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Research ArticleCELLULAR 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

Naseruddin Höti, De-e Zhu, Zhiyin Song, Zhengsheng Wu, Sartaj Tabassum and Mian Wu
Journal of Pharmacology and Experimental Therapeutics October 2004, 311 (1) 22-33; DOI: https://doi.org/10.1124/jpet.104.069104
Naseruddin Höti
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De-e Zhu
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Zhiyin Song
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Zhengsheng Wu
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Sartaj Tabassum
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Mian Wu
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This article has a correction. Please see:

  • Correction to “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” - December 01, 2004

Abstract

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.

Footnotes

  • This research was funded by the Key Project (KSCX2-2-01-004) from the Chinese Academy of Sciences, grants from National Natural Science Foundation of China (90208027, 30370308, and 30121001), and a 973 grant (2002CB713702) from the Ministry of Science and Technology of China.

  • doi:10.1124/jpet.104.069104.

  • ABBREVIATIONS: HPV, human papilloma virus; mAb, monoclonal antibody; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PBS, phosphate-buffered saline; TPT-CuCl2, tri-phenyl tin benzimidazolethiol copper chloride; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling; RT-PCR, reverse transcription-polymerase chain reaction; TBS, Tris-buffered saline; PI, propidium iodide; FACS, fluorescence-activated cell sorting; FITC, fluorescein isothiocyanate; GFP, green fluorescent protein; Smac/DIABLO, second mitochondria-derived activator of caspases; PARP-1, poly(ADP-ribose) polymerase-1; ALT, alanine aminotransferase; RBC, red blood cell.

  • ↵1 N.H. and D.Z. contributed equally to this work.

    • Received March 26, 2004.
    • Accepted May 27, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 311 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 311, Issue 1
1 Oct 2004
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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
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Research ArticleCELLULAR 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

Naseruddin Höti, De-e Zhu, Zhiyin Song, Zhengsheng Wu, Sartaj Tabassum and Mian Wu
Journal of Pharmacology and Experimental Therapeutics October 1, 2004, 311 (1) 22-33; DOI: https://doi.org/10.1124/jpet.104.069104

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Research ArticleCELLULAR 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

Naseruddin Höti, De-e Zhu, Zhiyin Song, Zhengsheng Wu, Sartaj Tabassum and Mian Wu
Journal of Pharmacology and Experimental Therapeutics October 1, 2004, 311 (1) 22-33; DOI: https://doi.org/10.1124/jpet.104.069104
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