SR-31747

Cholesterol is a major lipid component of the plasma membrane in animal cells. In addition to its structural requirement, cholesterol is essential in cell proliferation and other cell processes. The aim of the present study was to elucidate the stringency of the requirement for cholesterol as a regulator of proliferation and cell cycle progression, compared with other sterols of the cholesterol biosynthesis pathway. Human promyelocytic HL-60 cells were cultured in cholesterol-free medium and treated with different distal inhibitors of cholesterol biosynthesis (zaragozic acid, SKF 104976, SR 31747, BM 15766, and AY 9944), which allow the synthesis of isoprenoid derivatives and different sets of sterol intermediates, but not cholesterol. The results showed that only the inhibition of sterol Delta7-reductase was compatible with cell proliferation. Blocking cholesterol biosynthesis upstream of this enzyme resulted in the inhibition of cell proliferation and cell cycle arrest selectively in G2/M phase.

SR31747A is currently being evaluated in phase IIb clinical trials for prostate cancer treatment. The molecule is a peripheral sigma ligand that binds four proteins in human cells, i.e. SRBP-1, sigma-2, HSI and its relative SRBP-2. SR31747A is a dual agent with both immunomodulatory and antiproliferative activities. The molecule blocks proliferation of human and mouse lymphocytes, modulates the expression of pro- and anti-inflammatory cytokines, and was shown to protect animals in vivo against acute and chronic inflammatory conditions such as acute graft-versus-host reaction, lethality induced by staphylococcal enterotoxin B and lipopolysaccharide or rheumatoid arthritis. Besides these immunomodulatory activities, the molecule also inhibits the proliferation of various tumor cell lines in vitro in a time- and concentration-dependent manner. In vivo, SR31747A has potent antitumoral activity as demonstrated against mammary and prostatic tumoral cell lines injected into nude mice, where both tumor incidence and growth were decreased by more than 40% following daily SR31747A treatment at 25 mg/kg i.p. The recent literature on SR31747A in cancer is reviewed here. We focus specifically on preclinical data obtained in vivo and on studies aimed at deciphering the mode of action of the molecule.