Differentiation and drug resistance relationships in leukemia cells

It is well established that the effectiveness of anticancer drugs may result from combined cytotoxic and differentiation activities on tumor cells. Also, differentiating agents are able to alter the susceptibility of cancer cells to antineoplastic drug therapy. However, the acquisition and/or development of drug resistance that frequently appears in anticancer treatment can impair these interactions between differentiation agents and cytotoxic drugs. In the present study, we report that the acquisition of resistance to anthracyclines in two humans, promyeolocytic leukemia HL-60 and eythroleukemia K562 cell lines, results in a restricted maturation process induced by differentiating agents with respect to that exhibited by their corresponding drug-sensitive counterparts. Interestingly, differentiating agents are able to decrease the overexpression of drug-efflux pumps as it is the case of MRP1 in the resistant HL-60 cells, thus increasing the sensitivity of cells to drug treatment. In addition, susceptibility of the drug-sensitive cells to certain apoptotic stimuli is significantly reduced after differentiation. The results here reported indicate complex interactions between cytotoxic (drug therapy) and non-cytotoxic (differentiation) cancer treatments, which should be taken into account to improve therapeutic efficiency.