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.
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 anticancer drug discovery. The National Cancer Institute 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 the 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 of 1.6-18.2 microM), and compound 6 produced a unique pattern of tumor cell growth suppression. Five cell lines from different organs were hypersensitive to 6 (GI(50) values of 0.29-0.62 microM), and three others were moderately sensitive (GI(50) values of 2.2-5.1 microM), while the GI(50) values for most other cell lines ranged from 20 to 47 microM. Crinoid benzo[g]chromenones were also found to scavenge radicals in a modified DPPH assay.
Dai
Jingqiu
J
Department of Pharmacognosy, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi 38677-1848, USA.
Liu
Yang
Y
Jia
Hong
H
Zhou
Yu-Dong
YD
Nagle
Dale G
DG
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D001713:Biphenyl Compounds; D045744:Cell Line, Tumor; D003374:Coumarins / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004447:Echinodermata / Q000737:chemistry*; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors*; D008386:Marine Biology; D054547:National Cancer Institute (U.S.); D010219:Papua New Guinea; D010851:Picrates / Q000494:pharmacology; D014481:United States
D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D003374:Coumarins; D051793:Hypoxia-Inducible Factor 1; D010851:Picrates; C004931:1,1-diphenyl-2-picrylhydrazyl