Honokiol exerts an anticancer effect in T98G human glioblastoma cells through the induction of apoptosis and the regulation of adhesion molecules

Jeong,Jae  Ju; Lee,Jae  Heun; Chang,Ki  Churl; Kim,Hye  Jung

doi:10.3892/ijo.2012.1582

Honokiol exerts an anticancer effect in T98G human glioblastoma cells through the induction of apoptosis and the regulation of adhesion molecules

Authors:
- Jae Ju Jeong
- Jae Heun Lee
- Ki Churl Chang
- Hye Jung Kim
View Affiliations

Affiliations: Department of Pharmacology, School of Medicine and Institute of Health Sciences, Gyeongsang National University, Jinju, Republic of Korea
Published online on: August 7, 2012 https://doi.org/10.3892/ijo.2012.1582
Pages: 1358-1364

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Glioblastoma is one of the most lethal and common malignant human brain tumors, with aggressive proliferation and highly invasive properties. Honokiol derived from Magnolia officinalis is able to cross the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB), suggesting a strong possibility that it could be an effective drug for the treatment of brain tumors, including glioblastoma. Thus, we investigated the effects of honokiol on the expression of adhesion molecules in TNF-α-stimulated endothelial cells, and cancer growth and invasion were determined in T98G human glioblastoma cells. Honokiol dose-dependently inhibited the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vein endothelial cells (HUVECs) stimulated with TNF-α for 6 h. Pretreatment with honokiol significantly reduced the adhesion of T98G cells to HUVECs. Moreover, honokiol inhibited the invasion of T98G cells, suggesting that honokiol has an anti-metastatic effect. In addition, honokiol increased the cytotoxicity of T98G cells in a dose- and time-dependent manner as assayed by MTT. TUNEL assay showed that honokiol significantly induced apoptosis in T98G cells at doses of 10 µM or more. The induction of apoptotic cell death was mediated by the downregulation of the anti-apoptotic protein Bcl-2 and the upregulation of the pro-apoptotic protein Bax. Taken together, the results of this study suggest that honokiol exerts an anticancer effect by preventing metastasis and inducing apoptotic cell death of brain tumor cells.

View Figures

View References

1	Wen PY and Kesari S: Malignant gliomas in adults. N Engl J Med. 359:492–507. 2008. View Article : Google Scholar : PubMed/NCBI
2	Sehgal A: Molecular changes during the genesis of human gliomas. Semin Surg Oncol. 14:3–12. 1998. View Article : Google Scholar
3	Shapiro WR: Current therapy for brain tumors: back to the future. Arch Neurol. 56:429–432. 1999. View Article : Google Scholar : PubMed/NCBI
4	Chang HM and But PH: Pharmacology and applications of Chinese Materia Medica. 1. World Scientific Publishers; Singapore: pp. 878–880. 1986
5	Haraguchi H, Ishikawa H, Shirataki N and Fukuda A: Antiperoxidative activity of neolignans from magnolia obovata. J Pharm Pharmacol. 49:209–212. 1997. View Article : Google Scholar
6	Kuribara H, Stavinoha WB and Maruyama Y: Behavioural pharmacological characteristics of honokiol, an anxiolytic agent present in extracts of Magnolia bark, evaluated by an elevated plus-maze test in mice. J Pharm Pharmacol. 50:819–826. 1998. View Article : Google Scholar : PubMed/NCBI
7	Maruyama Y, Kuribara H, Morita M, Yuzurihara M and Weintraub ST: Identification of magnolol and honokiol as anxiolytic agents in extracts of saiboku-to, an oriental herbal medicine. J Nat Prod. 61:135–138. 1998. View Article : Google Scholar : PubMed/NCBI
8	Kuribara H, Stavinoha WB and Maruyama Y: Honokiol, a putative anxiolytic agent extracted from magnolia bark, has no diazepam-like side-effects in mice. J Pharm Pharmacol. 51:97–103. 1999.PubMed/NCBI
9	Kuribara H, Kishi E, Kimura M, Weintraub ST and Maruyama Y: Comparative assessment of the anxiolytic-like activities of honokiol and derivatives. Pharmacol Biochem Behav. 67:597–601. 2000. View Article : Google Scholar : PubMed/NCBI
10	Watanabe K, Watanabe H, Goto Y, Yamaguchi M, Yamamoto N and Hagino K: Pharmacological properties of magnolol and honokiol extracted from Magnolia officinalis: central depressant effects. Planta Med. 49:103–108. 1983. View Article : Google Scholar : PubMed/NCBI
11	Liou KT, Shen YC, Chen CF, Tsao CM and Tsai SK: Honokiol protects rat brain from focal cerebral ischemia-reperfusion injury by inhibiting neutrophil infiltration and reactive oxygen species production. Brain Res. 992:159–166. 2003. View Article : Google Scholar
12	Hibasami H, Achiwa Y, Katsuzaki H, Imai K, Yoshioka K, Nakanishi K, Ishii Y, Hasegawa M and Komiya T: Honokiol induces apoptosis in human lymphoid leukemia molt 4B cells. Int J Mol Med. 2:671–673. 1998.PubMed/NCBI
13	Yang SE, Hsieh MT, Tsai TH and Hsu SL: Downmodulation of Bcl-X_L, release of cytochrome c and sequential activation of caspases during honokiol induced apoptosis in human squamous lung cancer CH27 cells. Biochem Pharmacol. 63:1641–1651. 2002.PubMed/NCBI
14	Wang T, Chen F, Chen Z, Wu YF, Xu XL, Zheng S and Hu X: Honokiol induces apoptosis through p53-independent pathway in human colorectal cell line RKO. World J Gastroenterol. 10:2205–2208. 2004.PubMed/NCBI
15	Hirano T, Gotoh M and Oka K: Natural flavonoids and lignans are potent cytostatic agents against human leukemic HL-60 cells. Life Sci. 55:1061–1069. 1994. View Article : Google Scholar : PubMed/NCBI
16	Crane C, Panner A, Pieper RO, Arbiser J and Parsa AT: Honokiol-mediated inhibition of PI3K/mTOR pathway: a potential strategy to overcome immunoresistance in glioma, breast, and prostate carcinoma without impacting T cell function. J Immunother. 32:585–592. 2009. View Article : Google Scholar
17	Wang X, Duan X, Yang G, Zhang X, Deng L, Zheng H, Deng C, Wen J, Wang N, Peng C, Zhao X, Wei Y and Chen L: Honokiol crosses BBB and BCSFB, and inhibits brain tumor growth in rat 9L intracerebral gliosarcoma model and human U251 xenograft glioma model. PLoS One. 6:e184902011. View Article : Google Scholar : PubMed/NCBI
18	Fox SB, Turner GD, Gatter KC and Harris AL: The increased expression of adhesion molecules ICAM-3, E-selectin and P-selectins on breast cancer endothelium. J Pathol. 177:369–376. 1995. View Article : Google Scholar : PubMed/NCBI
19	Christiansen I, Sundstrom C, Enblad G and Totterman TH: Soluble vascular cell adhesion molecule-1 (sVCAM-1) is an independent prognostic marker in Hodgkin’s disease. Br J Haematol. 102:701–709. 1998.
20	Christiansen I, Sundstrom C and Totterman TH: Elevated serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) closely reflect tumour burden in chronic B-lymphocytic leukaemia. Br J Haematol. 103:1129–1137. 1998. View Article : Google Scholar : PubMed/NCBI
21	Wang X, Clowes C, Duarte R and Pu QQ: Serum ICAM-1 concentrations following conventional dose consolidation chemotherapy for acute myeloid leukemia and after high dose chemotherapy with autologous haematopoietic stem cell rescue. Int J Oncol. 17:591–595. 2000.PubMed/NCBI
22	Maeda K, Kang SM, Sawada T, Nishiguchi Y, Yashiro M, Ogawa Y, Ohira M, Ishikawa T, Hirakawa YS and Chung CK: Expression of intercellular adhesion molecule-1 and prognosis in colorectal cancer. Oncol Rep. 9:511–514. 2002.PubMed/NCBI
23	Becker JC, Dummer R, Hartmann AA, Burg G and Schmidt RE: Shedding of ICAM-1 from human melanoma cell lines induced by IFN-gamma and tumor necrosis factor-alpha. Functional consequences on cell-mediated cytotoxicity. J Immunol. 147:4398–4401. 1991.
24	Osborn L, Hession C, Tizard R, Vassallo C, Luhowskyj S, Chi-Rosso G and Lobb R: Direct expression cloning of vascular cell adhesion molecule-1, a cytokine-induced endothelial protein that binds to lymphocytes. Cell. 59:1203–1211. 1989. View Article : Google Scholar : PubMed/NCBI
25	Springer TA: Traffic signal for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell. 76:301–314. 1994. View Article : Google Scholar : PubMed/NCBI
26	Kim HJ, Tsoy I, Park JM, Chung JI, Shin SC and Chang KC: Anthocyanins from soybean seed coat inhibit the expression of TNF-α-induced genes associated with ischemia/reperfusion in endothelial cell by NF-κB-dependent pathway and reduce rat myocardial damages incurred by ischemia and reperfusion in vivo. FEBS Lett. 580:1391–1397. 2006.PubMed/NCBI
27	Nizamutdinova IT, Oh HM, Min YN, Park SH, Lee MJ, Kim JS, Yean MH, Kang SS, Kim YS, Chang KC and Kim HJ: Paeonol suppresses intercellular adhesion molecule-1 expression in tumor necrosis factor-α-stimulated human umbilical vein endothelial cells by blocking p38, ERK and nuclear factor-κB signaling pathways. Int Immunopharmacol. 7:343–350. 2007.PubMed/NCBI
28	Zhang GJ and Adachi I: Serum levels of soluble intercellular adhesion molecule-1 and E-selectin in metastatic breast carcinoma: correlations with clinicopathological features and prognosis. Int J Oncol. 14:71–77. 1999.
29	Thompson EW and Price JT: Mechanisms of tumour invasion and metastasis: emerging targets for therapy. Expert Opin Ther Targets. 6:217–233. 2002. View Article : Google Scholar : PubMed/NCBI
30	Balkwill F and Mantovani A: Inflammation and cancer: back to Virchow? Lancet. 357:539–545. 2001. View Article : Google Scholar : PubMed/NCBI
31	Nizamutdinova IT, Lee GW, Lee JS, Cho MK, Son KH, Jeon SJ, Kang SS, Kim YS, Lee JH, Seo HG, Chang KC and Kim HJ: Tanshinone I suppresses growth and invasion of human breast cancer cells, MDA-MB-231, through regulation of adhesion molecules. Carcinogenesis. 29:1885–1892. 2008. View Article : Google Scholar : PubMed/NCBI
32	Goping IS, Gross A, Lavoie JN, Nguyen M, Jemmerson R, Roth K, Korsmeyer SJ and Shore GC: Regulation targeting of BAX to mitochondria. J Cell Biol. 143:207–215. 1998. View Article : Google Scholar : PubMed/NCBI
33	Kuwana T and Newmeyer DD: Bcl-2 family proteins and the role of mitochondria in apoptosis. Curr Opin Cell Biol. 15:691–699. 2003. View Article : Google Scholar : PubMed/NCBI
34	Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor GR, Thompson CB and Koresmeyer SJ: Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science. 292:727–730. 2001. View Article : Google Scholar : PubMed/NCBI
35	Klemke M, Weschenfelder T, Konstandin MH and Samstag Y: High affinity interaction of integrin alpha4beta1 (VLA-4) and vascular cell adhesion molecule 1 (VCAM-1) enhances migration of human melanoma cells across activated endothelial cell layers. J Cell Physiol. 212:368–374. 2007. View Article : Google Scholar
36	Wu TC: The role of vascular cell adhesion molecule-1 in tumor immune evasion. Cancer Res. 67:6003–6006. 2007. View Article : Google Scholar : PubMed/NCBI