Role of Nitric Oxide in the Chemistry and Anticancer Activity of Etoposide (VP-16,213)
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- 作者：Birandra K. Sinha ; Suchandra Bhattacharjee ; Saurabh Chatterjee ; JinJie Jiang ; Ann G. Motten ; Ashutosh Kumar ; Michael Graham Espey ; Ronald P. Mason
- 刊名：Chemical Research in Toxicology
- 出版年：2013
- 出版时间：March 18, 2013
- 年：2013
- 卷：26
- 期：3
- 页码：379-387
- 全文大小：358K
- 年卷期：v.26,no.3(March 18, 2013)
- ISSN：1520-5010
文摘
Originally identified as an innate cytotoxin, nitric oxide (p>路 p>NO) formation in tumors can influence chemotherapy and exacerbate cancer progression. Here, we examined the hypothesis that p>路 p>NO generation contributes to cancer cell drug resistance toward the widely used anticancer drug Etoposide (VP-16). The UV鈥搗is spectrum of VP-16 was not changed by exposure of VP-16 to p>路 p>NO in aqueous buffer. In contrast, reddish-orange compound(s) characteristic of o-quinone- and nitroso-VP-16 were readily generated in a hydrophobic medium (chloroform) in an oxygen-dependent manner. Similar products were also formed when the VP-16 radical, generated from VP-16 and horseradish peroxidase/H2O2, was exposed directly to p>路 p>NO in chloroform in the presence of oxygen. Separation and spectral analysis of VP-16 reaction extracts by electron spin resonance and UV鈥搗is indicated the generation of the phenoxy radical and the o-quinone of VP-16, as well as putative nitroxide, iminoxyl, and other nitrogen oxide intermediates. Nitric oxide products of VP-16 displayed significantly diminished topoisomerase II-dependent cleavage of DNA and cytotoxicity to human HL-60 leukemia cells. LPS-mediated induction of nitric oxide synthase in murine macrophages resulted in VP-16 resistance compared to Raw cells. Furthermore, p>路 p>NO products derived from iNOS rapidly reacted with VP-16 leading to decreased DNA damage and cytotoxicity. Together, these observations suggest that the formation of p>路 p>NO in tumors (associated macrophages) can contribute to VP-16 resistance via the detoxification of VP-16.