Advances in molecular signaling mechanisms of ß-phenethyl isothiocyanate antitumor effects.

ß-Phenethyl isothiocyanate (PEITC) is an important phytochemical from cruciferous vegetables and is being evaluated for chemotherapeutic activity in early phase clinical trials. Moreover, studies in cell culture and in animals found that the anticarcinogenic activities of PEITC involved all the major stages of tumor growth: initiation, promotion, and progression. A number of mechanisms have been proposed for the chemopreventive activities of this compound. Here, we focus on the major molecular signaling pathways for the anticancer activities of PEITC. These include (1) activation of apoptosis pathways; (2) induction of cell cycle arrest; and (3) inhibition of the survival pathways. Furthermore, we also discussed the regulation of drug-metabolizing enzymes, including cytochrome P450s, metabolizing enzymes, and multidrug resistance.

Preferential induction of CYP1A1 over CYP1B1 in human breast cancer MCF-7 cells after exposure to berberine.

Estrogens are considered the major breast cancer risk factor, and the carcinogenic potential of estrogens might be attributed to the DNA modification caused by derivatives formed during metabolism. 17ß-estradiol (E2), the main steroidal estrogen present in women, is metabolized via two major pathways: formation of the 2-hydroxyestradiol (2-OH E2) and 4-hydroxyestradiol (4-OH E2) through the action of Cytochrome P450 (CYP) 1A1 and 1B1, respectively. Previous reports suggested that 2-OH E2 have putative protective effects, while 4-OH E2 is genotoxic and has potent carcinogenic activity. Thus, the ratio of 2-OH E2/4-OH E2 is a critical determinant of the toxicity of E2 in mammary cells. In the present study, we investigated the effects of the berberine on the expression profile of the estrogen metabolizing enzymes CYP1A1 and CYP1B1 in breast cancer MCF-7 cells. Berberine treatment produced significant induction of both forms at the level of mRNA expression, but with increased doses produced 16~ to 52~fold greater inductions of CYP1A1 mRNA over CYP1B1 mRNA. Furthermore, berberine dramatically increased CYP1A1 protein levels but did not influence CYP1B1 protein levels in MCF-7 cells. In conclusion, we present the first report to show that berberine may provide protection against breast cancer by altering the ratio of CYP1A1/CYP1B1, could redirect E2 metabolism in a more protective pathway in the breast cancer MCF-7 cells.