Orlistat Inhibits Cancer Growth

NEW YORK (Reuters Health) - The anti-obesity drug orlistat inhibits fatty acid synthase (FAS) in tumor cells, investigators in La Jolla, California, report in the March 15th issue of Cancer Research. Orlistat inhibited prostate cancer cell growth in vitro and in vivo, and preliminary studies showed efficacy in colon and breast cancer cell lines as well.

Using a new activity-based screening strategy developed by Activx Biosciences, Dr. Jeffrey W. Smith at The Burnham Institute and colleagues found that FAS is expressed in three prostate cancer cell lines but not in normal prostate epithelial cells.

Orlistat, which is marketed by Roche as Xenical, selectively inhibited FAS in prostate, colon, and breast cancer cells.

In an interview with Reuters Health, Dr. Smith noted that the "amazing technology" that allows drugs to be screened against "hundreds if not thousands of enzyme targets" was unavailable when Roche first developed Orlistat, and so the drug's effect on FAS had not been recognized.

Of three prostate cancer cell lines, orlistat's antiproliferative effects in vitro were most pronounced in PC-3 cells, although a slight effect was also observed in androgen-dependent LNCaP cells. Normal epithelial cells and fibroblasts were not affected.

Orlistat induced "substantial levels" of apoptosis in PC-3 and LNCaP cells, while more moderate effects were observed DU-145 cells.

The authors then examined the effect of Orlistat in vivo. After PC-3 cells were grown to 100 mm³ in mice, the animals were treated at 240 mg/kg/day intraperitoneally for 3 weeks. Tumor volume on day 28 was significantly smaller in treated animals versus untreated animals, while causing no apparent toxicity or weight loss.

Orlistat possesses extremely low oral bioavailability, the authors note, suggesting that a nonoral formulation will be required for treating tumors not affecting the GI tract.

"We are working with chemists at Texas A and M to synthesize other beta-lactones with higher bioavailability and more potency in inhibiting FAS," Dr. Smith told Reuters Health. They are also working to elucidate the mechanisms behind its differential effects on cell cycle arrest and apoptosis, and to develop additional antitumor targets.

Source: Cancer Res 2004;64. [ Google search on this article ]

MeSH Headings: Genital Neoplasms, Male : Neoplasms : Neoplasms by Site : Prostatic Neoplasms : Urogenital Neoplasms : Diseases