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BRCA1 Modulates Sensitivity to 5F-203 by Regulating Xenobiotic Stress-Inducible Protein Levels and EROD Activity

BRCA1 Modulates Sensitivity to 5F-203 by Regulating Xenobiotic Stress-Inducible Protein Levels and EROD Activity

Hyo Jin Kang, Hee Jeong Kim, Sang Hoon Kwon, Brian Donghoon Kang, Thomas E Eling, Sang Han Lee, Insoo Bae

Cancer Chemother Pharmacol. 2008 Sep;62(4):689-97.

PMID: 18074135

Abstract:

Purpose:
We have investigated the effects of BRCA1 over-expression and knockdown on 5F-203-induced gene expression and cytotoxicity in human breast cancer cells. 5F-203 is a chemotherapeutic prodrug that both induces a p450 enzyme, CYP1A1, and is metabolically activated by CYP1A1.
Methods:
We used several molecular biological techniques to confirm our findings. BRCA1 regulates sensitivity to 5F-203 by regulating the expression of CYP1A1 mRNA and its EROD activity. XRE-Luc reporter assays, semi-quantitative RT-PCR, Western blot analysis, EROD activity measurements, gene knockdown and MTT cell survival assays were used for this study.
Results:
Our results show that the ability of 5F-203 treatments to increase CYP1A1 mRNA level and CYP1A1 enzymatic activity (EROD activity) are affected by BRCA1 protein levels. In addition, the ability of 5F-203 treatments to induce proteins, P53 and P53 target genes such as P21, is significantly decreased in BRCA1 knockdown cells, suggesting that BRCA1-related effects could at least partially explain why BRCA1 knockdown increases resistance to 5F-203-mediated cytotoxicity. We also observed altered expression of the two major transcription factors (AhR and ARNT) that affect CYP1A1 expression when BRCA1 protein levels are altered.
Conclusion:
BRCA1 is an important protein, which affects 5F-203-mediated cytotoxicity. Our findings are potentially clinically significant; they suggest that those patients most likely to respond to this new prodrug will have tumors containing normal amounts of BRCA1.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP260443898	5F-203		260443-89-8	Price

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