Oxymatrine induces nasopharyngeal cancer cell death through inhibition of PI3K/AKT and NF‑κB pathways

Ni,Zhili; Yi,Jingmei

doi:10.3892/mmr.2017.7822

Oxymatrine induces nasopharyngeal cancer cell death through inhibition of PI3K/AKT and NF‑κB pathways

Authors:
- Zhili Ni
- Jingmei Yi
View Affiliations

Affiliations: Department of Otorhinolaryngology Head and Neck Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, P.R. China, Department of Paediatrics, Chinese PLA General Hospital, Beijing 100853, P.R. China
Published online on: October 19, 2017 https://doi.org/10.3892/mmr.2017.7822
Pages: 9701-9706

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

Oxymatrine may inhibit tumor cell proliferation, induce cell cycle arrest, promote apoptosis, induce tumor cell differentiation and fight against tumor angiogenesis, as well as inhibit tumor invasion and metastasis. The present study aimed to investigate the anticancer effects of oxymatrine on nasopharyngeal cancer (NPC) cell death, and the underlying molecular mechanisms of these effects. NPC HK‑1 cells were incubated overnight and treated with oxymatrine (0, 2, 4, 6 and 8 mg/ml) for 1, 2 or 3 days. The results demonstrated that oxymatrine significantly inhibited NPC cell proliferation in a time‑ and dose‑dependent manner. Oxymatrine treatment also induced apoptosis, induced the activities of caspase‑3 and caspase‑9, promoted p53 and Bax protein expression, and suppressed cyclin D protein expression in these cells. The protein expression levels of phosphoinositide 3 kinase (PI3K), phosphorylated (p)‑AKT, p‑mammalian target of rapamycin, p‑p70 ribosomal protein S6 kinase and nuclear factor (NF)‑κB were significantly downregulated by oxymatrine treatment. In conclusion, results from the present study suggested that oxymatrine may induce NPC cell death through the inhibition of PI3K/AKT and NF‑κB signaling pathways.

View Figures

View References

1	Casanova M, Özyar E, Patte C, Orbach D, Ferrari A, Veyrat-Follet C, Errihani H, Pan J, Zhang L, Shen L, et al: International randomized phase 2 study on the addition of docetaxel to the combination of cisplatin and 5-fluorouracil in the induction treatment for nasopharyngeal carcinoma in children and adolescents. Cancer Chemother Pharmacol. 77:289–298. 2016. View Article : Google Scholar : PubMed/NCBI
2	Chen Y, Liu MZ, Liang SB, Zong JF, Mao YP, Tang LL, Guo Y, Lin AH, Zeng XF and Ma J: Preliminary results of a prospective randomized trial comparing concurrent chemoradiotherapy plus adjuvant chemotherapy with radiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma in endemic regions of china. Int J Radiat Oncol Biol Phys. 71:1356–1364. 2008. View Article : Google Scholar : PubMed/NCBI
3	Li JG, Yuan X, Zhang LL, Tang YQ, Liu L, Chen XD, Gong XC, Wan GF, Liao YL, Ye JM and Ao F: A randomized clinical trial comparing prophylactic upper versus whole-neck irradiation in the treatment of patients with node-negative nasopharyngeal carcinoma. Cancer. 119:3170–3176. 2013. View Article : Google Scholar : PubMed/NCBI
4	Zhao M, Luo R, Liu Y, Gao L, Fu Z, Fu Q, Luo X, Chen Y, Deng X, Liang Z, et al: miR-3188 regulates nasopharyngeal carcinoma proliferation and chemosensitivity through a FOXO1-modulated positive feedback loop with mTOR-p-PI3K/AKT-c-JUN. Nat Commun. 7:113092016. View Article : Google Scholar : PubMed/NCBI
5	Zheng D, Zhu G, Liao S, Yi W, Luo G, He J, Pei Z, Li G and Zhou Y: Dysregulation of the PI3K/Akt signaling pathway affects cell cycle and apoptosis of side population cells in nasopharyngeal carcinoma. Oncol Lett. 10:182–188. 2015.PubMed/NCBI
6	Viana LR and Gomes-Marcondes MC: A leucine-rich diet modulates the tumor-induced down-regulation of the MAPK/ERK and PI3K/Akt/mTOR signaling pathways and maintains the expression of the ubiquitin-proteasome pathway in the placental tissue of NMRI mice. Biol Reprod. 92:492015. View Article : Google Scholar : PubMed/NCBI
7	Wong CH, Loong HH, Hui CW, Lau CP, Hui EP, Ma BB and Chan AT: Preclinical evaluation of the PI3K-mTOR dual inhibitor PF-04691502 as a novel therapeutic drug in nasopharyngeal carcinoma. Invest New Drugs. 31:1399–1408. 2013. View Article : Google Scholar : PubMed/NCBI
8	Tasioudi KE, Sakellariou S, Levidou G, Theodorou D, Michalopoulos NV, Patsouris E, Korkolopoulou P and Saetta AA: Immunohistochemical and molecular analysis of PI3K/AKT/mTOR pathway in esophageal carcinoma. APMIS. 123:639–647. 2015. View Article : Google Scholar : PubMed/NCBI
9	Shin SY, Kim CG, Jung YJ, Lim Y and Lee YH: The UPR inducer DPP23 inhibits the metastatic potential of MDA-MB-231 human breast cancer cells by targeting the Akt-IKK-NF-κB-MMP-9 axis. Sci Rep. 6:341342016. View Article : Google Scholar : PubMed/NCBI
10	Zheng H, Dai W, Cheung AK, Ko JM, Kan R, Wong BW, Leong MM, Deng M, Kwok TC, Chan JY, et al: Whole-exome sequencing identifies multiple loss-of-function mutations of NF-κB pathway regulators in nasopharyngeal carcinoma. Proc Natl Acad Sci USA. 113:pp. 11283–11288. 2016; View Article : Google Scholar : PubMed/NCBI
11	Liang L and Huang J: Oxymatrine inhibits epithelial-mesenchymal transition through regulation of NF-κB signaling in colorectal cancer cells. Oncol Rep. 36:1333–1338. 2016. View Article : Google Scholar : PubMed/NCBI
12	Lin B, Li D and Zhang L: Oxymatrine mediates Bax and Bcl-2 expression in human breast cancer MCF-7 cells. Pharmazie. 71:154–157. 2016.PubMed/NCBI
13	Peng PJ, Ou XQ, Chen ZB, Liao H, Peng YL, Wang SY, Zhang HY and Lin Z: Multicenter phase II study of capecitabine combined with nedaplatin for recurrent and metastatic nasopharyngeal carcinoma patients after failure of cisplatin-based chemotherapy. Cancer Chemother Pharmacol. 72:323–328. 2013. View Article : Google Scholar : PubMed/NCBI
14	Chen Y, Sun Y, Liang SB, Zong JF, Li WF, Chen M, Chen L, Mao YP, Tang LL, Guo Y, et al: Progress report of a randomized trial comparing long-term survival and late toxicity of concurrent chemoradiotherapy with adjuvant chemotherapy versus radiotherapy alone in patients with stage III to IVB nasopharyngeal carcinoma from endemic regions of China. Cancer. 119:2230–2238. 2013. View Article : Google Scholar : PubMed/NCBI
15	Zhang Y, Zhao L, Huang P, Wu J, Wang F, Huang Y and Zhang L: Open-label, single-arm phase II study of pemetrexed in the treatment of patients with recurrent or metastatic nasopharyngeal carcinoma who have had prior platinum-based chemotherapy. Cancer Chemother Pharmacol. 70:611–615. 2012. View Article : Google Scholar : PubMed/NCBI
16	Bourouba M, Benyelles-Boufennara A, Terki N, Baraka-Kerboua E, Bouzid K and Touil-Boukoffa C: Epidermal growth factor receptor (EGFR) abundance correlates with p53 and Bcl-2 accumulation and patient age in a small cohort of North African nasopharyngeal carcinoma patients. Eur Cytokine Netw. 22:38–44. 2011.PubMed/NCBI
17	Kao CL, Cho J, Lee YZ, Cheng YB, Chien CY, Hwang CF, Hong YR, Tseng CN and Cho CL: Ethanolic extracts of pluchea indica induce apoptosis and antiproliferation effects in human nasopharyngeal carcinoma cells. Molecules. 20:11508–11523. 2015. View Article : Google Scholar : PubMed/NCBI
18	Wu C, Huang W, Guo Y, Xia P, Sun X, Pan X and Hu W: Oxymatrine inhibits the proliferation of prostate cancer cells in vitro and in vivo. Mol Med Rep. 11:4129–4134. 2015. View Article : Google Scholar : PubMed/NCBI
19	Xu M, Cheung CC, Chow C, Lun SW, Cheung ST and Lo KW: Overexpression of PIN1 enhances cancer growth and aggressiveness with cyclin D1 induction in EBV-associated nasopharyngeal carcinoma. PLoS One. 11:e01568332016. View Article : Google Scholar : PubMed/NCBI
20	Liao D, Wu Y, Pu X, Chen H, Luo S, Li B, Ding C, Huang GL and He Z: Cyclin D1 G870A polymorphism and risk of nasopharyngeal carcinoma: A case-control study and meta-analysis. PLoS One. 9:e1132992014. View Article : Google Scholar : PubMed/NCBI
21	Peng G, Cao RB, Li YH, Zou ZW, Huang J and Ding Q: Alterations of cell cycle control proteins SHP-1/2, p16, CDK4 and cyclin D1 in radioresistant nasopharyngeal carcinoma cells. Mol Med Rep. 10:1709–1716. 2014. View Article : Google Scholar : PubMed/NCBI
22	Liu Y, Bi T, Wang Z, Wu G, Qian L, Gao Q and Shen G: Oxymatrine synergistically enhances antitumor activity of oxaliplatin in colon carcinoma through PI3K/AKT/mTOR pathway. Apoptosis. 21:1398–1407. 2016. View Article : Google Scholar : PubMed/NCBI
23	Yu X, Zhen Y, Yang H, Wang H, Zhou Y, Wang E, Marincola FM, Mai C, Chen Y, Wei H, et al: Loss of connective tissue growth factor as an unfavorable prognosis factor activates miR-18b by PI3K/AKT/C-Jun and C-Myc and promotes cell growth in nasopharyngeal carcinoma. Cell Death Dis. 4:e6342013. View Article : Google Scholar : PubMed/NCBI
24	Yuen JW, Chung GT, Lun SW, Cheung CC, To KF and Lo KW: Epigenetic inactivation of inositol polyphosphate 4-phosphatase B (INPP4B), a regulator of PI3K/AKT signaling pathway in EBV-associated nasopharyngeal carcinoma. PLoS One. 9:e1051632014. View Article : Google Scholar : PubMed/NCBI
25	Chen J: Roles of the PI3K/Akt pathway in Epstein-Barr virus-induced cancers and therapeutic implications. World J Virol. 1:154–161. 2012. View Article : Google Scholar : PubMed/NCBI
26	Zhu DD, Zhang J, Deng W, Yip YL, Lung HL, Tsang CM, Law WT, Yang J, Lau VM, Shuen WH, et al: Significance of NF-κB activation in immortalization of nasopharyngeal epithelial cells. Int J Cancer. 138:1175–1185. 2016. View Article : Google Scholar : PubMed/NCBI
27	Lin ML, Lu YC, Chung JG, Wang SG, Lin HT, Kang SE, Tang CH, Ko JL and Chen SS: Down-regulation of MMP-2 through the p38 MAPK-NF-kappaB-dependent pathway by aloe-emodin leads to inhibition of nasopharyngeal carcinoma cell invasion. Mol Carcinog. 49:783–797. 2010.PubMed/NCBI