Mol Aspects Med 21:167–223īoatright KM, Salvesen GS (2003) Mechanisms of caspase activation. Proc Natl Acad Sci USA 98:13681–13686īertram JS (2000) The molecular biology of cancer. Blood 102:652–658īennett BL, Sasaki DT, Murray BW, O’Leary EC, Sakata ST, Xu W, Leisten JC, Motiwala A, Pierce S, Satoh Y, Bhagwat SS, Manning AM, Anderson DW (2001) SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase.

J Natl Cancer Inst 93:1062–1074Īron JL, Parthun MR, Marcucci G, Kitada S, Mone AP, Davis ME, Shen T, Murphy T, Wickham J, Kanakry C, Lucas DM, Reed JC, Grever MR, Byrd JC (2003) Depsipeptide (FR901228) induces histone acetylation and inhibition of histone deacetylase in chronic lymphocytic leukemia cells concurrent with activation of caspase 8-mediated apoptosis and down-regulation of c-FLIP protein. The pro-apoptotic activity of H-Ras(V12) responding to HDACI indicates a potential value of this new class of anticancer agents in treating Ras-related human cancers.Īdjei AA (2001) Blocking oncogenic Ras signaling for cancer therapy. ConclusionĮxpression of H-Ras(V12) increased susceptibility of HT29 cells to HDACI FR901228 and Trichostatin A for inducing apoptosis. Deacetylation of FR901228-induced acetylation of core histones was accelerated by H-Ras(V12) in cells undergoing apoptosis. Both p21 Cip1 and p27 Kip1 were induced in FR901228-treated cells arrested in either the G0/G1 or G2/M phase of the cell cycle. Expression of H-Ras(V12) changed the intrinsic modulation of Raf in cells responding to FR901228 treatment.

ResultsĪctivation of caspase-3, -7, and -8, and serine protease by FR901228 was facilitated by oncogenic H-Ras to induce apoptosis. The mode of action of HDACI FR901228 was studied by its ability to modulate protein phosphorylation, acetylation, and expression levels in various signaling pathways, measured by Western blot analysis. The pro-apoptotic activity of oncogenic H-Ras(V12) was verified by its ability to increase susceptibility of human colorectal adenocarcinoma HT29 cells to HDACI for inducing apoptosis and growth inhibition, assayed by various methods. To verify the pro-apoptotic activity of oncogenic H-Ras in the increased susceptibility of human cancer cells to histone deacetylase inhibitor (HDACI).

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