Nobiletin acts as a potential anticancer agent against osteosarcoma by regulating ERK and AKT signaling pathways
The current study was aimed to evaluate the anti-proliferative activity of nobiletin, a flavonoid, on osteosarcoma cell line, SaOS-2. Furthermore, we attempted to investigate the signaling pathways involved in the cell growth inhibition mechanism. Upon exposure, nobiletin showed significant cell inhibitory effect on SaOS-2 cells in a dose dependent manner as evidenced by MTT assay and LDH assay. Moreover, flow cytometric analysis demonstrated that upon treatment with nobiletin, SaOS-2 cells underwent apoptosis and showed increased number of cells arrested in G2/M phase. Activation of caspase-9 and -3 indicate the activation of apoptotic signaling pathway in SaOS-2 cells. Additionally, it was observed that the cell inhibitory effect was regulated by the activation of ERK signaling pathway while AKT signaling pathway was down regulated in SaOS-2 cells after 24 h of Nobiletin treatment.
American Cancer Society. Cancer: Facts and figures. Atlants, Ga, American Cancer Society, 2014.
Aoki K, Yokosuka A, Mimaki Y, Fukunaga K, Yamakuni T. Nobiletin induces inhibitions of Ras activity and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling to suppress cell proliferation in C6 rat glioma cells. Biol Pharm Bull. 2013; 36: 540-47.
Chen C, Ono M, Takeshima M, Nakano S. Antiproliferative and apoptosis-inducing activity of nobiletin against three subtypes of human breast cancer cell lines. Anticancer Res. 2014; 34: 1785-92.
Gullett NP, Ruhul Amin AR, Bayraktar S, Pezzuto JM, Shin DM, Khuri FR, Aggarwal BB, Surh YJ, Kucuk O. Cancer prevention with natural compounds. Semin Oncol. 2010; 37: 258-81.
Harborne JB, Williams CA. Advances in flavonoid research since 1992. Phytochemistry 2000; 55: 481-504.
Hartwell LH, Kastan MB. Cell cycle control and cancer. Science 1994; 266: 1821-28.
Hartwell LH, Weinert TA. Checkpoints: controls that ensure the order of cell cycle events. Science 1989; 246: 629-34.
Hunt TR, Schwappach JR, Anderson HC. Healing of a segmental defect in the rat femur with use of an extract from a cultured human osteosarcoma cell-line (SaOS-2). A preliminary report. J Bone Joint Surg Am. 1996; 78: 41-48.
Ishii K, Tanaka S, Kagami K, Henmi K, Toyoda H, Kaise T, Hirano T. Effects of naturally occurring poly-methyoxyflavonoids on cell growth, p-glycoprotein func-tion, cell cycle, and apoptosis of daunorubicin-resistant T lymphoblastoid leukemia cells. Cancer Invest. 2010; 28: 220-29.
Kim H, Seo E-M, Sharma AR, Ganbold B, Park J,Sharma G, Kang YH, Song DK, Lee SS, Nam JS. Regulation of Wnt signaling activity for growth suppression induced by quercetin in 4T1 murine mammary cancer cells. Int J Oncol. 2013; 43: 1319-25.
Kroemer G, Galluzzi L, Brenner C. Mitochondrial membrane permeabilization in cell death. Physiol Rev. 2007; 87: 99-163.
Lai CS, Li S, Chai CY, Lo CY, Dushenkov S, Ho CT, Pan MH, Wang YJ. Anti-inflammatory and antitumor promotional effects of a novel urinary metabolite, 3',4'-didemethyl nobiletin, derived from nobiletin. Carcinogenesis 2008; 29: 2415-24.
Lai E, Teodoro T, Volchuk A. Endoplasmic reticulum stress: signaling the unfolded protein response. Physiology (Bethesda) 2007; 22: 193-201.
Legrand C, Bour JM, Jacob C, Capiaumont J, Martial A, Marc A, Wudtke M, Kretzmer G, Demangel C, Duval D, Hache J. Lactate dehydrogenase (LDH) activity of the cultured eukaryotic cells as marker of the number of dead cells in the medium. J Biotechnol. 1992; 25: 231-43.
Li RW, Theriault AG, Au K, Douglas TD, Casaschi A, Kurowska EM, Mukherjee R. Citrus polymethoxylated flavones improve lipid and glucose homeostasis and modulate adipocytokines in fructose-induced insulin resistant hamsters. Life Sci. 2006; 79: 365-73.
Luo G, Guan X, Zhou L. Apoptotic effect of citrus fruit extract nobiletin on lung cancer cell line A549 in vitro and in vivo. Cancer Biol Ther. 2008; 7: 966-73.
Luo G, Zeng Y, Zhu L, Zhang YX, Zhou LM. Inhibition effect and its mechanism of Nobiletin on proliferation of lung cancer cells. Sichuan Da Xue Xue Bao Yi Xue Ban 2009; 40: 449-53.
Ma X, Jin S, Zhang Y, Wan L, Zhao Y, Zhao L. Inhibitory effects of Nobiletin on hepatocellular carcinoma in vitro and in vivo. Phytother Res. 2014; 28: 560-67.
Murakami A, Nakamura Y, Torikai K, Tanaka T, Koshiba T, Koshimizu K, Kuwahara S, Takahashi Y, Ogawa K, Yano M, Tokuda H, Nishino H,Mimaki Y, Sashida Y, Kitanaka S, Ohigashi H. Inhibitory effect of citrus nobiletin on phorbol ester-induced skin inflammation, oxidative stress, and tumor promotion in mice. Cancer Res. 2000; 60: 5059-66.
Murakami A, Shigemori T, Ohigashi H. Zingiberaceous and citrus constituents, 1?-cetoxychavicol acetate, zerumbone, auraptene, and nobiletin, suppress lipopolysaccharide-induced cyclooxygenase-2 expression in RAW264.7 murine macrophages through different modes of action. J Nutr. 2005; 135: 2987S-92S.
Nakajima A, Yamakuni T, Haraguchi M, Omae N, Song SY, Kato C, Nakagawasai O, Tadano T, Yokosuka A, Mimaki Y, Sashida Y, Ohizumi Y. Nobiletin, a citrus flavonoid that improves memory impairment, rescues bulbectomy-induced cholinergic neurodegeneration in mice. J Pharmacol Sci. 2007; 105: 122-26.
Neuhouser ML. Dietary flavonoids and cancer risk: evidence from human population studies. Nutr Cancer 2004; 50: 1-7.
Newman DJ, Cragg GM. Natural products as sources of new drugs over the last 25 years. J Nat Prod.2007; 70: 461-77.
Park HH. Structural features of caspase-activating complexes. Int J Mol Sci. 2012; 13: 4807-18.
Sato T, Koike L, Miyata Y, Hirata M, Mimaki Y, Sashida Y, Yano M, Ito A. Inhibition of activator protein-1 binding activity and phosphatidylinositol 3-hinase pathway by nobiletin, a polymethoxy flavonoid, results in augmentation of tissue inhibitor of metalloproteinases-1 production and suppression of production of matrix metalloproteinases-1 and -9 in human fibrosarcoma HT-1080 cells. Cancer Res. 2002; 62: 1025-29.
Shi MD, Liao YC, Shih YW, Tsai LY. Nobiletin attenuates metastasis via both ERK and PI3K/Akt pathways in HGF-treated liver cancer HepG2 cells. Phytomedicine 2013; 20: 743-52.
Tang M, Ogawa K, Asamoto M, Hokaiwado N, Seeni A,Suzuki S, Takahashi S, Tanaka T, Ichikawa K, Shirai T. Protective effects of citrus nobiletin and auraptene in transgenic rats developing adenocarcinoma of the prostate (TRAP) and human prostate carcinoma cells. Cancer Sci. 2007; 98: 471-77.
Wu JJ, Cui Y, Yang YS, Jung SC, Hyun JW, Maeng YH, Park DB, Lee SR, Kim SJ, Eun SY. Mild mitochondrial depolarization is involved in a neuroprotective mechanism of Citrus sunki peel extract. Phytother Res. 2013; 27: 564-71.
Copyright (c) 2014 Fu-Wen Niu, Yong-Jie Zhang, Kun Li, Mao-Shu Zhang
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