Sodwanone and yardenone triterpenes from a South African species of the marine sponge Axinella inhibit hypoxia-inducible factor-1 (HIF-1) activation in both breast and prostate tumor cells.
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. A T47D breast tumor cell-based reporter assay was used to evaluate the NCI Open Repository of marine invertebrates and algae lipid extracts for HIF-1 inhibitory activity. Bioassay-guided fractionation and isolation of an active extract from Axinella sp. yielded seven new sodwanone triterpenoids [3-epi-sodwanone K (1), 3-epi-sodwanone K 3-acetate (2), 10,11-dihydrosodwanone B (4), sodwanones T-W (3, 7, 8, 9)], the new yardenone triterpene 12R-hydroxyyardenone (10), and the previously reported compounds sodwanone A (5), sodwanone B (6), and yardenone (11). The structures and relative configurations of these Axinella metabolites were determined spectroscopically. The absolute configuration of 1 was determined by the modified Mosher ester procedure. Sodwanone V (8) inhibited both hypoxia-induced and iron chelator (1,10-phenanthroline)-induced HIF-1 activation in T47D breast tumor cells (IC50 15 microM), and 8 was the only sodwanone that inhibited HIF-1 activation in PC-3 prostate tumor cells (IC50 15 microM). Compounds 1, 3, 4, and 5 inhibited hypoxia-induced HIF-1 activation in T47D cells (IC50 values 20-25 microM). Compound 2 was cytotoxic to T47D cells (IC50 22 microM), and 8 showed cytotoxicity to MDA-MB-231 breast tumor cells (IC50 23 microM).
Dai
Jingqiu
J
Department of Pharmacognosy, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677-1848, USA.
Fishback
James A
JA
Zhou
Yu-Dong
YD
Nagle
Dale G
DG
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D008297:Male; D008386:Marine Biology; D015394:Molecular Structure; D011161:Porifera / Q000737:chemistry*; D011471:Prostatic Neoplasms / Q000378:metabolism; D013019:South Africa; D014315:Triterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology
D000970:Antineoplastic Agents; D051793:Hypoxia-Inducible Factor 1; D014315:Triterpenes