Inhibitory Effect of Cigarette Smoke Extract on Experimental Lung Metastasis of Mouse Melanoma by Suppressing Tumor Invasion


We investigated the effect of a nicotine-and tar-free cigarette smoke extract (CSE) using an experimental metastasis mouse model which was intravenously injected with B16-BL6 mouse melanoma cells. Three-hour pretreatment of cells with various concentrations of CSE (0, 0.1, 0.3, and 1%) dose-dependently reduced the number of lung metastatic nodules 14 days after tumor injection. To elucidate the mechanism of this anti-metastatic effect of CSE, we examined the invasion and migration activities of B16-BL6 cells pretreated with CSE for three hours in vitro. CSE significantly reduced the invasion of cells at 1% and the migration at 0.3% and 1%. Under the same pretreatment conditions, CSE had no effect on the proliferation of cells. These findings suggest that CSE contains some ingredients that suppress hematogenic lung metastasis via inhibition of the invasion and migration activities of mouse melanoma cells.

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Y. Takahashi, S. Horiyama, Y. Kimoto, N. Yoshikawa, M. Kunitomo, S. Kagota, K. Shinozuka and K. Nakamura, "Inhibitory Effect of Cigarette Smoke Extract on Experimental Lung Metastasis of Mouse Melanoma by Suppressing Tumor Invasion," Pharmacology & Pharmacy, Vol. 3 No. 3, 2012, pp. 316-321. doi: 10.4236/pp.2012.33042.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] National Institutes of Health (US), “Tobacco and the Clinician: Interventions for Medical and Dental Practice,” Bethesda (MD), US Department of Health, NIH Publication No. 94-3693, 1994.
[2] US Office on Smoking and Health, “Smoking and Health: A Report of the Surgeon General,” Washington (DC), US Department of Health, Education, and Welfare, DHEW Publication No. 79-50066, 1979.
[3] R. Davis, W. Rizwani, S. Banerjee, M. Kovacs, E. Haura, D. Coppola and S. Chellappan, “Nicotine Promotes Tumor Growth and Metastasis in Mouse Models of Lung Cancer,” PLoS One, Vol. 4, 2009, p. e7524. doi:10.1371/journal.pone.0007524
[4] R. Gopalakrishna, Z. H. Chen and U. Gundimeda, “Tobacco Smoke Tumor Promoters, Catechol and Hydroquinone, Induce Oxidative Regulation of Protein Kinase C and Influence Invasion and Metastasis of Lung Carcinoma Cells,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 91, No. 25, 1994, pp. 12233-12237.
[5] K. A. E. I. Sayed and P. W. Sylvester, “Biocatalytic and Semisynthetic Studies of the Anticancer Tobacco Cembranoids,” Expert Opinion on Investiga-tional Drugs, Vol. 16, No. 6, 2007, pp. 877-887.
[6] Y. Saito, H. Takizawa, S. Konishi, D. Yoshida and S. Mizusaki, “Identification of Cembratriene-4,6-diol as Antitu-mor-Promoting Agent from Cigarette Smoke,” Carcino-genesis, Vol. 6, No. 8, 1985, pp. 1189-1194. doi:10.1093/carcin/6.8.1189
[7] K. A. E. I. Sayed, S. Laphookhieo, H. N. Baraka, M. Yousaf, A. Hebert, D. Bagaley, F. A. Rainey, A. Muralidharan, S. Thomas and G. V. Shah, “Biocatalytic and Semisynthetic Optimization of the Anti-Invasive Tobacco (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol, Bio-organic and Medical Chemistry, Vol. 16, No. 6, 2008, pp. 2886-2893.
[8] M. Yokode, T. Kita, H. Arai, C. Kawai, S. Narumiya and M. Fujiwara, “Cholesteryl Ester Accumulation in Macrophages Incubated with Low Density Lipoprotein Pretreated with Cigarette Smoke Extract,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 85, No. 7, 1988, pp. 2344-2348.
[9] Ogasawara M and Suzuki H, “Inhibition by Evodiamine of Hepatocyte Growth Factor-Induced Invasion and Migration of Tumor Cells,” Biological and Pharmaceutical Bulletin, Vol. 27, No. 4, 2004, pp. 578-582. doi:10.1248/bpb.27.578
[10] C. Takahashi, Z. Sheng, T. P. Horan, H. Kitayama, M. Maki, K. Hitomi, Y. Kitaura, S. Takai, R. M. Sasahara, A. Horimoto, Y. Ikawa, B. J. Ratzkin, T. Arakawa and M. Noda, “Regulation of Matrix Metalloproteinase-9 and Inhibition of Tumor Invasion by the Membrane-Anchored Glycoprotein RECK,” Pro-ceedings of the National Academy of Sciences of the United States of America, Vol. 95, No. 22, 1998, pp. 13221-13226. doi:10.1073/pnas.95.22.13221
[11] I. J. Fidler, “Selection of Successive Tumour Lines for Metastasis,” Nature: New Biology, Vol. 118, 1973, pp. 148-149.
[12] Y. Nakamura, D. J. Romberger, L. Tate, R. F. Ertl, M. Kawamoto, Y. Adachi, T. Mio, J. H. Sisson, J. R. Spurzem and S. I. Rennard, “Cigarette Smoke Inhibits Lung Fibroblast Proliferation and Chemotaxis,” American Journal of Respiratory and Critical Care Medicine, Vol. 151, No. 5, 1995, pp. 1497-1503.
[13] A. Zlonik, “Chemokines In-neoplastic Progression,” Seminars in Cancer Biology, Vol. 14, No. 3, 2004, pp. 181-185. doi:10.1016/j.semcancer.2003.10.004
[14] J. Condeelis and J. W. Pollard, “Macrophages: Obligate Partners for Tumor Cell Migration, Invasion, and Metastasis,” Cell, Vol. 124, No. 5, 2006, pp. 263-266. doi:10.1016/j.cell.2006.01.007
[15] P. N. Devreotes and C. Janetopoulos, “Eukaryotic Chemotaxis: Distinctions between Directional Sensing and Polarization,” Journal of Biological Chemistry, Vol. 278, No. 23, 2003, pp. 20445-20448. doi:10.1074/jbc.R300010200
[16] A. Müller, B. Homey, H. Soto, N. Ge, D. Catron, M. E. Buchanan, T. McCla-nahan, E. Murphy, W. Yuan, S. N. Wagner, J. L. Barrera, A. Mohar, E. Verástegui and A. Zlotnik, “Involvement of Chemokine Receptors in Breast Cancer Metastasis,” Nature, Vol. 410, 2001, pp. 50-56. doi:10.1038/35065016
[17] G. La Rocca, R. Anzalone, F. Magno, F. Farina, F. Cappello and G. Zummo, “Cigarette Smoke Exposure Inhibits Extracellular MMP-2 (Gelatinase A) Activity in Human Lung Fibroblasts,” Respiratory Research, Vol. 8, 2007, p. 23. doi:10.1186/1465-9921-8-23
[18] D. Hoffmann, I. Hoffmann and K. El-Bayoumy, “The Less Harmful Cig-arette: A Controversial Issue. A Tribute to Ernst L. Wynder,” Chemical Research in Toxicology, Vol. 14, 2001, pp. 767-790. doi:10.1021/tx000260u
[19] M. Kunitomo, Y. Yamaguchi, S. Kagota, N. Yoshikawa, K. Nakamura and K. Shinozuka, “Biochemical Evidence of Atherosclerosis Progression Mediated by Increased Oxid-ative Stress in Apolipoprotein E-Deficient Spontaneously Hyperlipidemic Mice Exposed to Chronic Cigarette Smoke,” Journal of Pharmacological Sciences, Vol. 110, No. 3, 2009, pp. 354-361. doi:10.1254/jphs.09100FP
[20] W. A. Pryor and K. Stone, “Oxidants in Cigarette Smoke. Radicals, Hydrogen Peroxide, Peroxynitrate, and Peroxynitrite,” Annals of the New York Academy of Sciences, Vol. 686, 1993, pp. 12-28.
[21] B. Frei, T. M. Forte, B. N. Ames and C. E. Cross, “Gas Phase Oxidants of Cigarette Smoke Induce Lipid Peroxidation and Changes in Lipoprotein Properties in Human Blood Plasma. Protective Effects of Ascorbic Acid,” The Biochemical Journal, Vol. 277, 1991, pp. 133-138.
[22] R. B. Bridges, J. H. Kraal, L. J. Huang and B. M. Chancellor, “Effects of Tobacco Smoke on Chemotaxis and Glucose Metabolism of Polymorphonuclear Leukocytes,” Infection and Immunity, Vol. 15, No. 1, 1977, pp. 115-123.
[23] D. G. Hatzinikolaou, V. Lagesson, A. J. Stavridou, A. E. Pouli, L. Lagesson-Andrasko and J. C. Stavrides, “Analysis of the Gas Phase of Cigarette Smoke by Gas Chromatography Coupled with UV-Diode Array Detection. Analytical Chemistry, Vol. 78, No. 13, 2006, pp. 4509-4516. doi:10.1021/ac052004y
[24] M. Dixon and E. C. Webb, “Enzymes,” Academic Press Inc., New York, 1964, pp. 937-943.

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