Nitidine chloride inhibits the malignant behavior of human glioblastoma cells by targeting the PI3K/AKT/mTOR signaling pathway

Liu,Ming; Wang,Jiwei; Qi,Qichao; Huang,Bin; Chen,Anjing; Li,Xingang; Wang,Jian

doi:10.3892/or.2016.4998

Nitidine chloride inhibits the malignant behavior of human glioblastoma cells by targeting the PI3K/AKT/mTOR signaling pathway

Authors:
- Ming Liu
- Jiwei Wang
- Qichao Qi
- Bin Huang
- Anjing Chen
- Xingang Li
- Jian Wang
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Affiliations: Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Wenhua Xi Road, Jinan, Shandong 250012, P.R. China
Published online on: August 3, 2016 https://doi.org/10.3892/or.2016.4998
Pages: 2160-2168

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Abstract

Recent studies have demonstrated that nitidine chloride (NC), a natural bioactive alkaloid, displays potent antitumor activity in various types of cancer. In the present study, NC was examined for efficacy in the treatment of human glioblastoma multiforme (GBM) as well as the molecular basis for its more general inhibitory effects in cancer. U251 and U87 GBM cell lines were exposed to three concentrations of NC (5, 25 and 50 µM) in vitro, and tumor cell growth was assessed on the basis of proliferation, migration and energy metabolism. Decreases in viability and proliferation reached ~50% for both cell lines with 50 µM NC at 24 h as assessed by cell viability Cell Counting Kit-8 (CCK-8) and EdU assays. In wound closure and Transwell assays, migration and invasion were inhibited at 50 µM after 24 h (~20 and 80%, respectively; P<0.05). ATP and L-lactate levels were also decreased after treatment with NC (50 µM, 24 h; P<0.05 and P<0.01, respectively). Finally, in western blot analysis, phosphorylation of Akt and mTOR was suppressed by NC, but partially restored when cells were treated simultaneously with a novel Akt activator, SC79. Partial restoration was also observed in viability/proliferation (U251 and U87, ~15 vs. 40%; NC vs. NC + SC79; P<0.05) and invasion (U251 and U87, ~30 vs. 60%; NC vs. NC + SC79; P<0.05). Our results demonstrated that NC inhibits development of GBM by targeting the PI3K/Akt/mTOR signaling pathway and provides a potential therapeutic agent for the treatment of GBM.

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1	Ricard D, Idbaih A, Ducray F, Lahutte M, Hoang-Xuan K and Delattre JY: Primary brain tumours in adults. Lancet. 379:1984–1996. 2012. View Article : Google Scholar : PubMed/NCBI
2	Stupp R, Brada M, van den Bent MJ, Tonn JC and Pentheroudakis G; ESMO Guidelines Working Group: High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 25(Suppl 3): iii93–iii101. iii2014. View Article : Google Scholar : PubMed/NCBI
3	Van Meir EG, Hadjipanayis CG, Norden AD, Shu HK, Wen PY and Olson JJ: Exciting new advances in neuro-oncology: The avenue to a cure for malignant glioma. CA Cancer J Clin. 60:166–193. 2010. View Article : Google Scholar : PubMed/NCBI
4	Gordaliza M: Natural products as leads to anticancer drugs. Clin Transl Oncol. 9:767–776. 2007. View Article : Google Scholar : PubMed/NCBI
5	Newman DJ, Cragg GM and Snader KM: The influence of natural products upon drug discovery. Nat Prod Rep. 17:215–234. 2000. View Article : Google Scholar : PubMed/NCBI
6	Fang Z, Tang Y, Jiao W, Xing Z, Guo Z, Wang W, Shi B, Xu Z and Liu Z: Nitidine chloride inhibits renal cancer cell metastasis via suppressing AKT signaling pathway. Food Chem Toxicol. 60:246–251. 2013. View Article : Google Scholar : PubMed/NCBI
7	Lin J, Shen A, Chen H, Liao J, Xu T, Liu L, Lin J and Peng J: Nitidine chloride inhibits hepatic cancer growth via modulation of multiple signaling pathways. BMC Cancer. 14:7292014. View Article : Google Scholar : PubMed/NCBI
8	Sun X, Lin L, Chen Y, Liu T, Liu R, Wang Z, Mou K, Xu J, Li B and Song H: Nitidine chloride inhibits ovarian cancer cell migration and invasion by suppressing MMP-2/9 production via the ERK signaling pathway. Mol Med Rep. 13:3161–3168. 2016.PubMed/NCBI
9	Zhai H, Hu S, Liu T, Wang F, Wang X, Wu G, Zhang Y, Sui M, Liu H and Jiang L: Nitidine chloride inhibits proliferation and induces apoptosis in colorectal cancer cells by suppressing the ERK signaling pathway. Mol Med Rep. 13:2536–2542. 2016.PubMed/NCBI
10	Javadov S, Baetz D, Rajapurohitam V, Zeidan A, Kirshenbaum LA and Karmazyn M: Antihypertrophic effect of Na⁺/H⁺ exchanger isoform 1 inhibition is mediated by reduced mitogen-activated protein kinase activation secondary to improved mitochondrial integrity and decreased generation of mitochondrial-derived reactive oxygen species. J Pharmacol Exp Ther. 317:1036–1043. 2006. View Article : Google Scholar : PubMed/NCBI
11	Bettum IJ, Gorad SS, Barkovskaya A, Pettersen S, Moestue SA, Vasiliauskaite K, Tenstad E, Øyjord T, Risa Ø, Nygaard V, et al: Metabolic reprogramming supports the invasive phenotype in malignant melanoma. Cancer Lett. 366:71–83. 2015. View Article : Google Scholar : PubMed/NCBI
12	Keunen O, Johansson M, Oudin A, Sanzey M, Rahim SA, Fack F, Thorsen F, Taxt T, Bartos M, Jirik R, et al: Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma. Proc Natl Acad Sci USA. 108:3749–3754. 2011. View Article : Google Scholar : PubMed/NCBI
13	Warburg O: On the origin of cancer cells. Science. 123:309–314. 1956. View Article : Google Scholar : PubMed/NCBI
14	Gao Y, Su Y, Qu L, Xu S, Meng L, Cai SQ and Shou C: Mitochondrial apoptosis contributes to the anti-cancer effect of Smilax glabra Roxb. Toxicol Lett. 207:112–120. 2011. View Article : Google Scholar : PubMed/NCBI
15	Youle RJ and van der Bliek AM: Mitochondrial fission, fusion, and stress. Science. 337:1062–1065. 2012. View Article : Google Scholar : PubMed/NCBI
16	Kasahara A and Scorrano L: Mitochondria: From cell death executioners to regulators of cell differentiation. Trends Cell Biol. 24:761–770. 2014. View Article : Google Scholar : PubMed/NCBI
17	Zhao J, Lendahl U and Nistér M: Regulation of mitochondrial dynamics: Convergences and divergences between yeast and vertebrates. Cell Mol Life Sci. 70:951–976. 2013. View Article : Google Scholar :
18	Jo H, Mondal S, Tan D, Nagata E, Takizawa S, Sharma AK, Hou Q, Shanmugasundaram K, Prasad A, Tung JK, et al: Small molecule-induced cytosolic activation of protein kinase Akt rescues ischemia-elicited neuronal death. Proc Natl Acad Sci USA. 109:10581–10586. 2012. View Article : Google Scholar : PubMed/NCBI
19	Liu N, Li P, Zang S, Liu Q, Ma D, Sun X and Ji C: Novel agent nitidine chloride induces erythroid differentiation and apoptosis in CML cells through c-Myc-miRNAs axis. PLoS One. 10:e01168802015. View Article : Google Scholar : PubMed/NCBI
20	Ou X, Lu Y, Liao L, Li D, Liu L, Liu H and Xu H: Nitidine chloride induces apoptosis in human hepatocellular carcinoma cells through a pathway involving p53, p21, Bax and Bcl-2. Oncol Rep. 33:1264–1274. 2015.
21	Sun M, Zhang N, Wang X, Cai C, Cun J, Li Y, Lv S and Yang Q: Nitidine chloride induces apoptosis, cell cycle arrest, and synergistic cytotoxicity with doxorubicin in breast cancer cells. Tumour Biol. 35:10201–10212. 2014. View Article : Google Scholar : PubMed/NCBI
22	Pan X, Han H, Wang L, Yang L, Li R, Li Z, Liu J, Zhao Q, Qian M, Liu M, et al: Nitidine Chloride inhibits breast cancer cells migration and invasion by suppressing c-Src/FAK associated signaling pathway. Cancer Lett. 313:181–191. 2011. View Article : Google Scholar : PubMed/NCBI
23	Pérez-Escuredo J, Dadhich RK, Dhup S, Cacace A, Van Hée VF, De Saedeleer CJ, Sboarina M, Rodriguez F, Fontenille MJ, Brisson L, et al: Lactate promotes glutamine uptake and metabolism in oxidative cancer cells. Cell Cycle. 15:72–83. 2016. View Article : Google Scholar
24	Knudson CM and Brown NM: Mitochondria potential, bax 'activation,' and programmed cell death. Methods Mol Biol. 414:95–108. 2008.
25	Kang M, Ou H, Wang R, Liu W and Tang A: The effect of nitidine chloride on the proliferation and apoptosis of nasopharyngeal carcinoma cells. J BUON. 19:130–136. 2014.PubMed/NCBI
26	Wang J, Wu J, Wu H, Liu X, Chen Y, Wu J, Hu C and Zou D: Liraglutide protects pancreatic β-cells against free fatty acids in vitro and affects glucolipid metabolism in apolipoprotein E^−/− mice by activating autophagy. Mol Med Rep. 12:4210–4218. 2015.PubMed/NCBI
27	Manning BD and Cantley LC: AKT/PKB signaling: Navigating downstream. Cell. 129:1261–1274. 2007. View Article : Google Scholar : PubMed/NCBI