GSTP1-activated nitric oxide (NO)-releasing prodrug PABA/NO enhances effectiveness of docetaxel in non-small-cell lung cancer (NSCLC) cells

Monday, October 24, 2011 — Poster Session I
Noon – 2:00 p.m.	Natcher Conference Center	NCI	BIOCHEM/CHEM-15

Authors

• AE Maciag
• C Luthers
• RJ Holland
• L Shi
• LW Fornwald
• JE Saavedra
• PJ Sinko
• RK Prud'homme
• LK Keefer

Abstract

Docetaxel, a semisynthetic taxane, has demonstrated activity in the treatment of a broad range of malignancies, including 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 glutathione S-transferase P1 (GSTP1). Diazeniumdiolate-based nitric oxide (NO)-releasing prodrugs are a growing class of promising NO-based cancer therapeutics. PABA/NO, an O2-arylated diazeniumdiolate, was designed using a structure-based modeling approach to generate cytotoxic NO upon activation by GSTP1, and has shown tumoristatic activity in ovarian cancer xenografts. We hypothesized that treatment of NSCLC cells highly expressing GSTP1 with PABA/NO may enhance effectiveness of docetaxel through depletion of glutathione and increase in oxidative/nitrosative stress. We tested this hypothesis in vitro, in NSCLC cell lines. All cell lines exhibited enhanced lethality in response to the combination of the drugs. Docetaxel alone induced cell cycle arrest, while combination with PABA/NO resulted in apoptotic cell death. For in vivo treatments we formulated both drugs in nanoparticles, to achieve concurrent delivery to the cancer cells. Stability and cellular metabolism of the formulated drugs were studied using mass spectrometry techniques. Evaluation of in vivo efficacy is in progress.

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