Carboxyamido-triazole (CAI), a Signal Transduction Inhibitor Induces Growth Inhibition and Apoptosis in Bladder Cancer Cells by Modulation of Bcl-2

• Published in: Anticancer research 2004-09, Vol.24 (5A), p.2869-2877
• Main Authors: PERABO, Frank G. E, WIRGER, Andreas, KAMP, Stefan, LINDNER, Heike, SCHMIDT, Doris H, MÜLLER, Stefan C, KOHN, Elise C
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Biological and medical sciences; Calcium - metabolism; Carcinoma, Transitional Cell - drug therapy; Carcinoma, Transitional Cell - metabolism; Carcinoma, Transitional Cell - pathology; Cell Growth Processes - drug effects; Cell Line, Tumor; fas Receptor - biosynthesis; fas Receptor - immunology; Humans; Medical sciences; Nephrology. Urinary tract diseases; Proto-Oncogene Proteins c-bcl-2 - biosynthesis; Signal Transduction - drug effects; Triazoles - pharmacology; Tumors; Tumors of the urinary system; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - metabolism; Urinary Bladder Neoplasms - pathology; Urinary tract. Prostate gland
• ISSN: 0250-7005; 1791-7530

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.