The Selectivity of Austocystin D Arises from Cell-Line-Specific Drug Activation by Cytochrome P450 Enzymes

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• 作者：Kevin M. Marks ; Eun Sun Park ; Alexander Arefolov ; Katie Russo ; Keiko Ishihara ; Jennifer E. Ring ; Jon Clardy ; Astrid S. Clarke ; Henry E. Pelish
• 刊名：Journal of Natural Products
• 出版年：2011
• 出版时间：April 25, 2011
• 年：2011
• 卷：74
• 期：4
• 页码：567-573
• 全文大小：921K
• 年卷期：v.74,no.4(April 25, 2011)
• ISSN：1520-6025

文摘

The natural product austocystin D was identified as a potent cytotoxic agent with in vivo antitumor activity and selectivity for cells expressing the multidrug resistance transporter MDR1. We sought to elucidate the mechanism of austocystin D鈥檚 selective cytotoxic activity. Here we show that the selective cytotoxic action of austocystin D arises from its selective activation by cytochrome P450 (CYP) enzymes in specific cancer cell lines, leading to induction of DNA damage in cells and in vitro. The potency and selectivity of austocystin D is lost upon inhibition of CYP activation and does not require MDR1 expression or activity. Furthermore, the pattern of cytotoxicity of austocystin D was distinct from doxorubicin and etoposide and unlike aflatoxin B₁, a compound that resembles austocystin D and is also activated by CYP enzymes to induce DNA damage. Theses results suggest that austocystin D may be of clinical benefit for targeting or overcoming chemoresistance.