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.
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.
Höti
Naseruddin
N
Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui, People's Republic of China.
Zhu
De-E
DE
Song
Zhiyin
Z
Wu
Zhengsheng
Z
Tabassum
Sartaj
S
Wu
Mian
M
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation; D005260:Female; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D009363:Neoplasm Proteins; D009947:Organotin Compounds / Q000494:pharmacology*; D027383:Papillomaviridae / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000077022:Survivin; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*; D002583:Uterine Cervical Neoplasms / Q000473:pathology; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
D051017:Apoptosis Regulatory Proteins; C494772:BAK1 protein, human; C494826:BAX protein, human; C107489:BIRC5 protein, human; C494774:Bak1 protein, rat; C494828:Bax protein, rat; D002352:Carrier Proteins; C412403:DIABLO protein, human; C489013:DIABLO protein, rat; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins; D009947:Organotin Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C490337:triphenyl tin benzimidazolethiol; D045304:Cytochromes c; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases