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.
ABSTRACT
The present study selected and characterized a multidrug-resistant HL-60 human acute promyelocytic leukemia cell line, HL-60/RS, by exposure to stepwise incremental doses of doxorubicin. The drug-resistant HL-60/RS cells exhibited 85.68-fold resistance to doxorubicin and were cross-resistant to other chemotherapeutics, including cisplatin, daunorubicin, cytarabine, vincristine and etoposide. The cells over-expressed the transporters P-glycoprotein, multidrug-resistance-related protein 1 and breast-cancer-resistance protein, encoded by the adenosine triphosphate-binding cassette (ABC)B1, ABCC1 and ABCG2 genes, respectively. Unlike other recognized chemoresistant leukemia cell lines, HL-60/RS cells were also strongly cross-resistant to arsenic trioxide. The proportion of leukemia stem cells (LSCs) increased synchronously with increased of drug resistance in the doxorubicin-induced HL-60 cell population. The present study confirmed that doxorubicin-induced HL-60 cells exhibited multidrug-resistance and high arsenic-trioxide resistance. Drug-resistance in these cells may be due to surviving chemoresistant LSCs in the HL-60 population, which have been subjected to long and consecutive selection by doxorubicin.
