Carboxyamido-triazole (CAI), a signal transduction inhibitor induces growth inhibition and apoptosis in bladder cancer cells by modulation of Bcl-2.
Pro- and anti-apoptotic factors and intracellular signaling pathways are targets for therapeutic development of anticancer agents. Carboxyamido-triazole (CAI) is an inhibitor of transmembrane calcium influx and intracellular calcium-requiring signal transduction pathways. The present study investigates the effects of CAI on human transitional cancer cell (TCC) viability and apoptosis, and evaluates whether apoptotic resistance may be overcome pharmacologically. Both well-differentiated (RT4, RT112/grade 1) and poorly-differentiated (T24/grade 3; SUP/grade 4) human TCC lines were shown to express Fas. Upon exposure to agonistic monoclonal Fas antibody, only well-differentiated TCC lines underwent apoptotic cell death. CAI exposure reduced cell viability and caused an at least additive anti-apoptotic effect in combination with the Fas antibody in the Fas-insensitive TCC lines. Under the same conditions under which CAI treatment augmented Fas-mediated apoptosis, it was shown to reduce intracellular bcl-2 quantity. This response to CAI indicates that apoptotic cell death is enhanced by the reduction of bcl-2 protein expression. We suggest that the antitumor effect of CAI is at least partially based on restoring a pathway of apoptosis. It may cause transformation of cell homeostasis that leads to the alteration of apoptotic mechanisms, thus allowing highly malignant tumor cells to re-enter the physiological course of cell elimination.
Perabo
Frank G E
FG
Department of Urology, University Hospital, Bonn University, 53105 Bonn, USA. perabo@lycos.com
Wirger
Andreas
A
Kamp
Stefan
S
Lindner
Heike
H
Schmidt
Doris H
DH
Müller
Stefan C
SC
Kohn
Elise C
EC
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019014:fas Receptor / Q000096:biosynthesis / Q000276:immunology
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D014230:Triazoles; D019014:fas Receptor; C062058:carboxyamido-triazole; D002118:Calcium