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CELLULAR AND MOLECULAR

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

Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Anhui, People's Republic of China (N.H., Z.D.E., S.Z., M.W.); School of Biological Sciences, Nanyang Technological University, Singapore (M.W.); Department of Pathology, Anhui Medical University, Anhui, People's Republic of China (Z.W.); and Department of Chemistry, Aligarh University, Aligarh, India (S.T.)

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.

Address correspondence to: Dr. Mian Wu, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, People's Republic of China, 230027. E-mail: wumian88{at}yahoo.com