Mitochondria-mediated and p53-associated apoptosis induced in human cancer cells by a novel selenophene derivative, D-501036.

Abstract

D-501036 [2,5-bis(5-hydroxymethyl-2-selenienyl)-3-hydroxymethyl-N-methylpyrrol], a novel selenophene derivative, is a highly potent cytotoxic agent with broad spectrum antitumor activity. The present study was undertaken to explore the mechanism(s) through which D-501036 exerts its action mode on the cancer cell death. D-501036 was found to suppress the growth of KB and HepG(2) cells in an irreversible manner. The results of annexin-V assays and PARP cleavage studies were consistent with the D-501036-induced apoptosis. Findings provided a strong support for the induction of mitochondria-mediated apoptosis by this drug. The examination of two canonical pathways of initiation caspases, those for caspases -8 and -9, revealed that caspase-9 protein and the activities of caspases -9 and -3 were increased in a dose- and time-dependent manner. The concentrations of Fas/Fas-L and procaspase-8 and the activity of caspase-8 were not altered. Furthermore, the mitochondrial membrane potential permeability and the release of cytochrome c to the cytosol were both increased by D-501036. The concentrations of the pro-apoptotic protein Bax and translocation of Bax from the cytosol to the mitochondria were increased in response to D-501036, whereas the concentrations of the anti-apoptotic protein Bcl-2 were decreased. Two DNA damage-related pro-apoptotic proteins, Puma and Noxa, were upregulated in a dose- and time-dependent manner. These pro-apoptotic and anti-apoptotic proteins are downstream effectors of p53. Accordingly, the phosphorylated and total forms of p53 were induced and p53 was translocated from the cytosol to the mitochondria in response to D-501036 treatment. Collectively, we conclude that D-501036 induces cellular apoptosis through the p53-associated mitochondrial pathway.

• Authors: Her-Shyong Shiah, Wan-Shu Lee, Shin-Hun Juang, Pao-Chiung Hong, Chia-Chi Lung, Ching-Jer Chang, Kai-Ming Chou, Jang-Yang Chang
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 73 Issue 5 Pg. 610-9 (Mar 01 2007) ISSN: 0006-2952 [Print] England
• PMID: 17150195 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2,5-bis(5-hydroxymethyl-2-selenienyl)-3-hydroxymethyl-N-methylpyrrole
• Antineoplastic Agents
• Organoselenium Compounds
• Pyrroles
• Tumor Suppressor Protein p53
• Cytochromes c
• Caspase 3
• Caspase 8
• Caspase 9

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Caspase 3 (metabolism)
• Caspase 8 (metabolism)
• Caspase 9 (metabolism)
• Cell Line, Tumor
• Cytochromes c (metabolism)
• Cytosol (metabolism)
• Gene Expression Regulation (drug effects)
• Humans
• Mitochondria (metabolism)
• Molecular Structure
• Organoselenium Compounds (chemistry, pharmacology)
• Pyrroles (chemistry, pharmacology)
• Tumor Suppressor Protein p53 (metabolism)