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.