SELECTIVE INDUCTION OF APOPTOSIS IN MULTIDRUG-RESISTANT HL60R CELLS BY THE THIAZOLOBENZOIMIDAZOLE DERIVATIVE DIFLUOROPHENYL)-1H,3H-THIAZOLO[3,4-A]BENZIMIDAZOLE (TBZ)

We investigated the antitumour effects of 1-(2,6-difluorophenyl)-1H,3H -thiazolo [3,4-a]benzimidazole (TBZ) a new anti-HIV-1 agent, on human promyelocytic HL60 leukaemia, both a parental and a multidrug resistan t form (HL60R). HL60R overexpresses P-glycoprotein and, like HL60, lac ks p53 protein expression. HL60 and HL60R show similar levels of Bcl-2 protein. In contrast to the conventional chemotherapeutic agents daun orubicin, etoposide and mitoxantrone, TBZ caused equal or even greater cytotoxicity in HL60R than. in HL60, and this result was associated w ith a more marked induction of apoptosis in the drug resistant cells, The antitumour activity of TBZ occurred in the range of concentrations higher than those required to exert antiviral activity. TBZ seems to act: in the presence of P-glycoprotein and Bcl-2 and in the absence of p53 and is able to circumvent the mechanisms of drug resistance and a nti-apoptosis present in HL60R cells. (C) 1998 Elsevier Science Ltd. A ll rights reserved.