Background: Multidrug resistance (MDR) is a major obstacle in cancer therapy, largely driven by efflux transporters such as P-glycoprotein (P-gp). Current strategies remain limited, highlighting the need for novel agents. Natural chalcones are promising modulators, and 2',6'-dihydroxy-4'-methoxydihydrochalcone (DHMC), isolated from Fissistigma cupreonitens, represents a unique candidate with dual, dose-dependent effects.
Purpose: To define the biphasic actions of DHMC in MDR cancer and elucidate the molecular mechanisms underlying its pro-apoptotic and chemosensitizing activities.
Methods: Drug-sensitive (HeLa S3, KB, MDA-MB-231) and resistant (KB/VIN, MDA-MB-231/DOC) cell lines were tested. Assays included cytotoxicity, apoptosis, cell cycle, ROS, mitochondrial potential, and transporter efflux. Mechanistic studies involved STAT3 phosphorylation, Western blotting, docking, ATPase activity, and efflux kinetics. Apoptosis antibody arrays with GO/KEGG analyses identified signaling pathways. Zebrafish xenografts assessed in vivo efficacy.
Results: DHMC displayed concentration-dependent dual actions. High doses promoted apoptosis and cell cycle arrest, with bioinformatics implicating CD40LG, TNF, and MAPK pathways in immune-related apoptosis. Low doses enhanced chemosensitivity by inhibiting P-gp, MRP1, and BCRP, increasing intracellular drug accumulation. Mechanistically, DHMC suppressed P-gp expression and non-competitively blocked efflux, leading to >130-fold reversal of paclitaxel resistance in KB/VIN cells. Zebrafish models confirmed tumor suppression and synergy with paclitaxel without toxicity.
Conclusion: DHMC acts as a novel natural chalcone that overcomes MDR via dual mechanisms, apoptosis induction and transporter inhibition, underscoring its importance as a potential adjuvant in cancer therapy.
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