Thailandepsins: bacterial products with potent histone deacetylase inhibitory activities and broad-spectrum antiproliferative activities - PubMed (original) (raw)

. 2011 Oct 28;74(10):2031-8.

doi: 10.1021/np200324x. Epub 2011 Jul 27.

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Thailandepsins: bacterial products with potent histone deacetylase inhibitory activities and broad-spectrum antiproliferative activities

Cheng Wang et al. J Nat Prod. 2011.

Abstract

Histone deacetylase (HDAC) inhibitors have emerged as a new class of anticancer drugs, with one synthetic compound, SAHA (vorinostat, Zolinza; 1), and one natural product, FK228 (depsipeptide, romidepsin, Istodax; 2), approved by FDA for clinical use. Our studies of FK228 biosynthesis in Chromobacterium violaceum no. 968 led to the identification of a cryptic biosynthetic gene cluster in the genome of Burkholderia thailandensis E264. Genome mining and genetic manipulation of this gene cluster further led to the discovery of two new products, thailandepsin A (6) and thailandepsin B (7). HDAC inhibition assays showed that thailandepsins have selective inhibition profiles different from that of FK228, with comparable inhibitory activities to those of FK228 toward human HDAC1, HDAC2, HDAC3, HDAC6, HDAC7, and HDAC9 but weaker inhibitory activities than FK228 toward HDAC4 and HDAC8, the latter of which could be beneficial. NCI-60 anticancer screening assays showed that thailandepsins possess broad-spectrum antiproliferative activities with GI50 for over 90% of the tested cell lines at low nanomolar concentrations and potent cytotoxic activities toward certain types of cell lines, particularly for those derived from colon, melanoma, ovarian, and renal cancers. Thailandepsins thus represent new naturally produced HDAC inhibitors that are promising for anticancer drug development.

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Figures

Figure 1

Figure 1. Comparison of two homologous biosynthetic gene clusters and discrete genes necessary for the biosynthesis of FK228 (2) or thailandepsins A (6) and B (7)

Each gene cluster is depicted in a row, under which is the deduced respective modular biosynthetic pathway. A, ACP, AL, AT, C, DH, E, KR, KS, PCP and TE are standard abbreviations of the nonribosomal peptide synthetase (NRPS) or polyketide synthase (PKS) domain names whose full name and respective function can be found in Fischbach et al. Sfp and AT are the generic protein names of their respective genes defined in the main text.

Figure 2

Figure 2. Metabolic profiling of the wild type strain (BthWT) and BthΔ_tdpAB_ mutant strain of B. thailandensis E264

Panels a, b and c are the HPLC traces of extract of the medium control, BthWT strain or BthΔ_tdpAB_ strain, respectively. Panels d and e are ESI-LC-MS spectra of the HPLC Peak 1 and Peak 2 of the BthWT sample (Panel b). Panels f and g are ESI-LC-MS spectra of the reduced HPLC Peak 1 and Peak 2 of the BthWT sample (Panel b), showing a +2 m/z shift of every ion signal.

Figure 3

Figure 3. In vitro antiproliferative/cytotoxic activities of thailandepsins A (6) and B (7) in comparison with FK228 (2)

(a) Heat map representation of antiproliferative/cytotoxic activities of 6 and 7 across NCI-60 cell lines, with higher activity (lower index value) in warmer (darker if printed in black-white) color. GI50, growth-inhibition indicator; TGI, cytostatic effect indicator; LC50, cytotoxic effect indicator. Compound concentration in M was converted to log10 value for continuous color scale transformation. Mean panel response values were expressed in µM. (b) Statistics comparison of antiproliferation/cytotoxicity profile between 2, 6, and 7 across NCI-60 cell lines.

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