%0 Journal Article %A Naseruddin Höti %A De-e Zhu %A Zhiyin Song %A Zhengsheng Wu %A Sartaj Tabassum %A Mian Wu %T p53-Dependent Apoptotic Mechanism of a New Designer Bimetallic Compound Tri-phenyl Tin Benzimidazolethiol Copper Chloride (TPT-CuCl2): In Vivo Studies in Wistar Rats as Well as in Vitro Studies in Human Cervical Cancer Cells %D 2004 %R 10.1124/jpet.104.069104 %J Journal of Pharmacology and Experimental Therapeutics %P 22-33 %V 311 %N 1 %X We have studied the effect of tri-phenyl tin benzimadazolethiolcopper chloride (TPT-CuCl2), a novel bimetallic compound, on the regulation of apoptosis in HeLa cells, MCF-7 cells, and in vivo Wistar rat model. TPT-CuCl2 induces significant apoptosis in HeLa cell line characterized by DNA fragmentation and chromosome condensation. Comet assay revealed that TPT-CuCl2 targets and causes severe damage to the DNA. Treatment of HeLa cells with TPT-CuCl2 rescues the accumulation of p53 from the suppression of human papilloma virus E6, resulting in a dramatic up-regulation of Bax and Bak and down-regulation of the antiapoptotic factor Survivin. Apoptotic induction by TPT-CuCl2 was shown to mediate in a p53-depedent manner; loss of p53 impairs the release of cytochrome c and Smac/DIABLO from mitochondria to cytosol. Moreover, we have shown that TPT-CuCl2 induced-apoptosis was through an intrinsic mitochondrial pathway, which was inhibited by viral oncoprotein E1B19K. Caspase-3 was found to be indispensable in TPT-CuCl2-triggered apoptosis signaling pathway, because caspase-3 deficient cell line MCF-7 was resistant to TPT-CuCl2. Furthermore, in vivo studies using C6 glioblastoma xenograft rat model revealed that TPT-CuCl2 exhibits significant antiproliferative activity against tumor development with minimal cytotoxicity toward normal physiological function of the experimental rats. These findings imply the attractiveness of TPT-CuCl2 as a drug candidate for further development. The American Society for Pharmacology and Experimental Therapeutics %U https://jpet.aspetjournals.org/content/jpet/311/1/22.full.pdf