INHIBITION OF TUMOR-CELL GROWTH BY MONOTERPENES IN-VITRO - EVIDENCE OF A RAS-INDEPENDENT MECHANISM OF ACTION

(+)-Limonene (d-limonene) and related monoterpenes show chemopreventiv e activity against rodent mammary carcinoma and inhibit the growth of cancer cells in vitro, One suggested mechanism for the anti-tumorigeni c effect of (+)-limonene is inhibition of the post-translational isopr enylation of growth controlling Pas oncoproteins. We have here examine d the growth inhibitory effects of (+)-limonene and other related mono terpenes on PANC-1 pancreas carcinoma cells (carrying a K-ras mutation ) and on 12V-H-ras-transformed rat fibroblasts, (+)- and (-)-perillyl alcohol, 7-methyl-perillyl alcohol, (+)-limonene oxide and (+)-perilli c acid methyl ester were all found to efficiently inhibit cell growth at 1 mM, whereas (+)-limonene caused an approximately 50% growth reduc tion at 5 mM, Whereas BZA-BB, an inhibitor of Ras farnesyl transferase , was found to induce morphological reversion of 12v-H-ras-transformed cells, (+)-perillyl alcohol and (+)-limonene did not induce reversion . Furthermore, monoterpenes did not decrease MAP kinase enzyme activit y or collagenase promoter activity in PANC-1 cells, two functions know n to be down-stream from Pas, We conclude that although effective in i nhibiting the growth of tumor cells harboring activated res oncogenes, limonene and (+)-perillyl alcohol are unlikely to act by inhibiting R as function.