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Aryl hydrocarbon receptor mediates sensitivity of MCF-7 breast cancer cells to antitumor agent 2-(4-amino-3-methylphenyl) benzothiazole

  1. Author:
    Loaiza-Perez, A. I.
    Trapani, V.
    Hose, C.
    Singh, S. S.
    Trepel, J. B.
    Stevens, M. F. G.
    Bradshaw, T. D.
    Sausville, E. A.

  2. Author Address

    NCI, Dev Therapeut Program, Div Canc Treatment & Diag, NIH, 9000 Rockville Pike, Bldg 10 Rm 6N115, Bethesda, MD 20892 USA. NCI, Dev Therapeut Program, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. NCI, Med Branch, NIH, Bethesda, MD 20892 USA. NCI, Dev Therapeut Program, Div Canc Treatment & Diag, NIH, Frederick, MD 20892 USA. Univ Nottingham, Sch Pharmaceut Sci, Canc Res Labs, Nottingham, England. Loaiza-Perez AI NCI, Dev Therapeut Program, Div Canc Treatment & Diag, NIH, 9000 Rockville Pike, Bldg 10 Rm 6N115, Bethesda, MD 20892 USA.
    1. Year: 2002
  2. Journal: Molecular Pharmacology
    1. 61
    2. 1
    3. Pages: 13-19
  4. Type of Article: Article
  1. Abstract:

    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 CYP1A1 and CYP1B1 transcription in sensitive MCF-7 cells, accompanied by AhR translocation to the nucleus, increase in xenobiotic-responsive element (XRE)-driven luciferase activity, and induction of protein/DNA complexes on the XRE sequence of the CYP1A1 promoter. MDA-MB-435 and PC3 cells, resistant to DF 203, did not show drug-induced CYP1A1 and CYP1B1 gene expression. AhR was observed to be constitutively localized in the nucleus, with no induction of XRE-driven luciferase activity in transiently transfected cells and weak or no induction of protein/DNA complexes on the XRE sequence of CYP1A1. Taken together, these data elucidate a novel basis for antitumor drug action: induction in sensitive cells of a metabolizing system for the drug itself. These results suggest that clarification of the basis for differential engagement of AhR-related signaling in different tumor cell types may aid in further preclinical development and perhaps early clinical studies.

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