title: Dihydrolipoic acid inhibits skin tumor promotion through anti-inflammation and anti-oxidation.
abstract: alpha-Lipoic acid (LA) has been intensely investigated as a therapeutic agent for several diseases, including hepatic disorder and diabetic polyneuropathy. However, the effects of LA or its reduced form, dihydrolipoic acid (DHLA), on cancer chemoprevention has never been reported. In the present study, we examined the effects of DHLA/LA on the production of nitric oxide (NO) by inducible NO synthase (iNOS) and the formation of prostaglandin E2 (PGE(2)) by cyclooxygenase-2 (COX-2), two important mediators associated with inflammation. DHLA/LA significantly inhibited lipopolysaccharide (LPS)-induced NO and PGE(2) formation in RAW 264.7 cells. Meanwhile, treatment with DHLA/LA suppressed the expression of iNOS protein but, unexpectedly, did not affect or increase the expression of COX-2 protein. The in vivo anti-inflammatory and antitumor-promoting activities were evaluated by a topical 12-O-tetradecanoylphorbol 13-acetate (TPA) application to mouse skin with measurement of edema formation, epidermal thickness and hydrogen peroxide production. DHLA significantly inhibited the priming and activation stages of skin inflammation induced by a double TPA application, by decreasing the inflammatory parameters. Furthermore, DHLA inhibited DMBA (0.3 micromol)/TPA (2.0 nmol)-induced skin tumor formation by reducing the tumor incidence and tumor multiplicity. When applied topically onto the shaven backs of mice prior to TPA, DHLA markedly inhibited the expression of iNOS protein. DHLA also strongly and directly inhibited COX-2 activity. These results suggest that DHLA can be a possible chemopreventive agent in inflammation-associated tumorigenesis.
authors.affiliation: Institute of Biomedical Technology, Taipei Medical University, Taipei, Taiwan, ROC.
authors.forename: Yuan-Soon
authors.initials: YS
authors.lastname: Ho
authors.forename: Ching-Shu
authors.initials: CS
authors.lastname: Lai
authors.forename: Hsin-I
authors.initials: HI
authors.lastname: Liu
authors.forename: Sheng-Yow
authors.initials: SY
authors.lastname: Ho
authors.forename: Chein
authors.initials: C
authors.lastname: Tai
authors.forename: Min-Hsiung
authors.initials: MH
authors.lastname: Pan
authors.forename: Ying-Jan
authors.initials: YJ
authors.lastname: Wang
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004347:Drug Interactions; D005260:Female; D007249:Inflammation / Q000139:chemically induced; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000517:prevention & control*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D008063:Thioctic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D008070:Lipopolysaccharides; D009573:Nitrites; D008063:Thioctic Acid; C015144:dihydrolipoic acid; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate