-AM uptake assay.
RESULTS:DODHC promoted apoptosis in MDR cancer cells by suppressing survivin expression and activating the extrinsic apoptotic pathway. It also induced G2/M phase cell cycle arrest by downregulating cell division control protein 2 (CDC2) and cyclin B1 (CCNB1), thereby inhibiting cell proliferation. Additionally, DODHC reduced both total and phosphorylated STAT3 levels in MDR cancer cells without affecting P-gp activity. In vivo, DODHC significantly inhibited tumor growth in MDR cancer models, both as a monotherapy and in combination with paclitaxel.
CONCLUSION:This study highlights DODHC as a dual inhibitor of STAT3 and survivin, demonstrating its potential as a promising candidate for the treatment of MDR cancers.
