Apoptotic effects of thiazolobenzimidazole derivatives on sensitive and multidrug resistant leukaemic cells.
We investigated the cytotoxic activity of eight thiazolobenzimidazole derivatives on sensitive HL60 and multidrug-resistant (MDR) (HL60R) leukaemia cell lines. The antitumour effects of these compounds were compared with those of RS-TBZ, a thiazolobenzimidazole derivative, previously described in our reports, that was able to induce apoptosis more markedly in MDR cells than in the parental sensitive cell lines. Only two compounds in this study proved to have interesting effects: (a) the S-enantiomer of TBZ, that was able to induce apoptosis in MDR cells in a slightly more selective manner than TBZ (racemic form); and (b) TBZ-4-OCH3 (TBZ-4-OCH3), that showed cytotoxic and apoptotic effects on sensitive and resistant leukaemia cells greater than TBZ, without cytotoxic effects on normal haemopoietic progenitor cells. Moreover, we observed that TBZ-4-OCH3 was also active in cells expressing Bcr-Abl, an oncogene that confers resistance to apoptosis induced by several stimuli, including cytotoxic agents. The inhibition of caspase-9 and caspase-3 by specific polypeptide inhibitors decreased the apoptotic effects of TBZ-4-OCH3 in HL60 cells indicating that apoptosis induced by this compound was, at least partly, caspase-mediated. On the contrary, the blocking of FL-associated cell surface antigen (Fas) using a specific Fas-blocking monoclonal antibody did not affect the level of apoptosis induced by TBZ-4-OCH3 suggesting that the Fas pathway was not involved. In addition, the caspase 8 inhibitor was unable to inhibit the apoptotic activity of TBZ-4-OCH3. The very low toxicity shown by TBZ-4-OCH3 in normal haemopoietic progenitor cells and its high activity in sensitive and MDR neoplastic cells suggest a possible clinical use for this new compound.
Grimaudo
S
S
Divisione di Ematologia e Servizio A.I.D.S., Facolta' di Medicina, Universita' di Palermo, Palermo, Italy. dusonc@unipa.it
Raimondi
M V
MV
Capone
F
F
Chimirri
A
A
Poretto
F
F
Monforte
A M
AM
Simoni
D
D
Tolomeo
M
M
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000737:chemistry / Q000627:therapeutic use*; D061945:Caspase Inhibitors; D002453:Cell Cycle / Q000187:drug effects; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000473:pathology; D013844:Thiazoles / Q000737:chemistry / Q000627:therapeutic use*; D019014:fas Receptor / Q000378:metabolism
D000970:Antineoplastic Agents; D001562:Benzimidazoles; D061945:Caspase Inhibitors; D013844:Thiazoles; D019014:fas Receptor; C073244:1-(2',6'-difluorophenyl)-1H,3H-thiazolo(3,4-a)benzimidazole