RT Journal Article
SR Electronic
T1 Anti-Colon Cancer Activity of Largazole, a Marine-Derived Tunable Histone Deacetylase Inhibitor
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.110.172387
DO 10.1124/jpet.110.172387
A1 Yanxia Liu
A1 Lilibeth A Salvador
A1 Seongrim Byeon
A1 Yongcheng Ying
A1 Jason C Kwan
A1 Brian K Law
A1 Jiyong Hong
A1 Hendrik Luesch
YR 2010
UL http://jpet.aspetjournals.org/content/early/2010/08/25/jpet.110.172387.abstract
AB Histone deacetylases (HDACs) are validated targets for anticancer therapy as attested by the approval of SAHA and FK228 to treat cutaneous T-cell lymphoma. We recently described the bioassay-guided isolation, structure determination, synthesis, and target identification of largazole, a marine-derived antiproliferative natural product which is a pro-drug that releases a potent HDAC inhibitor, largazole thiol. Here we characterize the anticancer activity of largazole using in vitro and in vivo cancer models. Screening against the NCI's 60 cell lines revealed that largazole is particularly active against several colon cancer cell types. Consequently we tested largazole, along with several synthetic analogues, for HDAC inhibition in human HCT116 colon cancer cells. Enzyme inhibition strongly correlated with the growth inhibitory effects, and differential activity of largazole analogues was rationalized by molecular docking to an HDAC1 homology model. Comparative genome-wide transcript profiling revealed a close overlap of genes that are regulated by largazole, FK228 and SAHA. Several of these genes can be related to largazole's ability to induce cell cycle arrest and apoptosis. Stability studies suggested reasonable bioavailability of the active species, largazole thiol. We established that largazole inhibits HDACs in tumor tissue in vivo using a human HCT116 xenograft mouse model. Largazole strongly stimulated histone hyperacetylation in the tumor, showed efficacy in inhibiting tumor growth and induced apoptosis in the tumor. This effect is likely mediated by modulation of levels of cell cycle regulators, by antagonism of the AKT pathway through IRS-1 downregulation, and by reduction of epidermal growth factor receptor levels.