Abstract C75: CYP2S1 and CYP2W1 mediate 2-(3,4-dimethoxyphenyl)-5-fluorobenzothiazole (GW610, NSC 721648) sensitivity in breast and colorectal cancer cells.

Abstract

Abstract Phortress, the lysylamide prodrug of 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F203, NSC 703786) is under clinical evaluation. CYP1A1-catalyzed bioactivation of 5F203 is crucial for antitumor activity. 2-(3,4-Dimethoxyphenyl)-5-fluorobenzothiazole (GW610, NSC 721648) is a structurally related experimental antitumor agent. In order to understand the mechanism of action of GW610, we investigated roles of cytochrome P450 enzymes CYP2S1 and CYP2W1 in mediating benzothiazoles activity. Stable isogenic breast (MCF-7, MDA-MB-468) and colorectal (HCC2998, KM12) cancer cell lines depleted for CYP1A1, CYP2S1 or CYP2W1 were generated. The sensitivity of these cells to 5F203 and GW610 was compared with vector control cells. 5F203 exhibited potent activity against breast cancer cells, whereas GW610 was effective against both breast and colorectal carcinoma cells. CYP1A1 was induced in breast and colon cancer cells, whereas induction of CYP2S1 and CYP2W1 was observed in breast cancer cells only following treatment with 5F203 or GW610. Depletion of CYP1A1 abrogated 5F203 and GW610 activity; in contrast, CYP2S1 depletion enhanced sensitivity of breast and colon cancer cells to 5F203 and GW610. Intriguingly, CYP2W1 knockdown caused marked resistance to GW610 in HCC2998 (>7-fold) and KM12 (>90-fold) colorectal cancer cells only. The results indicate that CYP2S1 is involved in deactivation of benzothiazoles, but CYP2W1, expressed in colorectal tumors and a putative therapeutic target, is important for bioactivation of GW610 in colorectal carcinoma cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C75.