Vitexin induces G2/M‑phase arrest and apoptosis via Akt/mTOR signaling pathway in human glioblastoma cells

Zhang,Guangning; Li,Dongyuan; Chen,Hao; Zhang,Junchen; Jin,Xingyi

doi:10.3892/mmr.2018.8394

Vitexin induces G2/M‑phase arrest and apoptosis via Akt/mTOR signaling pathway in human glioblastoma cells

Authors:
- Guangning Zhang
- Dongyuan Li
- Hao Chen
- Junchen Zhang
- Xingyi Jin
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Affiliations: Department of Neurosurgery, Affiliated Hospital of Jining Medical University, Jining, Shandong 272000, P.R. China, Department of Neurosurgery, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
Published online on: January 8, 2018 https://doi.org/10.3892/mmr.2018.8394
Pages: 4599-4604

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Abstract

Glioblastoma is a common primary brain tumor with aggressive malignancy, which results in poor outcomes, short survival time and high mortality. Vitexin, an active ingredient from natural products, has been reported to inhibit cell growth and induce cell apoptosis in various cancer cell lines including hepatocellular carcinoma, oral and esophageal cancer. To the best of the authors knowledge, the present study was the first to investigate anticancer effects of vitexin on human glioblastoma cells and potential underlying mechanisms. The present study demonstrated that vitexin inhibited cell viability in a dose‑ and time‑dependent manner. In the present study, vitexin induced G2/M cell cycle arrest, as demonstrated by flow cytometry. Induction of cell apoptosis following vitexin treatment, was further indicated by observation of morphological alterations, flow cytometry analysis and detection of cleaved‑poly (ADP‑ribose) polymerase. The present study also demonstrated that vitexin inhibited RAC‑alpha serine/threonine‑protein kinase (Akt)/mechanistic target of rapamycin kinase (mTOR) signaling in human glioblastoma cells. Collectively, the results of the present study demonstrated that vitexin induced G2/M cell cycle arrest and apoptosis by inhibiting Akt/mTOR signaling in human glioblastoma cells. Vitexin may in the future be used as a therapeutic agent for treatment of malignant glioblastoma.

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1	Kubelt C, Hattermann K, Sebens S, Mehdorn HM and Held-Feindt J: Epithelial-to-mesenchymal transition in paired human primary and recurrent glioblastomas. Int J Oncol. 46:2515–2525. 2015. View Article : Google Scholar : PubMed/NCBI
2	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
3	Omuro A and DeAngelis LM: Glioblastoma and other malignant gliomas: A clinical review. JAMA. 310:1842–1850. 2013. View Article : Google Scholar : PubMed/NCBI
4	Woehrer A, Bauchet L and Barnholtz-Sloan JS: Glioblastoma survival: Has it improved? Evidence from population-based studies. Curr Opin Neurol. 27:666–674. 2014.PubMed/NCBI
5	Cuddapah VA, Robel S, Watkins S and Sontheimer H: A neurocentric perspective on glioma invasion. Nat Rev Neurosci. 15:455–465. 2014. View Article : Google Scholar : PubMed/NCBI
6	Wirsching HG, Galanis E and Weller M: Glioblastoma. Handb Clin Neurol. 134:381–397. 2016. View Article : Google Scholar : PubMed/NCBI
7	Arévalo ÁST, Erices JI, Uribe DA, Howden J, Niechi I, Muñoz S, Martín RS and Monrás CAQ: Current therapeutic alternatives and new perspectives in glioblastoma multiforme. Curr Med Chem. 24:2781–2795. 2017. View Article : Google Scholar : PubMed/NCBI
8	Desjardins A, Rich JN, Quinn JA, Vredenburgh J, Gururangan S, Sathornsumetee S, Reardon DA, Friedman AH, Bigner DD and Friedman HS: Chemotherapy and novel therapeutic approaches in malignant glioma. Front Biosci. 10:2645–2668. 2005. View Article : Google Scholar : PubMed/NCBI
9	Gaitan E, Cooksey RC, Legan J and Lindsay RH: Antithyroid effects in vivo and in vitro of vitexin: A C-glucosylflavone in millet. J Clin Endocrinol Metab. 80:1144–1147. 1995. View Article : Google Scholar : PubMed/NCBI
10	He M, Min JW, Kong WL, He XH, Li JX and Peng BW: A review on the pharmacological effects of vitexin and isovitexin. Fitoterapia. 115:74–85. 2016. View Article : Google Scholar : PubMed/NCBI
11	Wang Y, Zhen Y, Wu X, Jiang Q, Li X, Chen Z, Zhang G and Dong L: Vitexin protects brain against ischemia/reperfusion injury via modulating mitogen-activated protein kinase and apoptosis signaling in mice. Phytomedicine. 22:379–384. 2015. View Article : Google Scholar : PubMed/NCBI
12	Che X, Wang X, Zhang J, Peng C, Zhen Y, Shao X, Zhang G and Dong L: Vitexin exerts cardioprotective effect on chronic myocardial ischemia/reperfusion injury in rats via inhibiting myocardial apoptosis and lipid peroxidation. Am J Transl Res. 8:3319–3328. 2016.PubMed/NCBI
13	An F, Yang G, Tian J and Wang S: Antioxidant effects of the orientin and vitexin in Trollius chinensis Bunge in D-galactose-aged mice. Neural Regen Res. 7:2565–2575. 2012.PubMed/NCBI
14	Yang L, Yang ZM, Zhang N, Tian Z, Liu SB and Zhao MG: Neuroprotective effects of vitexin by inhibition of NMDA receptors in primary cultures of mouse cerebral cortical neurons. Mol Cell Biochem. 386:251–258. 2014. View Article : Google Scholar : PubMed/NCBI
15	He JD, Wang Z, Li SP, Xu YJ, Yu Y, Ding YJ, Yu WL, Zhang RX, Zhang HM and Du HY: Vitexin suppresses autophagy to induce apoptosis in hepatocellular carcinoma via activation of the JNK signaling pathway. Oncotarget. 7:84520–84532. 2016.PubMed/NCBI
16	Yang SH, Liao PH, Pan YF, Chen SL, Chou SS and Chou MY: The novel p53-dependent metastatic and apoptotic pathway induced by vitexin in human oral cancer OC2 cells. Phytother Res. 27:1154–1161. 2013. View Article : Google Scholar : PubMed/NCBI
17	An F, Wang S, Tian Q and Zhu D: Effects of orientin and vitexin from Trollius chinensis on the growth and apoptosis of esophageal cancer EC-109 cells. Oncol Lett. 10:2627–2633. 2015. View Article : Google Scholar : PubMed/NCBI
18	Schwartz GK and Shah MA: Targeting the cell cycle: A new approach to cancer therapy. J Clin Oncol. 23:9408–9421. 2005. View Article : Google Scholar : PubMed/NCBI
19	Stewart ZA, Westfall MD and Pietenpol JA: Cell-cycle dysregulation and anticancer therapy. Trends Pharmacol Sci. 24:139–145. 2003. View Article : Google Scholar : PubMed/NCBI
20	Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
21	Kim G, Kim TH, Hwang EH, Chang KT, Hong JJ and Park JH: Withaferin A inhibits the proliferation of gastric cancer cells by inducing G2/M cell cycle arrest and apoptosis. Oncol Lett. 14:416–422. 2017. View Article : Google Scholar : PubMed/NCBI
22	Liberal J, Carmo A, Gomes C, Cruz MT and Batista MT: Urolithins impair cell proliferation, arrest the cell cycle and induce apoptosis in UMUC3 bladder cancer cells. Invest New Drugs. Jun 20–2017.(Epub ahead of print). View Article : Google Scholar : PubMed/NCBI
23	Silva IT, Geller FC, Persich L, Dudek SE, Lang KL, Caro MS, Durán FJ, Schenkel EP, Ludwig S and Simões CM: Cytotoxic effects of natural and semisynthetic cucurbitacins on lung cancer cell line A549. Invest New Drugs. 34:139–148. 2016. View Article : Google Scholar : PubMed/NCBI
24	King KL and Cidlowski JA: Cell cycle and apoptosis: Common pathways to life and death. J Cell Biochem. 58:175–180. 1995. View Article : Google Scholar : PubMed/NCBI
25	Kiraz Y, Adan A, Kartal Yandim M and Baran Y: Major apoptotic mechanisms and genes involved in apoptosis. Tumour Biol. 37:8471–8486. 2016. View Article : Google Scholar : PubMed/NCBI
26	Burgess DJ: Apoptosis: Refined and lethal. Nat Rev Cancer. 13:792013. View Article : Google Scholar : PubMed/NCBI
27	Germain M, Affar EB, D'Amours D, Dixit VM, Salvesen GS and Poirier GG: Cleavage of automodified poly(ADP-ribose) polymerase during apoptosis. Evidence for involvement of caspase-7. J Biol Chem. 274:28379–28384. 1999. View Article : Google Scholar : PubMed/NCBI
28	Granato M, Rizzello C, Gilardini Montani MS, Cuomo L, Vitillo M, Santarelli R, Gonnella R, D'Orazi G, Faggioni A and Cirone M: Quercetin induces apoptosis and autophagy in primary effusion lymphoma cells by inhibiting PI3K/AKT/mTOR and STAT3 signaling pathways. J Nutr Biochem. 41:124–136. 2017. View Article : Google Scholar : PubMed/NCBI
29	Ding L, Ding L, Wang S, Wang S, Wang W, Wang W, Lv P, Lv P, Zhao D, Zhao D, et al: Tanshinone IIA affects autophagy and apoptosis of glioma cells by inhibiting phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling pathway. Pharmacology. 99:188–195. 2017. View Article : Google Scholar : PubMed/NCBI
30	Wang Y, Sun Y, Wu Y and Zhang J: Cucurbitacin E inhibits osteosarcoma cells proliferation and invasion through attenuation of PI3K/AKT/mTOR signaling. Biosci Rep. BSR201601652016. View Article : Google Scholar : PubMed/NCBI
31	Li Y, Li S, Meng X, Gan RY, Zhang JJ and Li HB: Dietary natural products for prevention and treatment of breast cancer. Nutrients. 9:E7282017. View Article : Google Scholar : PubMed/NCBI
32	Kou X, Fan J and Chen N: Potential molecular targets of ampelopsin in prevention and treatment of cancers. Anticancer Agents Med Chem. Apr 12–2017.(Epub ahead of print). PubMed/NCBI
33	Zhou J, Hu H, Long J, Wan F, Li L, Zhang S, Shi YE and Chen Y: Vitexin 6, a novel lignan, induces autophagy and apoptosis by activating the Jun N-terminal kinase pathway. Anticancer Drugs. 24:928–936. 2013. View Article : Google Scholar : PubMed/NCBI
34	Tan Z and Zhang Y, Deng J, Zeng G and Zhang Y: Purified vitexin compound 1 suppresses tumor growth and induces cell apoptosis in a mouse model of human choriocarcinoma. Int J Gynecol Cancer. 22:360–366. 2012. View Article : Google Scholar : PubMed/NCBI
35	Xia Y, Lei Q, Zhu Y, Ye T, Wang N, Li G, Shi X, Liu Y, Shao B, Yin T, et al: SKLB316, a novel small-molecule inhibitor of cell-cycle progression, induces G2/M phase arrest and apoptosis in vitro and inhibits tumor growth in vivo. Cancer Lett. 355:297–309. 2014. View Article : Google Scholar : PubMed/NCBI
36	Bendale Y, Bendale V and Paul S: Evaluation of cytotoxic activity of platinum nanoparticles against normal and cancer cells and its anticancer potential through induction of apoptosis. Integr Med Res. 6:141–148. 2017. View Article : Google Scholar : PubMed/NCBI
37	Cao FJ, Zhu LF, Kuang Q, Li XQ, Zhou BH, Yang XJ and Zhou L: Cytotoxic activity, apoptosis induction and structure-activity relationship of 8-OR-2-aryl-3,4-dihydroisoquinolin-2-ium salts as promising anticancer agents. Bioorg Med Chem Lett. 27:55–60. 2017. View Article : Google Scholar : PubMed/NCBI
38	Ivanovska I, Muhoro CN and Irusta PM: Anti-tumor therapeutic molecules that target the programmed cell death machinery. Mini Rev Med Chem. 6:1033–1042. 2006. View Article : Google Scholar : PubMed/NCBI
39	Kolenko VM, Uzzo RG, Bukowski R and Finke JH: Caspase-dependent and -independent death pathways in cancer therapy. Apoptosis. 5:17–20. 2000. View Article : Google Scholar : PubMed/NCBI
40	Wang H, Zhang T, Sun W, Wang Z, Zuo D, Zhou Z, Li S, Xu J, Yin F, Hua Y and Cai Z: Erianin induces G2/M-phase arrest, apoptosis, and autophagy via the ROS/JNK signaling pathway in human osteosarcoma cells in vitro and in vivo. Cell Death Dis. 7:e22472016. View Article : Google Scholar : PubMed/NCBI
41	Croce CM and Reed JC: Finally, an apoptosis-targeting therapeutic for cancer. Cancer Res. 76:5914–5920. 2016. View Article : Google Scholar : PubMed/NCBI
42	Su Z, Yang Z, Xu Y, Chen Y and Yu Q: Apoptosis, autophagy, necroptosis, and cancer metastasis. Mol Cancer. 14:482015. View Article : Google Scholar : PubMed/NCBI
43	Huang G, Zou B, Lv J, Li T, Huai G, Xiang S, Lu S, Luo H, Zhang Y, Jin Y and Wang Y: Notoginsenoside R1 attenuates glucose-induced podocyte injury via the inhibition of apoptosis and the activation of autophagy through the PI3K/Akt/mTOR signaling pathway. Int J Mol Med. 39:559–568. 2017. View Article : Google Scholar : PubMed/NCBI
44	Ko JH, Lee JH, Jung SH, Lee SG, Chinnathambi A, Alharbi SA, Yang WM, Um JY, Sethi G and Ahn KS: 2,5-Dihydroxyacetophenone induces apoptosis of multiple myeloma cells by regulating the MAPK activation pathway. Molecules. 22:E11572017. View Article : Google Scholar : PubMed/NCBI
45	Fulda S: Synthetic lethality by co-targeting mitochondrial apoptosis and PI3K/Akt/mTOR signaling. Mitochondrion. 19:85–87. 2014. View Article : Google Scholar : PubMed/NCBI