Epigenetic regulation, specifically inhibition of histone deacetylases (HDACs), is a validated therapeutic target as shown by the recent approval of vorinostat and romidepsin for the treatment of cutaneous T cell lymphoma. Using bioassay-guided isolation and target identification, Liu et al. identified largazole as a marine cyanobacterial-derived antiproliferative prodrug that releases the potent HDAC inhibitor largazole thiol. Genes regulated by largazole overlap with those regulated by other HDAC inhibitors and interestingly include down-regulation of cyclin-dependent kinase 6 and its regulatory protein cyclin D1 and insulin receptor substrate 1 (IRS-1). Largazole strongly down-regulates IRS-1 both in vitro and in vivo. In vitro and in vivo, largazole induces apoptosis through inhibition of AKT phosphorylation, which may be a consequence of down-regulation of IRS-1. Unlike romidepsin, largazole thiol is stable in plasma, and the thiol, which is rapidly formed in the plasma, has direct antiproliferative activity, and largazole is well tolerated in vivo. Largazole represents a novel marine-derived HDAC inhibitor with potent in vitro activity and in vivo efficacy and the potential to investigate the role of HDACs in other disease indications where cellular reprogramming of transcription may be advantageous.
See article at J Pharmacol Exp Ther 2010, 335:351–361.
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