Selective induction of apoptosis in multidrug resistant HL60R cells by the thiazolobenzoimidazole derivative 1-(2,6-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 resistant form (HL60R). HL60R overexpresses P-glycoprotein and, like HL60, lacks p53 protein expression. HL60 and HL60R show similar levels of Bcl-2 protein. In contrast to the conventional chemotherapeutic agents daunorubicin, etoposide and mitoxantrone, TBZ caused equal or even greater cytotoxicity in HL60R than in HL60, and this result was associated with 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 anti-apoptosis present in HL60R cells.
Grimaudo
S
S
Istituto Farmacochimico Facolta di Farmacia, Università di Palermo, Italy.
Tolomeo
M
M
Chimirri
A
A
Zappala
M
M
Gancitano
R A
RA
D'Alessandro
N
N
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D019380:Anti-HIV Agents / Q000627:therapeutic use; D017209:Apoptosis; D001562:Benzimidazoles / Q000627:therapeutic use*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D018922:HL-60 Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013844:Thiazoles / Q000627:therapeutic use*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019380:Anti-HIV Agents; D001562:Benzimidazoles; D019253:Proto-Oncogene Proteins c-bcl-2; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; C073244:1-(2',6'-difluorophenyl)-1H,3H-thiazolo(3,4-a)benzimidazole