A Novel Resveratrol-Arsenic Trioxide Combination Treatment Synergistically Induces Apoptosis of Adriamycin-Selected Drug-Resistant Leukemia K562 Cells.

Abstract

Leukemia cells can develop resistance to apoptosis induced by chemotherapeutic agents. Concomitant multidrug resistance of cells remains the greatest clinical obstacle in the effective treatment of blood and solid tumors. Natural products have been identified that possess the capacity to modulate chemotherapeutic resistance and induce apopotosis. In this study, we generated adriamycin-resistant K562 leukemia (K562/RA) cells and compared the responses of sensitive and resistant leukemia cells to the natural products arsenic trioxide (ATO) and resveratrol (Rsv), with a view to determining whether Rsv potentiates the sensitivity of drug-resistant cells to ATO-induced apoptosis and the associated molecular mechanisms. Our results showed that resistance of K562/RA cells induced by adriamycin treatment was significantly higher (115.81-fold) than that of parental K562 cells. Simultaneously, K562/RA cells were cross-resistant to multiple agents, with the exception of ATO. Rsv enhanced the sensitivity of K562/RA cells to ATO and reduced the required dose of ATO as well as associated adverse reactions by promoting the proliferation inhibitory and apoptosis-inducing effects of ATO, which may be associated with reduced expression of the drug resistance genes mdr1/P-gp, mrp1/MRP1 and bcrp/BCRP, as well as the apoptotic inhibitory genes bcl-2, NF-κB and P53, and conversely, activation of caspase-3. Our collective findings indicate that ATO and Rsv synergistically enhance the sensitivity of drug-resistant leukemia cells to apoptosis.