Caspase 3 in breast cancer.
ABSTRACT An inability to undergo apoptosis is widely thought to contribute to both tumorigenesis and tumor progression. One of the key mediators of apoptosis is the thiol protease caspase 3. In this investigation, caspase 3 mRNA and protein expression in breast cancer was examined.
Caspase 3 was measured at the mRNA level using reverse transcription-PCR and at the protein level using both Western blotting and activity assays. Levels of apoptosis were determined using an ELISA, which detects nucleosomes released during DNA fragmentation.
Relative levels of caspase 3 mRNA were similar in breast carcinomas (n = 103), fibroadenomas (n = 25), and normal breast tissues (n = 6). However, levels of both the precursor and active forms of caspase 3 were significantly higher in carcinomas compared with both fibroadenomas (P = 0.0188) and normal breast tissues (P = 0.0002). Levels of apoptosis were also highest in the carcinomas and correlated significantly with active caspase 3 levels (r = 0.481; P = 0.0003). In the carcinomas, expression of caspase 3 showed no significant relationship with either tumor size, tumor grade, nodal status, or steroid receptor status but was significantly higher in ductal carcinomas than in lobular carcinomas (P = 0.0188).
We conclude that rates of apoptosis as measured by both caspase 3 activation and nucleosome release are higher in breast cancer than in nonmalignant breast tissue. This finding would appear to conflict with the widely held belief that apoptosis is reduced in malignancy. The proliferation:apoptosis ratio, however, may be higher in carcinomas than in the corresponding normal tissue.
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ABSTRACT: A series of novel benzothiazole derivatives bearing ortho-hydroxy N-carbamoylhydrazone moiety were synthesized and evaluated for their cytotoxic activities. Six potent compounds were further examined for their procaspase-3 kinase activity.European Journal of Medicinal Chemistry. 01/2014; 86:257–269.
Dataset: ACTA Biologica Hungarica 2013
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ABSTRACT: Purpose Procaspase-3, a proenzyme of apoptotic executioner caspase-3, is overexpressed in numerous tumors. We aimed to characterize a novel procaspase-3 activator, WF-210, which may have potential as an anticancer drug. Experimental Design The procaspase-3 activating ability, antitumor efficacy, mechanisms of action, and toxicity profiles of WF-210 were investigated in vitro and in vivo, using normal cells, cancer cells, and mouse xenograft models. The role of procaspase-3 in WF-210-induced apoptosis was explored by manipulating procaspase-3 expression in cultured cells. Results WF-210 activated procaspase-3 with an EC50 of 0.95 μM, less than half that of its mother compound PAC-1 (2.08 μM). The mechanism involved the chelation of inhibitory zinc ions, subsequently resulting in an auto-activation of procaspase-3. WF-210 was more cytotoxic than PAC-1 to human cancer cells, but less cytotoxic to normal cells. Cancer cells with high procaspase-3 expression, like HL-60 and U-937, were particularly sensitive. WF-210 induced the apoptosis of HL-60 and U-937 cells by activating procaspases and promoting proteasome-dependent degradation of XIAP and Survivin. The level of WF-210-induced apoptosis in cultured cells was related to the level of procaspase-3 expression. Finally, WF-210 was superior to PAC-1 in retarding the in vivo growth of breast, liver and gallbladder xenograft tumors which overexpress procaspase-3, and induced no substantial weight loss or neurotoxicity. WF-210 and PAC-1 had no effect on the growth of MCF-7 xenograft tumors, which do not express procaspase-3. Conclusion We identified WF-210 as a potent small-molecule activator of procaspase-3. The favorable antitumor activity and acceptable toxicity profile of WF-210 provide a strong rationale for its clinical evaluation in the treatment of tumors with high procaspase-3 expression.Molecular Oncology 12/2014; · 6.70 Impact Factor