Inhibitory effects of oleic and docosahexaenoic acids on lung metastasis by colon-carcinoma-26 cells are associated with reduced matrix metalloproteinase-2 and -9 activities.
In order to determine the effects of single unsaturated fatty acids (UFAs) or combinations on establishment of lung metastatic colonies, UFAs were administered orally to CDF1 mice bearing s.c. implants of the highly metastatic colon carcinoma 26. Oleic acid (OA), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) demonstrated significant inhibition. In the case of DHA, this inhibitory potential was markedly reduced by co-administration of linoleic acid (LA) or EPA. Furthermore, while tumor cells treated with DHA showed a very low potential for lung colony formation when injected i.v., this again being partially reversed by co-administration of EPA. UFAs were found to be well absorbed into tumor tissues after oral administration, causing marked changes in relative levels, the arachidonic acid (AA) content, in particular, being markedly decreased by treatment with DHA or EPA, but not with DHA plus EPA or with DHA plus LA. Investigation of the gelatinolytic activity of the 57-kDa and 92-kDa isoforms of type-IV collagenase (MMP-2 and MMP-9, respectively) showed a clear reduction in the former by treatment with OA, while DHA, but not DHA plus LA or EPA, caused a decrease in the 92-kDa isoform, which was well correlated with AA content in tumor tissues (r = 0.900, p < 0.001). These results suggest that inhibition of metastasis due to treatment with OA and DHA might be due to depressed type-IV collagenase activity.
Suzuki
I
I
Chemotherapy Division, National Cancer Center Research Institute, Tokyo, Japan.
Iigo
M
M
Ishikawa
C
C
Kuhara
T
T
Asamoto
M
M
Kunimoto
T
T
Moore
M A
MA
Yazawa
K
K
Araki
E
E
Tsuda
H
H
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002277:Carcinoma / Q000378:metabolism* / Q000517:prevention & control / Q000556:secondary*; D017364:Collagenases / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000473:pathology*; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D015118:Eicosapentaenoic Acid / Q000494:pharmacology; D018093:Gelatinases / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000517:prevention & control / Q000556:secondary*; D008297:Male; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D019301:Oleic Acid / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014410:Tumor Stem Cell Assay
D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; D019301:Oleic Acid; D015118:Eicosapentaenoic Acid; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9