Inhibition of tumor cell growth by monoterpenes in vitro: evidence of a Ras-independent mechanism of action.
(+)-Limonene (d-limonene) and related monoterpenes show chemopreventive activity against rodent mammary carcinoma and inhibit the growth of cancer cells in vitro. One suggested mechanism for the anti-tumorigenic effect of (+)-limonene is inhibition of the post-translational isoprenylation of growth controlling Ras oncoproteins. We have here examined the growth inhibitory effect of (+)-limonene and other related monoterpenes 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 (+)-perillic acid methyl ester were all found to efficiently inhibit cell growth at 1 mM, whereas (+)-limonene caused an approximately 50% growth reduction at 5 mM. Whereas BZA-5B, 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 activity or collagenase promoter activity in PANC-1 cells, two functions known to be down-stream from Ras. We conclude that although effective in inhibiting the growth of tumor cells harboring activated ras oncogenes, limonene and (+)-perillyl alcohol are unlikely to act by inhibiting Ras function.
Karlson
J
J
Department of Oncology, Karolinska Hospital, Stockholm, Sweden.
Borg-Karlson
A K
AK
Unelius
R
R
Shoshan
M C
MC
Wilking
N
N
Ringborg
U
U
Linder
S
S
D019883:Alkyl and Aryl Transferases; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D017364:Collagenases / Q000235:genetics; D053138:Cyclohexenes; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051231:Farnesyltranstransferase; D005347:Fibroblasts / Q000187:drug effects; D011905:Genes, ras; D000077222:Limonene; D039821:Monoterpenes; D009842:Oligopeptides / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011401:Promoter Regions, Genetic; D051381:Rats; D013729:Terpenes / Q000494:pharmacology*; D014166:Transferases / Q000037:antagonists & inhibitors; D018631:ras Proteins / Q000378:metabolism / Q000502:physiology*
D000970:Antineoplastic Agents; C090156:BZA 5B; D053138:Cyclohexenes; D004791:Enzyme Inhibitors; D039821:Monoterpenes; D009842:Oligopeptides; D013729:Terpenes; D001569:Benzodiazepines; C032208:perillyl alcohol; D000077222:Limonene; D014166:Transferases; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D017364:Collagenases; D018631:ras Proteins