Benzochromenones from the Marine Crinoid Comantheria rotula Inhibit Hypoxia-Inducible Factor-1 (HIF-1) in Cell-Based Reporter Assays and Differentially Suppress the Growth of Certain Tumor Cell Lines

Abstract

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that promotes tumor cell adaptation and survival under hypoxic conditions. HIF-1 is currently recognized as an important molecular target for anti-cancer drug discovery. The NCI Open Repository of marine invertebrates and algae lipid extracts was evaluated using a T47D breast tumor cell-based reporter assay for HIF-1 inhibitory activity. Bioassay-guided fractionation of an active extract from a crinoid Comantheria rotula yielded seven benzo[g]chromen-4-one and benzo[h]chromen-4-one pigments (1-7). The structures of the new benzo[g]chromenone dimer 9,9'-oxybis-neocomantherin (1) and another new natural pigment 5 were deduced from spectroscopic and spectrometric data. The crinoid pigments significantly inhibited both hypoxia-induced and iron chelator-induced HIF-1 luciferase reporter activity in breast and prostate tumor cells. However, inhibition of HIF-1 in the reporter assay did not translate into a significant decrease in expression of the downstream HIF-1 target secreted vascular endothelial growth factor (VEGF). Compound 1 was found to inhibit tumor cell growth in the NCI 60-cell line panel (GI 50 values 1.6 to 18.2 μM) and 6 produced a unique pattern of tumor cell growth suppression. Five cell lines from different organs were hypersensitive to 6 (GI 50 values 0.29 to 0.62 μM) and three others were moderately sensitive (GI 50 values 2.2 to 5.1 μM), while the GI 50 values for most other cell lines ranged from 20 to 47 μM. Crinoid benzo[g]chromenones were also found to scavenge radicals in a modified DPPH assay.

The novel Akt inhibitor Palomid 529 (P529) enhances the effect of radiotherapy in prostate cancer

“…This drug is a derivative of 3-hydroxy dibenzo [b,d]pyran-6-one, which was previously described to share structural similarities with the potent antiangiogenic and antitumour compound 2-methoxyestradiol, and to exhibit selective antiproliferative activity for endothelial cells (Schmidt et al, 2003). Recently, benzochromenones were reported to differentially suppress the growth of certain tumour cell lines (Dai et al, 2007). In addition, P529 showed to reduce tumour growth, angiogenesis, and vascular permeability in an in vivo model of glioblastoma (Xue et al, 2008).…”

Marine natural products as inhibitors of hypoxic signaling in tumors

“…Bioassay-guided fractionation of the extract yielded seven benzo[ g ]chromen-4-one and benzo[ h ]chromen-4-one pigments ( 2 – 8 ) (Dai et al, 2007a). The crinoid pigments significantly inhibited both hypoxia-induced (IC 50 values 1.7 to 7.3 μ M) and iron chelator-induced HIF-1-dependent luciferase reporter activity (IC 50 values 0.6 to 3.0 μ M) in T47D cells.…”

“…Since hypoxia-induced HIF-1 signaling is believed to be regulated, at least in part, by the ROS species generated by mitochondrial ETC complex III, it was postulated that certain types of radical scavengers may be able to inhibit HIF-1 signaling. The crinoid compounds 2 – 8 were evaluated for their radical scavenging ability using a modified 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical assay (Dai et al, 2007a). Benzochromenones 2 – 5 and 7 were found to have about 40% of the DPPH radical scavenging capacity of Trolox, a commercially available standard radical scavenger, in a modified DPPH assay.…”

Anti-Inflammatory and Analgesic Effects of the Marine-Derived Compound Comaparvin Isolated from the Crinoid Comanthus bennetti

“…Gymnochrome D and isogymnochrome D, isolated from Gymnocrinus richeri, have shown potential activity against dengue virus [10]. Benzochromenones obtained from Comantheria rotula could inhibit tumor growth through inhibition of the expression of hypoxia-inducible factor-1 (HIF-1) [11]. Tetrabromospirocyclohexadienylisoxazole compounds obtained from Himerometra magnipinna can inhibit Streptomyces [12].…”