Triphenyl tin benzimidazolethiol, a novel antitumor agent, induces mitochondrial-mediated apoptosis in human cervical cancer cells via suppression of HPV-18 encoded E6.

Abstract

Here we report the effect of TPT-benzimidazolethiol, a novel anti-tumor agent developed by our group, on the apoptotic pathway of human cervical carcinoma cells. Treatment of HeLa cells with TPT-benzimidazolethiol arrests the cell cycle at G0/G1 phase and transcriptionally downregulates HPV-encoded E6, restoring p53 expression from E6 suppression. Increased p53 accumulation up-regulates p21/waf and ultimately induces apoptosis. The effect of TPT-benzimidazolethiol is far more potent in inducing apoptosis than cisplatin. Treatment with TPT-benzimidazolethiol in HeLa cells is accompanied by the up-regulation of Bak at the transcriptional level, resulting in the release of cytochrome c and Smac/DIABLO from mitochondria to cytosol and, subsequently, the activation of procaspase-9, -3 and PARP, suggesting that TPT-benzimidazolethiol induced-apoptosis signaling is by an intrinsic mitochondrial pathway. Taken together, we propose that TPT-benzimidazolethiol could has the potential to be developed into a new therapeutic agent for treating HPV-associated cervical neoplasia.

• Authors: Naseruddin Höti, Jun Ma, Sartaj Tabassum, Yi Wang, Mian Wu
• Journal: Journal of biochemistry (J Biochem) Vol. 134 Issue 4 Pg. 521-8 (Oct 2003) ISSN: 0021-924X [Print] England
• PMID: 14607978 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• BAK1 protein, human
• Benzimidazoles
• Fluorescent Dyes
• Membrane Proteins
• Oligonucleotides
• Organotin Compounds
• Tetrazolium Salts
• Thiazoles
• Tumor Suppressor Protein p53
• bcl-2 Homologous Antagonist-Killer Protein
• triphenyl tin benzimidazolethiol
• DNA
• triphenyltin
• Poly(ADP-ribose) Polymerases
• Caspases
• thiazolyl blue

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis
• Benzimidazoles (pharmacology)
• Caspases (metabolism)
• Cell Line, Tumor
• Cell Separation
• DNA (chemistry)
• Down-Regulation
• Female
• Flow Cytometry
• Fluorescent Dyes (pharmacology)
• G1 Phase
• HeLa Cells
• Humans
• Membrane Proteins (metabolism)
• Mitochondria (drug effects, pathology)
• Models, Chemical
• Oligonucleotides (chemistry, pharmacology)
• Organotin Compounds (chemistry, pharmacology)
• Poly(ADP-ribose) Polymerases (metabolism)
• Resting Phase, Cell Cycle
• Tetrazolium Salts (pharmacology)
• Thiazoles (pharmacology)
• Time Factors
• Transcription, Genetic
• Tumor Suppressor Protein p53 (metabolism)
• Up-Regulation
• Uterine Cervical Neoplasms (drug therapy, pathology)
• bcl-2 Homologous Antagonist-Killer Protein