Induction of chemoresistance in HL-60 cells concomitantly causes a resistance to apoptosis and the synthesis of P-glycoprotein

The appearance of multidrug-resistant (MDR) proteins or the acquisition of a defective apoptotic programme are major drawbacks in the treatment of can cers since both induce a resistance to classical chemotherapy. However, a l ink between the two mechanisms has not, as yet, been clearly established. I n this study, HL-60 cells cultured in the continual presence of a sub-letha l dose of doxorubicin (dox; HL-60/Dox) were used as a model to study acquir ed chemoresistance. During the induction of chemoresistance, the appearance of a functional P-glycoprotein (P-gp), in addition to the expression of an ti-apoptotic Bcl-2, Bcl-XL and pro-apoptotic Bax proteins was assessed. Par ental cells which are sensitive to dox, have no P-gp activity and express S cl-2 and Bax. After 4 weeks of treatment, a functional P-gp was detected in HL-60/Dox cells. In addition, the synthesis of Bcl-2 appeared to be replac ed by Bcl-XL while that of Bax remained unchanged. These cells were also re sistant to apoptosis induced by both P-gp and non-P-gp substrates. This ina bility to induce apoptosis could have resulted from the induction of the ex pression of the inhibitor of apoptosis protein (XIAP). Our data show that a cquired chemoresistance could involve a parallel induction of P-gp and an i mpairment of the apoptotic pathway.