Abstract
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 activity through DNA adduct formation. However, a biphasic dose-response relationship compromises its straightforward development as a chemotherapeutic agent. We investigated whether fluorinated benzothiazoles inhibit cancer cell growth without the biphasic dose-response, and whether the fluorinated benzothiazoles are also metabolized into reactive species, with binding to macromolecules in sensitive cancer cells. One fluorinated benzothiazole, 2-(4-amino-methylphenyl)-5-fluorobenzothiazole (5F 203, NSC 703786) did exhibit potent, antiproliferative activity without a biphasic dose-response. The fluorinated benzothiazoles were also metabolized only in cells, which subsequently showed evidence of cell death. We used microsomes from genetically engineered human B-lymphoblastoid cells expressing cytochromes P450 (CYP1A1, CYP1A2, or CYP1B1) to clarify the basis for fluorinated benzothiazole metabolism. 5F 203 induced CYP1A1 and CYP1B1 mRNA expression in sensitive breast and renal cancer cells, whereas 5F 203 induced CYP1A1 mRNA but not CYP1B1 mRNA expression in sensitive ovarian cancer cells. 5F 203 did not induce CYP1A1 or CYP1B1 mRNA expression in any “resistant” cancer cells. The fluorinated benzothiazoles induced CYP1A1 protein expression exclusively in sensitive cells. [14C]5F 203 bound substantially to subcellular fractions in sensitive cells but only minimally in resistant cells. These data are concordant with the antiproliferative activity of fluorinated benzothiazoles deriving from their ability to become metabolized and bind to macromolecules within sensitive cells.
Footnotes
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↵1 Current address: Consorzio Mario Negri Sud, Departimento di Biologia Cellulare e Oncologia via Nazionale, 66030 S. Maria Imbaro (CH).
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↵2 Current address: University of Maryland Greenebaum Cancer Center, 22 S. Greene Street, Baltimore, MD.
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Support was provided in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health and by the Cancer Research Campaign, United Kingdom.
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Disclaimer: The content of this article does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the U.S. government.
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This work was previously presented in abstract form at the 91st Annual American Association for Cancer Research meeting in San Francisco, California, April 1-5, 2000; the 92nd Annual American Association for Cancer Research meeting in New Orleans, Louisiana, March 24-28, 2001, and the 14th World Congress of Pharmacology meeting in San Francisco, California, July 7-12, 2002.
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This is part 25 of the series “Antitumor 2-(4-aminophenyl)benzothiazoles.”
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doi:10.1124/dmd.104.001057.
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ABBREVIATIONS: DF 203, 2-(4-amino-3-methylphenyl)benzothiazole (NSC 674495); 5F 203, 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (NSC 703786); 6F 203, 2-(4-amino-3-methylphenyl)-6-fluorobenzothiazole (NSC 702156); 5,6 di-F 203, 2-(4-amino-3-methylphenyl)-5,6-difluorobenzothiazole (711671); 4F 203, 2-(4-amino-3-methylphenyl)-4-fluorobenzothiazole (NSC 706705); 7F 203, 2-(4-amino-3-methylphenyl)-7-fluorobenzothiazole (NSC 711670); 6-OH 203, 2-(4-amino-3-methylphenyl)-6-hydroxybenzothiazole (NSC 703785); Phortress, lysylamide prodrug of 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole; DMSO, dimethyl sulfoxide; HPLC, high-performance liquid chromatography; MTT, 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide; AhR, aryl hydrocarbon receptor; QRT-PCR, quantitative real-time reverse transcription-polymerase chain reaction; TBS, Tween-buffered solution; GI50, concentration of compound needed to cause 50% growth inhibition; TGI, total growth inhibition; LC50, concentration of compound needed to cause 50% cell death (cytocidal activity); NCI, National Cancer Institute.
- Received June 24, 2004.
- Accepted September 3, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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