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

摘要

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 (GI50 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 (GI50 values 0.29 to 0.62 μM) and three others were moderately sensitive (GI50 values 2.2 to 5.1 μM), while the GI50 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.