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

  • M S Chua
  • E Kashiyama
  • T D Bradshaw
  • S F Stinson
  • E Brantley
  • E A Sausville
  • M F Stevens
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.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

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...

متن کامل

Fluorinated 2-(4-amino-3-methylphenyl)benzothiazoles induce CYP1A1 expression, become metabolized, and bind to macromolecules in sensitive human cancer cells.

Fluorinated 2-(4-amino-3-methylphenyl)benzothiazoles possess potent antiproliferative activity against certain cancer cells, similar to the unfluorinated 2-(4-amino-3-methylphenyl)benzothiazole (DF 203, NSC 674495). In "sensitive" cancer cells, DF 203 is metabolized by, can induce expression of, and binds covalently to CYP1A1. Metabolism appears to be essential for its antiproliferative activit...

متن کامل

CYP2S1 and CYP2W1 mediate 2-(3,4-dimethoxyphenyl)-5-fluorobenzothiazole (GW-610, NSC 721648) sensitivity in breast and colorectal cancer cells.

Both 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F-203; NSC 703786) and 2-(3,4-dimethoxyphenyl)-5-fluorobenzothiazole (GW-610; NSC 721648) are antitumor agents with novel mechanism(s). Previous studies have indicated that cytochrome (CYP) P450 1A1 is crucial for 5F-203 activity. In the present study, we investigated the functional role of 2 newly identified CYP P450 enzymes, CYP2S1 and C...

متن کامل

In vitro, in vivo, and in silico analyses of the antitumor activity of 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazoles.

Phortress is a novel, potent, and selective experimental antitumor agent. Its mechanism of action involves induction of CYP1A1-catalyzed biotransformation of 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203) to generate electrophilic species, which covalently bind to DNA, exacting lethal damage to sensitive tumor cells, in vitro and in vivo. Herein, we investigate the effects of DNA add...

متن کامل

Preclinical evaluation of amino acid prodrugs of novel antitumor 2-(4-amino-3-methylphenyl)benzothiazoles.

Novel 2-(4-aminophenyl)benzothiazoles (e.g., compounds 1 and 2) possess highly selective, potent antitumor properties in vitro and in vivo. Elucidation of the mechanism of action of this structurally simple class of compounds has occurred in parallel with selection of a candidate clinical agent. Antitumor benzothiazoles induce and are biotransformed by cytochrome P 450 1A1 to putative active, a...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • Cancer research

دوره 60 18  شماره 

صفحات  -

تاریخ انتشار 2000