PT  - JOURNAL ARTICLE
AU  - Anne Monks
AU  - Erik Harris
AU  - Curtis Hose
AU  - John Connelly
AU  - Edward A. Sausville
TI  - Genotoxic Profiling of MCF-7 Breast Cancer Cell Line Elucidates Gene Expression Modifications Underlying Toxicity of the Anticancer Drug 2-(4-Amino-3-methylphenyl)-5-fluorobenzothiazole
AID  - 10.1124/mol.63.3.766
DP  - 2003 Mar 01
TA  - Molecular Pharmacology
PG  - 766--772
VI  - 63
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/63/3/766.short
4100  - http://molpharm.aspetjournals.org/content/63/3/766.full
SO  - Mol Pharmacol2003 Mar 01; 63
AB  - A candidate antitumor agent, 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F-203), was empirically discovered through the National Cancer Institute's Anticancer Drug Screen from a unique growth inhibitory-response profile, indicating a novel mechanism of action. 5F-203 activates the CYP1 family of cytochrome P450, involving aryl hydrocarbon receptor translocation into the nucleus. To characterize more completely the pathways involved in 5F-203 toxicity, cDNA microarrays were used to determine gene expression changes in MCF-7, a 5F-203–sensitive breast cancer cell line, after treatment with 1 μM 5F-203. The mRNA expression of CYP1A1 and CYP1B1 were both increased approximately 20-fold after 24 h, but less after 6 h of treatment, confirming previous results. However, the most pronounced drug-induced change was in the PLAB gene, encoding one of the bone morphogenic proteins in the transforming growth factor-β (TGF-β) superfamily. Other induced gene expressions included the apoptosis-initiating receptor TNFRSF6 (CD95/FAS), the DNA-damage response genes CDKN1A (p21/Cip1), p53-induced gene-3, and DNA binding protein 2. In contrast, the transcription factor c-Myc showed reduced expression. Western blot analysis also showed induction of p53 protein expression in response to 5F-203 treatment. In contrast to the MCF-7 data, MDA-MB-435, a cancer cell line resistant to 5F-203, showed no change in expression of any of these genes or the p53 protein under the same conditions of 5F-203 treatment. These data are consistent with the idea that CYP1A1 and CYP1B1 activation leads to 5F-203 toxicity through DNA damage-induced apoptosis, as well as signaling through a variant member of the TGF-β superfamily.