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Chemopreventive Effect of Kava on 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone plus Benzo[a]pyrene–Induced Lung Tumorigenesis in A/J Mice

Authors' Affiliations: Departments of ¹ Medicinal Chemistry and ² Biostatistics, University of Minnesota, and ³ University of Minnesota Cancer Center, Minneapolis, Minnesota; ⁴ Comparative Pathology Shared Resource, University of Minnesota Cancer Center, Department of Veterinary Population Medicine, University of Minnesota, St. Paul, Minnesota; and ⁵ Hormel Institute, University of Minnesota, Austin, Minnesota

Requests for reprints: Chengguo Xing, University of Minnesota, 8-101 WDH, 308 Harvard Street Southeast, Minneapolis, MN 55455. Phone: 612-626-5675; Fax: 612-624-0139; E-mail: xingx009{at}umn.edu.

Lung cancer is the leading cause of cancer death, and chemoprevention is a potential strategy to help control this disease. Epidemiologic survey indicates that kava may be chemopreventive for lung cancer, but there is a concern about its potential hepatotoxicity. In this study, we evaluated whether oral kava could prevent 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) plus benzo[a]pyrene (B[a]P)–induced lung tumorigenesis in A/J mice. We also studied the effect of kava to liver. At a dose of 10 mg/g diet, 30-week kava treatment (8 weeks concurrent with NNK and B[a]P treatment followed by 22 weeks post-carcinogen treatment) effectively reduced lung tumor multiplicity by 56%. Kava also reduced lung tumor multiplicity by 47% when administered concurrently with NNK and B[a]P for 8 weeks. Perhaps most importantly, kava reduced lung tumor multiplicity by 49% when administered after the final NNK and B[a]P treatment. These results show for the first time the chemopreventive potential of kava against lung tumorigenesis. Mechanistically, kava inhibited proliferation and enhanced apoptosis in lung tumors, as shown by a reduction in proliferating cell nuclear antigen (PCNA), an increase in caspase-3, and cleavage of poly(ADP-ribose) polymerase (PARP). Kava treatment also inhibited the activation of nuclear factor BNF-B, a potential upstream mechanism of kava chemoprevention. Although not rigorously evaluated in this study, our preliminary data were not suggestive of hepatotoxicity. Based on these results, further studies are warranted to explore the chemopreventive potential and safety of kava.

Key Words: kava • chemoprevention • lung • tumorigenesis • B[a]P • NNK • hepatotoxicity • proliferation • apoptosis • NF-êB

Commentary

Kava, a Tonic for Relieving the Irrational Development of Natural Preventive Agents

Rajesh Agarwal and Gagan Deep
Cancer Prevention Research 2008 1: 409-412. [Full Text] [PDF]