Abstract
This study examined the in vitro cytotoxic activity and in vivo antitumor activity as well as intracellular apoptotic capacities of a prenylated flavonol, sophoflavescenol from Sophora flavescens, to evaluate prospective anti-tumorigenic drugs, and antitumor potential. In addition, the in vitro antioxidant and anti-inflammatory capacities were evaluated. Despite the small effect on human breast adenocarcinoma (MCF-7), sophoflavescenol showed cytotoxicity against human leukaemia (HL-60), Lewis lung carcinoma (LLC), and human lung adenocarcinoma epithelial (A549) cells. Interestingly, it also exerted potent in vivo antitumor activity by tumor growth inhibition in the LLC tumor model as well as apoptotic activity by caspase-3 activation in HL-60 cells. In addition, it exhibited potent antioxidant activities in 1,1-diphenyl-2-picrylhydrazyl, 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt radicals and lipid peroxidation assays. Sophoflavescenol exerted notable anti-inflammatory activity by inhibiting nitric oxide generation and tert-butylhydroperoxide-induced ROS generation rather than inhibiting nuclear factor kappa B activation in RAW 264.7 cells. The findings show that the antioxidant, anti-inflammatory, and apoptotic activities of sophoflavescenol might contribute to the antitumor activity without severe side effects, highlighting its potential for chemoprevention and/or anticancer drugs due to multi-effective targets in almost all stages of tumorigenesis, including initiation, promotion, and progression.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Blois, M. S., Antioxidant determination by the use of a stable free radical. Nature, 181, 1199–1200 (1958).
Choquenet, B., Couteau, C., Paparis, E., and Coiffard, L. J., Flavonoids and polyphenols, molecular families with sunscreen potential: determining effectiveness with an in vitro method. Nat. Prod. Commun., 4, 227–230 (2009).
Delmulle, L., Bellahcène, A., Dhooge, W., Comhaire, F., Roelens, F., Huvaere, K., Heyerick, A., Castronovo, V., and De Keukeleire, D., Anti-proliferative properties of prenylated flavonoids from hops (Humulus lupulus L.) in human prostate cancer cell lines. Phytomedicine, 13, 732–734 (2006).
Drisko, J. A., Chapman, J., and Hunter, V. J., The use of antioxidant therapies during chemotherapy. Gynecol. Oncol., 88, 434–439 (2003).
Gerl, R. and Vaux, D. L., Apoptosis in the development and treatment of cancer. Carcinogenesis, 26, 263–270 (2005).
Huang, W. Y., Cai, Y. Z., and Zhang, Y., Natural phenolic compounds from medicinal herbs and dietary plants: potential use for cancer prevention. Nutr. Cancer, 62, 1–20 (2010).
Igarashi, K. and Ohmuma, M., Effects of isorhamnetin, rhamnetin, and quercetin on the concentrations of cholesterol and lipoperoxide in the serum and liver and on the blood and liver antioxidative enzyme activities of rats. Biosci. Biotechnol. Biochem., 59, 595–601 (1995).
Jung, M. J., Kang, S. S., Jung, H. A., Kim, G. J., and Choi, J. S., Isolation of flavonoids and a cerebroside from the stem bark of Albizzia julibrissin. Arch. Pharm. Res., 27, 593–599 (2004).
Kensler, T. W., Chemoprevention by inducers of carcinogen detoxication enzymes. Environ. Health Perspect, 105, 965–970 (1997).
Kerry, N. and Rice-Evans, C., Inhibition of peroxynitrite-mediated oxidation of dopamine by flavonoid and phenolic antioxidants and their structural relationships. J. Neurochem., 73, 247–253 (1999).
Kim, J. Y., Jung, K. J., Choi, J. S., and Chung, H. Y., Hesperetin: a potent antioxidant against peroxynitrite. Free Radic. Res., 38, 761–769 (2004).
Kim, R., Recent advances in understanding the cell death pathways activated by anticancer therapy. Cancer, 103, 1551–1560 (2005).
Kondoh, M., Tasaki, E., Takiguchi, M., Higashimoto, M., Watanabe, Y., and Sato, M., Activation of caspase-3 in HL-60 cells treated with pyrithione and zinc. Biol. Pharm. Bull., 28, 757–759 (2005).
Kooy, N. W., Royall, J. A., Ischiropoulos, H., and Beckman, J. S., Peroxynitrite-mediated oxidation of dihydrorhodamine 123. Free Radic. Biol. Med., 16, 149–156 (1994).
Lee, E. O., Lee, H. J., Hwang, H. S., Ahn, K. S., Chae, C., Kang, K. S., Lu, J., and Kim, S. H., Potent inhibition of Lewis lung cancer growth by heyneanol A from the roots of Vitis amurensis through apoptotic and anti-angiogenic activities. Carcinogenesis, 27, 2059–2069 (2006).
Lee, N. K., Son, K. H., Chang, H. W., Kang, S. S., Park, H., Heo, M. Y., and Kim, H. P., Prenylated flavonoids as tyrosinase inhibitors. Arch. Pharm. Res., 27, 1132–1135 (2004).
Mei, J. M., Hord, N. G., Winterstein, D. F., Donald, S. P., and Phang, J. M., Expression of prostaglandin endoperoxide H synthase-2 induced by nitric oxide in conditionally immortalized murine colonic epithelial cells. FASEB J., 14, 1188–1201 (2000).
Moon, K. Y., Hahn, B. S., Lee, J., and Kim, Y. S., A cell-based assay system for monitoring NF-κB activity in human HaCat transfectant cells. Anal. Biochem., 292, 17–21 (2001).
Nishino, H., Tokuda, H., Satomi, Y., Masuda, M., Osaka, Y., Yogosawa, S., Wada, S., Mou, X. Y., Takayasu, J., Murakoshi, M., Jinnno, K., and Yano, M., Cancer prevention by antioxidants. Biofactors, 22, 57–61 (2004).
Okada, F. and Fujii, J., Prevention of tumor progression as the ultimate goal of cancer therapy. Cancer Ther., 3, 219–226 (2005).
Pannala, A., Razzaq, R., Halliwell, B., Singh, S., and Rice-Evans, C., Inhibition of peroxynitrite dependent nitration by hydroxycinnamic acids: nitration or electron donation? Free Radic. Biol. Med., 24, 594–606 (1998).
Park, J. S., Park, H. Y., Kim, D. H., Kim, D. H., and Kim, H. K., ortho-Dihydroxyisoflavone derivatives from aged Doenjang (Korean fermented soypaste) and its radical scavenging activity. Bioorg. Med. Chem. Lett., 18, 5006–5009 (2008).
Poulson, H. E., Prieme, H., and Loft, S., Role of oxidative DNA damage in cancer initiation and promotion. Eur. J. Cancer Prev., 71, 9–16 (1998).
Re, R., Pellegrini, N., Proteggente, A., Pannala, A., Yang, M., and Rice-Evans, C., Antioxidant activity applying an improved ABTS radical cation decolorization assay. Free Radic. Biol. Med., 26, 1231–1237 (1999).
Rickles, R., Pierce, L., and Lee, M. S., Combinations for the treatment of B-cell proliferative disorders. WO 2009011897 A1 20090122 (2009).
Ryu, S. Y., Choi, S. U., Kim, S. K., No, Z., Lee, C. O., Ahn, J. W., and Kim, S. H., In vitro antitumor activity of flavonoids from Sophora flavescens. Phytother. Res., 11, 51–53 (1997).
Serafini, M., Villano, D., Spera, G., and Pellegrini, N., Redox molecules and cancer prevention: the importance of understanding the role of the antioxidant network. Nutr. Cancer, 56, 232–240 (2006).
Shin, H. J., Kim, H. J., Kwak, J. H., Chun, H. O., Kim, J. H., Park, H., Kim, D. H., and Lee, Y. S., A prenylated flavonol, sophoflavescenol: a potent and selective inhibitor of cGMP phosphodiesterase 5. Bioorg. Med. Chem. Lett., 12, 2313–2316 (2002).
Sun, M., Han, J., Duan, J., Cui, Y., Wang, T., Zhang, W., Liu, W., Hong, J., Yao, M., Xiong, S., and Yan, X., Novel antitumor activities of Kushen flavonoids in vitro and in vivo. Phytother. Res., 21, 269–277 (2007).
Surh, Y. J., Kundu, J. K., Na, H. K., and Lee, J. S., Redoxsensitive transcription factors as prime targets for chemoprevention with anti-inflammatory and antioxidative phytochemicals. J. Nutr., 135, 2993S–3001S (2005).
Thangapazham, R. L., Sharma, A., and Maheshwari, R. K., Multiple molecular targets in cancer chemoprevention by curcumin. AAPS J., 8, E443–E449 (2006).
Utsugi, T., Shibata, J., Sugimoto, Y., Aoyagi, K., Wierzba, K., Kobunai, T., Terada, T., Oh-hara, T., Tsuruo, T., and Yamada, Y., Antitumor activity of a novel podophyllotoxin derivative (TOP-53) against lung cancer and lung metastatic cancer. Cancer Res., 56, 2809–2814 (1996).
Van le, T. K., Hung, T. M., Thuong, P. T., Ngoc, T. M., Kim, J. C., Jang, H. S., Cai, X. F., Oh, S. R., Min, B. S., Woo, M. H., Choi, J. S., Lee, H. K., and Bea, K., Oleanane-type triterpenoids from Aceriphyllum rossii and their cytotoxic activity. J. Nat. Prod., 72, 1419–1423 (2009).
Wätjen, W., Weber, N., Lou, Y. J., Wang, Z. Q., Chovolou, Y., Kampkötter, A., Kahl, R., and Proksch, P., Prenylation enhances cytotoxicity of apigenin and liquiritigenin in rat H4IIE hepatoma and C6 glioma cells. Food Chem. Toxicol., 45, 119–124 (2007).
Weinberg, F. and Chandel, N. S., Reactive oxygen species-dependent signaling regulates cancer. Cell. Mol. Life Sci., 66, 3663–3673 (2009).
Xie, Q. and Nathan, C., The high-output nitric oxide pathway: role and regulation. J. Leukoc. Biol., 56, 576–582 (1994).
Yazaki, K., Sasaki, K., and Tsurumaru, Y., Prenylation of aromatic compounds, a key diversification of plant secondary metabolites. Phytochemistry, 70, 1739–1745 (2009).
Yu, R., Mandlekar, S., Harvey, K. J., Ucker, D. S., and Kong, A. N., Chemopreventive isothiocyanates induce apoptosis and caspase-3-like protease activity. Cancer Res., 58, 402–408 (1998).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Jung, H.A., Jin, S.E., Choi, R.J. et al. Anti-tumorigenic activity of sophoflavescenol against Lewis lung carcinoma in vitro and in vivo . Arch. Pharm. Res. 34, 2087–2099 (2011). https://doi.org/10.1007/s12272-011-1212-y
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12272-011-1212-y