Role of Cyp1A1 in modulation of antitumor properties of the novel agent 2-(4-amino-3-methylphenyl)benzothiazole (DF 203, NSC 674495) in human breast cancer cells.
نویسندگان
چکیده
2-(4-Amino-3-methylphenyl)benzothiazole (DF 203, NSC 674495) is a candidate antitumor agent with potent and selective activity against human-derived tumor cell lines in vitro and in vivo. Only sensitive cell lines (e.g., MCF-7) were able to accumulate and metabolize DF 203, forming the main inactive metabolite, 2-(4-amino-3-methylphenyl)-6-hydroxybenzothiazole (6-OH 203). Selective metabolism may therefore underlie its antitumor profile. DF 203 6-hydroxylase activity by MCF-7 cells was not constitutive but induced only after pretreatment of cells with DF 203, 3-methylcholanthrene, or beta-naphthoflavone. 6-Hydroxylation was strongly inhibited by either goat antirat cytochrome P450 1A1 (CYP1A1) serum or alpha-naphthoflavone. Both alpha-naphthoflavone and 6-OH 203 abrogated DF 203-induced growth inhibition. Microsomes from genetically engineered human B-lymphoblastoid cells expressing CYP1A1, CYP1B1, or CYP2D6 metabolized DF 203 to 6-OH 203. Immunoblot analysis detected significantly enhanced CYP1A1 protein in a panel of sensitive breast cancer cell lines after exposure to DF 203. Neither constitutive expression nor induction of CYP1A1 protein was detected in nonresponsive breast (HBL 100, MDA-MB-435, and MCF-7/ADR) and prostate (PC 3 and DU 145) cancer cell lines. The expression of CYP1B1 was also modulated by DF 203 in the same sensitive cell lines. However, of the two isoforms, only CYP1A1 activity was irreversibly inhibited by DF 203 and significantly inhibited by 6-OH 203. In sensitive cell lines only, [14C]DF 203-derived radioactivity bound covalently to a Mr 50,000, protein which was immunoprecipitated by CYP1A1 antiserum. The covalent binding of [14C]DF 203 to recombinant CYP1A1 enzyme was NADPH-dependent and reduced by 6-OH 203 and glutathione. CYP1A1 appears essential for the metabolism of DF 203 and may have a pivotal, yet undefined, role in its antitumor activity.
منابع مشابه
Aryl hydrocarbon receptor mediates sensitivity of MCF-7 breast cancer cells to antitumor agent 2-(4-amino-3-methylphenyl) benzothiazole.
2-(4-Amino-3-methylphenyl) benzothiazole (NSC 674495; DF 203) demonstrates drug uptake and metabolism by tumor cells sensitive to the antiproliferative activity of the drug [J Med Chem 1999;42:4172-4184]. In insensitive cells, little metabolism occurs. Because CYP1A1 can metabolize DF 203, the aryl hydrocarbon receptor (AhR) may mediate drug action. We demonstrate here that DF 203 increases CYP...
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ورودعنوان ژورنال:
- Cancer research
دوره 60 18 شماره
صفحات -
تاریخ انتشار 2000