Chemoprevention by isothiocyanates

Abstract

Naturally occurring and synthetic isothiocyanates are among the most effective chemopreventive agents known. A wide variety of isothiocyanates prevents cancer in the rat lung, mammary gland, esophagus, liver, small intestine, colon, and bladder. Mechanistic studies have shown that this chemopreventive activity is due to favorable modification of phase I and phase II carcinogen metabolism, resulting in increased carcinogen excretion or detoxification and decreased carcinogen DNA interactions. Most studies reported that the isothiocyanate must be present at carcinogen exposure in order to effect tumorigenesis inhibition. Our studies focus on naturally occurring isothiocyanates phenethyl isothiocyanate (PEITC) and benzyl isothiocyanate (BITC) as lung cancer inhibitors. These studies employed the major lung carcinogens in tobacco smoke, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo(a)pyrene (BaP). Combining chemopreventive agents that inhibit tumorigenesis by NNK and BaP in rodents may be effective in addicted smokers. PEITC inhibits lung tumor induction by NNK in F-344 rats and A/J mice, while BITC inhibits BaP-induced lung tumorigenesis in A/J mice; combining the two inhibits lung tumorigenesis by combined NNK and BaP in A/J mice. PEITC selectively inhibits metabolic activation of NNK in the rodent lung, while inducing glucuronidation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), one of the major NNK metabolites. Thus, PEITC decreases DNA and hemoglobin adduct formation by NNK while increasing the amounts of NNAL and its glucuronide excreted in the urine. Presently available data indicate that non-toxic doses of PEITC can inhibit the metabolic activation and carcinogenicity of NNK in rat and mouse lung; BITC has similar effects on BaP activation and tumorigenicity in mouse lung. Thus, combinations of chemopreventive agents active against different carcinogens in tobacco smoke may be useful in the chemoprevention of lung cancer.