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Synergistic Inhibition of Lung Tumorigenesis by a Combination of Green Tea Polyphenols and Atorvastatin

Authors' Affiliations: ¹ Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey; ² Department of Biostatistics, School of Public Health, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey; and ³ Cancer Institute of New Jersey, New Brunswick, New Jersey

Requests for reprints: Chung S. Yang, Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854. Phone: 732-445-3400, ext. 244; Fax: 732-445-0687; E-mail: csyang{at}rci.rutgers.edu.

Purpose: The present study investigated the possible synergistic inhibitory effect of a novel combination of polyphenon E (PPE, a standardized green tea polyphenol preparation) and atorvastatin (trade name Lipitor) in a mouse tumorigenesis model and in human lung cancer H1299 and H460 cell lines.

Experimental Design: Female A/J mice were given two weekly i.p. injections of 4-(methylnitrosaminao)-1-(3-pyridyl)-1-butanone (150 mg/kg total dose); 1 week later, mice were treated with PPE (0.25% or 0.5% in drinking fluid), atorvastatin (200 or 400 ppm in diet), or PPE (0.25%) plus atorvastatin (200 ppm) for 16 weeks. The interaction of these two agents was also studied in human lung cancer H1299 and H460 cells.

Results: The individual agents, PPE or atorvastatin, were not effective in inhibiting lung tumorigenesis. The low-dose combination of PPE and atorvastatin, however, significantly reduced both the tumor multiplicity and tumor burden (by 56% and 55%, respectively, P < 0.05). Isobologram analysis of the interaction of the two agents indicated that the combination synergistically decreased tumor multiplicity (P = 0.0006) and tumor burden (P = 0.0009). The inhibition was associated with enhanced apoptosis and suppressed myeloid cell leukemia 1 (Mcl-1) level in adenoma as determined by immunohistochemistry and Western blots. Treatment with combinations of PPE and atorvastatin also synergistically decreased the number of viable H1299 and H460 cells as determined by isobologram analysis. This synergistic effect was associated with increased apoptosis as determined by the terminal deoxyribonucleotide transferase–mediated nick-end labeling assay. The combination of PPE and atorvastatin was more efficient in reducing the antiapoptotic protein Mcl-1 level and increasing the cleaved caspase-3 and cleaved poly(ADP)-ribose polymerase level than the single-agent treatment.

Conclusions: The present work showed that PPE and atorvastatin synergistically inhibited 4-(methylnitrosaminao)-1-(3-pyridyl)-1-butanone–induced lung tumorigenesis in mice and the growth of lung cancer H1299 and H460 cells, possibly through enhanced apoptosis. The results provide leads for future research on the application of this combination for the prevention and treatment of lung cancer.