Chemosensitizing potential of andrographolide in P-glycoprotein overexpressing multidrug-resistant cancer cell lines.

The P-glycoprotein (P-gp) plays a major role in the efflux of chemotherapeutic drugs and significantly limits chemotherapy efficacy. Chemosensitizers augment the therapeutic effects of anticancer agents by overcoming drug resistance mechanisms. In this study, the chemosensitizing property of andrographolide (Andro) in P-gp overexpressing multidrug-resistant (MDR) colchicine-selected KBChR 8-5 cells was evaluated. Molecular docking studies showed Andro exhibits higher binding interaction with P-gp than the other two ABC-transporters studied. Further, it inhibits P-gp transport function in a concentration dependant manner in the colchicine-selected KBChR 8-5 cells. Moreover, Andro downregulates P-gp overexpression via NF-κB signaling in these MDR cell lines. MTT-based cell-based assay illustrates that Andro treatment augments the PTX effect in the KBChR 8-5 cells. Further, the Andro plus PTX combination showed enhanced apoptotic cell death in KBChR 8-5 cells compared with PTX alone treatment. Therefore, the results showed that Andro enhances PTX therapeutic effect in the drug-resistant KBChR 8-5 cells.

Auranofin sensitizes breast cancer cells to paclitaxel chemotherapy by disturbing the cellular redox system.

The intrinsic redox status of cancer cells limits the efficacy of chemotherapeutic drugs. Auranofin, a Food and Drug Administration-approved gold-containing compound, documented with effective pharmacokinetics and safety profiles in humans, has recently been repurposed for anticancer activity. This study examined the paclitaxel-sensitizing effect of auranofin by targeting redox balance in the MDA-MB-231 and MCF-7 breast cancer cell lines. Auranofin treatment depletes the activities of superoxide dismutase, catalase, and glutathione peroxidase and alters the redox ratio in the breast cancer cell lines. Furthermore, it has been noticed that auranofin augmented paclitaxel-mediated cytotoxicity in a concentration-dependent manner in both MDA-MB-231 and MCF-7 cell lines. Moreover, auranofin increased the levels of intracellular reactive oxygen species (observed using 2, 7-diacetyl dichlorofluorescein diacetate staining) and subsequently altered the mitochondrial membrane potential (rhodamine-123 staining) in a concentration-dependent manner. Further, the expression of apoptotic marker p21 was found to be higher in auranofin plus paclitaxel-treated breast cancer cells compared to paclitaxel-alone treatment. Thus, the present results illustrate the chemosensitizing property of auranofin in MDA-MB-231 and MCF-7 breast cancer cell lines via oxidative metabolism. Therefore, auranofin could be considered a chemosensitizing agent during cancer chemotherapy.