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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.
J Pharmacol Exp Ther. 2004 Oct; 311(1):22-33.JP

Abstract

We have studied the effect of tri-phenyl tin benzimadazolethiolcopper chloride (TPT-CuCl(2)), a novel bimetallic compound, on the regulation of apoptosis in HeLa cells, MCF-7 cells, and in vivo Wistar rat model. TPT-CuCl(2) induces significant apoptosis in HeLa cell line characterized by DNA fragmentation and chromosome condensation. Comet assay revealed that TPT-CuCl(2) targets and causes severe damage to the DNA. Treatment of HeLa cells with TPT-CuCl(2) 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-CuCl(2) 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-CuCl(2) induced-apoptosis was through an intrinsic mitochondrial pathway, which was inhibited by viral oncoprotein E1B19K. Caspase-3 was found to be indispensable in TPT-CuCl(2)-triggered apoptosis signaling pathway, because caspase-3 deficient cell line MCF-7 was resistant to TPT-CuCl(2). Furthermore, in vivo studies using C6 glioblastoma xenograft rat model revealed that TPT-CuCl(2) 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-CuCl(2) as a drug candidate for further development.

Authors+Show Affiliations

Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui, People's Republic of China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15173313

Citation

Höti, Naseruddin, et al. "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." The Journal of Pharmacology and Experimental Therapeutics, vol. 311, no. 1, 2004, pp. 22-33.
Höti N, Zhu DE, Song Z, et al. 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. J Pharmacol Exp Ther. 2004;311(1):22-33.
Höti, N., Zhu, D. E., Song, Z., Wu, Z., Tabassum, S., & Wu, M. (2004). 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. The Journal of Pharmacology and Experimental Therapeutics, 311(1), 22-33.
Höti N, et al. 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. J Pharmacol Exp Ther. 2004;311(1):22-33. PubMed PMID: 15173313.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Höti,Naseruddin, AU - Zhu,De-E, AU - Song,Zhiyin, AU - Wu,Zhengsheng, AU - Tabassum,Sartaj, AU - Wu,Mian, Y1 - 2004/06/01/ PY - 2004/6/3/pubmed PY - 2004/12/16/medline PY - 2004/6/3/entrez SP - 22 EP - 33 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 311 IS - 1 N2 - We have studied the effect of tri-phenyl tin benzimadazolethiolcopper chloride (TPT-CuCl(2)), a novel bimetallic compound, on the regulation of apoptosis in HeLa cells, MCF-7 cells, and in vivo Wistar rat model. TPT-CuCl(2) induces significant apoptosis in HeLa cell line characterized by DNA fragmentation and chromosome condensation. Comet assay revealed that TPT-CuCl(2) targets and causes severe damage to the DNA. Treatment of HeLa cells with TPT-CuCl(2) 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-CuCl(2) 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-CuCl(2) induced-apoptosis was through an intrinsic mitochondrial pathway, which was inhibited by viral oncoprotein E1B19K. Caspase-3 was found to be indispensable in TPT-CuCl(2)-triggered apoptosis signaling pathway, because caspase-3 deficient cell line MCF-7 was resistant to TPT-CuCl(2). Furthermore, in vivo studies using C6 glioblastoma xenograft rat model revealed that TPT-CuCl(2) 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-CuCl(2) as a drug candidate for further development. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/15173313/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_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=15173313 DB - PRIME DP - Unbound Medicine ER -