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

Her Shyong Shiah, Wan Shu Lee, Shin Hun Juang, Pao Chiung Hong, Chia Chi Lung, Ching Jer Chang, Kai Ming Chou, Jang Yang Chang

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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 HepG2 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.

Original languageEnglish (US)
Pages (from-to)610-619
Number of pages10
JournalBiochemical Pharmacology
Volume73
Issue number5
DOIs
StatePublished - Mar 1 2007

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Keywords

  • Apoptosis
  • Caspase
  • Mitochondria
  • Selenophene derivative
  • p53

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

Cite this

Shiah, H. S., Lee, W. S., Juang, S. H., Hong, P. C., Lung, C. C., Chang, C. J., Chou, K. M., & Chang, J. Y. (2007). Mitochondria-mediated and p53-associated apoptosis induced in human cancer cells by a novel selenophene derivative, D-501036. Biochemical Pharmacology, 73(5), 610-619. https://doi.org/10.1016/j.bcp.2006.10.019