Carcinogenesis Advance Access originally published online on August 18, 2006
Carcinogenesis 2007 28(1):163-173; doi:10.1093/carcin/bgl145
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Pomegranate fruit extract inhibits prosurvival pathways in human A549 lung carcinoma cells and tumor growth in athymic nude mice
Department of Dermatology, University of Wisconsin Madison, WI 53706, USA
*To whom correspondence should be addressed. Helfaer Professor of Cancer Research, Director and Vice Chair of Research, Department of Dermatology, University of Wisconsin-Madison, 1300, University Avenue, Medical Sciences Center, B-25, Madison, WI 53706, USA. Tel: +1 608 263 3927; Fax: +1 608 263 5223; Email: hmukhtar{at}wisc.edu
Developing novel mechanism-based chemopreventive approaches for lung cancer through the use of dietary substances which humans can accept has become an important goal. In the present study, employing normal human bronchial epithelial cells (NHBE) and human lung carcinoma A549 cells, we first compared the growth inhibitory effects of pomegranate fruit extract (PFE). Treatment of PFE (50–150 µg/ml) for 72 h was found to result in a decrease in the viability of A549 cells but had only minimal effects on NHBE cells as assessed by the MTT and Trypan blue assays. PFE treatment of A549 cells also resulted in dose-dependent arrest of cells in G0–G1 phase of the cell cycle (as assessed by DNA cell cycle analysis). We further found that PFE treatment also resulted in (i) induction of WAF1/p21 and KIP1/p27, (ii) decrease in the protein expressions of cyclins D1, D2 and E, and (iii) decrease in cyclin-dependent kinase (cdk) 2, cdk4 and cdk6 expression. The treatment of cells with PFE inhibited (i) phosphorylation of MAPK proteins, (ii) inhibition of PI3K, (iii) phosphorylation of Akt at Thr308, (iv) NF-
B and IKK
, (v) degradation and phosphorylation of IB, and (vi) Ki-67 and PCNA. We also found that PFE treatment to A549 cells resulted in inhibition of NF-B DNA-binding activity. Oral administration of PFE (0.1 and 0.2%, wt/vol) to athymic nude mice implanted with A549 cells resulted in a significant inhibition in tumor growth. Our results provide a suggestion that PFE can be a useful chemopreventive/chemotherapeutic agent against human lung cancer.
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  N. Khan, F. Afaq, M.-H. Kweon, K. Kim, and H. Mukhtar Oral Consumption of Pomegranate Fruit Extract Inhibits Growth and Progression of Primary Lung Tumors in Mice Cancer Res., April 1, 2007; 67(7): 3475 - 3482. [Abstract] [Full Text] [PDF]
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