This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yang, Y.-M. Articles by Chung, F.-L. Search for Related Content PubMed PubMed Citation Articles by Yang, Y.-M. Articles by Chung, F.-L. Related Collections Preclinical Intervention Preclinical Intervention: In Vitro: Drugs, Mechanisms

N-Acetylcysteine Conjugate of Phenethyl Isothiocyanate Enhances Apoptosis in Growth-Stimulated Human Lung Cells

¹ Divisions of Carcinogenesis and Molecular Epidemiology, American Health Foundation Cancer Center, Institute for Cancer Prevention, Valhalla and ² Brander Cancer Research Institute, New York Medical College, Hawthorne, New York

Requests for reprints: Yang-Ming Yang, Department of Medicine, New York Medical College, Valhalla, NY 10595. Phone: 914-594-4776; Fax: 914-594-4726; E-mail: yang-ming_yang{at}nymc.edu.

We previously showed that dietary treatment with the N-acetylcysteine conjugate of phenethyl isothiocyanate (PEITC-NAC) inhibited benzo(a)pyrene-induced lung tumorigenesis in A/J mice, and that tumor inhibition was associated with induction of activator protein-1 (AP-1) activity and stimulation of apoptosis in the lungs of mice. In the present study, we show that PEITC-NAC also induces apoptosis and AP-1 activity in human lung adenocarcinoma A549 cells, and that activation of AP-1 is important in PEITC-NAC induced apoptosis in these cells. PEITC-NAC induced AP-1 binding activity in A549 cells in a dose- and time-dependent manner; peak activity appeared at 10 µmol/L after 24 hours. At that time, flow cytometric analysis showed a sub-G₁ peak, indicating that 4.5% of the cells had undergone apoptosis. When wild-type c-jun cDNA was transfected into A549 cells, PEITC-NAC–mediated apoptosis was greatly increased in the c-jun–transfected cells compared with the control vector–transfected cells, based on cell morphology and analysis of DNA fragmentation. Furthermore, cells that were pretreated with 100 nmol/L 12-O-tetradecanoyl phorbol-13-acetate, and then treated with 25 µmol/L PEITC-NAC, underwent enhanced apoptosis compared with cells that were treated with PEITC-NAC alone; cells treated with 12-O-tetradecanoyl phorbol-13-acetate alone showed active cell growth without apoptosis. Bivariate flow cytometric analysis of DNA strand breaks versus DNA content showed that apoptosis induced by PEITC-NAC occurred predominantly in the G₂-M phase. These findings suggest that growth-stimulated cells with an elevated basal AP-1 activity, i.e., A549 cells transfected with wild-type c-jun or treated with a tumor promoter, were more sensitive to PEITC-NAC–mediated apoptosis. The observation that PEITC-NAC induces apoptosis predominantly in growth-promoted cells, such as neoplastic cells, suggests a selective mechanism by which PEITC-NAC inhibits lung carcinogenesis.

This article has been cited by other articles:

				L. Mi, Z. Xiao, B. L. Hood, S. Dakshanamurthy, X. Wang, S. Govind, T. P. Conrads, T. D. Veenstra, and F.-L. Chung Covalent Binding to Tubulin by Isothiocyanates: A MECHANISM OF CELL GROWTH ARREST AND APOPTOSIS J. Biol. Chem., August 8, 2008; 283(32): 22136 - 22146. [Abstract] [Full Text] [PDF]

				L. Mi, X. Wang, S. Govind, B. L. Hood, T. D. Veenstra, T. P. Conrads, D. T. Saha, R. Goldman, and F.-L. Chung The Role of Protein Binding in Induction of Apoptosis by Phenethyl Isothiocyanate and Sulforaphane in Human Non-Small Lung Cancer Cells Cancer Res., July 1, 2007; 67(13): 6409 - 6416. [Abstract] [Full Text] [PDF]

				D. Xiao, K. L. Lew, Y. Zeng, H. Xiao, S. W. Marynowski, R. Dhir, and S. V. Singh Phenethyl isothiocyanate-induced apoptosis in PC-3 human prostate cancer cells is mediated by reactive oxygen species-dependent disruption of the mitochondrial membrane potential Carcinogenesis, November 1, 2006; 27(11): 2223 - 2234. [Abstract] [Full Text] [PDF]