title: CYP2S1 and CYP2W1 mediate 2-(3,4-dimethoxyphenyl)-5-fluorobenzothiazole (GW-610, NSC 721648) sensitivity in breast and colorectal cancer cells.
abstract: 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 CYP2W1, in mediating antitumor activity of benzothiazole compounds. We generated isogenic breast cancer (MDA-MB-468, MCF-7) and colorectal cancer (CRC; KM12 and HCC2998) cell lines depleted for CYP1A1, CYP2S1, or CYP2W1. The sensitivity of these cells to 5F-203 and GW-610 was then compared with vector control cells. 5F-203 exhibited potent activity against breast cancer cells, whereas GW-610 was effective against both breast and colorectal cancer cells. CYP1A1 was induced in both breast cancer and CRC cells, while CYP2S1 and CYP2W1 were selectively induced in breast cancer cells only following treatment with 5F-203 or GW-610. Depletion of CYP1A1 abrogated the sensitivity of breast cancer and CRC cells to 5F-203 and GW-610. Although depletion of CYP2S1 sensitized both breast cancer and CRC cells toward 5F-203 and GW-610, CYP2W1 knockdown caused marked resistance to GW-610 in CRC cells. Our results indicate that CYP-P450 isoforms, with the exception of CYP1A1, play an important role in mediating benzothiazole activity. CYP2S1 appears to be involved in deactivation of benzothiazoles, whereas CYP2W1 is important for bioactivation of GW-610 in CRC cells. Because CYP2W1 is highly expressed in colorectal tumors, GW-610 represents a promising agent for CRC therapy.
authors.affiliation: School of Postgraduate Studies and Research, International Medical University, 126 Jalan 19/155B, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.
authors.forename: Boon Shing
authors.initials: BS
authors.lastname: Tan
authors.forename: Kai Hung
authors.initials: KH
authors.lastname: Tiong
authors.forename: Ashwin
authors.initials: A
authors.lastname: Muruhadas
authors.forename: Nirmal
authors.initials: N
authors.lastname: Randhawa
authors.forename: Heng Lungh
authors.initials: HL
authors.lastname: Choo
authors.forename: Tracey D
authors.initials: TD
authors.lastname: Bradshaw
authors.forename: Malcolm F G
authors.initials: MF
authors.lastname: Stevens
authors.forename: Chee-Onn
authors.initials: CO
authors.lastname: Leong
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D052160:Benzothiazoles / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D013844:Thiazoles / Q000494:pharmacology
chemical_list: C507816:2-(3,4-dimethoxyphenyl)-5-fluorobenzothiazole; C425784:2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole; D000970:Antineoplastic Agents; D052160:Benzothiazoles; D013844:Thiazoles; D003577:Cytochrome P-450 Enzyme System; C422564:CYP2S1 protein, human; C569463:CYP1A1 protein, human; C509336:CYP2W1 protein, human; D019363:Cytochrome P-450 CYP1A1; D000072467:Cytochrome P450 Family 2