PABA/NO, a lead anti-cancer agent of the O2-arylated diazeniumdiolate class, was designed to be preferentially metabolized by the p isoform of glutathione S transferases, (GSTP1). This compound has displayed significant cytotoxicity and anti- tumorigenic properties both in vitro and in vivo. Analogous compounds have been shown to be effective arylators of cellular thiols including glutathione (GSH). The de-arylation of the diazeniumdiolate and subsequent nitric oxide (NO) liberation results in an oxidative/nitrosative burst crucial for the initiation of cellular stress signaling pathways. Due to the inherent instability of the PABA group to hydrolysis at pH 7.4 a significant portion of the compound decomposes in the cell to form a phenolic compound which does not react with GSH, release NO, or display anti-proliferative activity in vitro.Docetaxel (DTX) has demonstrated activity in the treatment of a broad range of malignancies, including non-small cell lung cancer (NSCLC). Considerable numbers of patients, however, do not respond to the treatment. Analysis of nonresponders' tumor samples revealed elevated expression of genes controlling the cellular redox environment, glutathione and thioredoxin systems, including GSTP1. An oxidative burst prior to docetaxel treatment may sensitize cancer cells to its cytotoxicity resulting in a more efficacious therapy.The two aims of this project are as follows: 1) design new analogues of PABA/NO that have increased stability to both hydrolysis and uncatalyzed GSH metabolism, which should improve the GSTP1 selectivity and the anti-proliferative efficacy of the PABA/NO platform. 2) Evaluate the efficacy of these compounds in combination with clinically approved chemotherapeutics, such as docetaxel, with innate oxidative and DNA damaging properties.

GSTP1-activated O<sup>2</sup>-arylated diazeniumdiolate PABA/NO and second generation analogs enhance the cytotoxicity of docetaxel in nonsmall cell lung cancer (NSCLC) cells

246th National Meeting (2013)

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GSTP1-activated O2-arylated diazeniumdiolate PABA/NO and second generation analogs enhance the cytotoxicity of docetaxel in nonsmall cell lung cancer (NSCLC) cells

GSTP1-activated O²-arylated diazeniumdiolate PABA/NO and second generation analogs enhance the cytotoxicity of docetaxel in nonsmall cell lung cancer (NSCLC) cells