Triphenyl tin benzimidazolethiol, a novel antitumor agent, induces mitochondrial-mediated apoptosis in human cervical cancer cells via suppression of HPV-18 encoded E6.
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.
Höti
Naseruddin
N
Department of Molecular and Cell Biology, Key Laboratory of Structural Biology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, 230027, People's Republic of China.
Ma
Jun
J
Tabassum
Sartaj
S
Wang
Yi
Y
Wu
Mian
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001562:Benzimidazoles / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002469:Cell Separation; D004247:DNA / Q000737:chemistry; D015536:Down-Regulation; D005260:Female; D005434:Flow Cytometry; D005456:Fluorescent Dyes / Q000494:pharmacology; D016193:G1 Phase; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology*; D008956:Models, Chemical; D009841:Oligonucleotides / Q000737:chemistry / Q000494:pharmacology; D009947:Organotin Compounds / Q000737:chemistry / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D016192:Resting Phase, Cell Cycle; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D050998:bcl-2 Homologous Antagonist-Killer Protein
D000970:Antineoplastic Agents; C494772:BAK1 protein, human; D001562:Benzimidazoles; D005456:Fluorescent Dyes; D008565:Membrane Proteins; D009841:Oligonucleotides; D009947:Organotin Compounds; D013778:Tetrazolium Salts; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D050998:bcl-2 Homologous Antagonist-Killer Protein; C490337:triphenyl tin benzimidazolethiol; D004247:DNA; C030665:triphenyltin; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; C022616:thiazolyl blue