Curcumol inhibits the proliferation of gastric adenocarcinoma MGC-803 cells via downregulation of IDH1

Zang,Shilei; Tang,Qiling; Dong,Fangrui; Liu,Huan; Li,Lili; Guo,Fang; Pan,Xuediao; Lin,Haorong; Zeng,Weibin; Cai,Zhaoxu; Zhong,Qibin; Zang,Ning; Zang,Linquan

doi:10.3892/or.2017.6028

Curcumol inhibits the proliferation of gastric adenocarcinoma MGC-803 cells via downregulation of IDH1

Authors:
- Shilei Zang
- Qiling Tang
- Fangrui Dong
- Huan Liu
- Lili Li
- Fang Guo
- Xuediao Pan
- Haorong Lin
- Weibin Zeng
- Zhaoxu Cai
- Qibin Zhong
- Ning Zang
- Linquan Zang
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Affiliations: New Drug Screening Center, Pharmaceutical College, Guangdong Pharmaceutical University, Guangzhou, Guangdong 510006, P.R. China, Xinhua College of Sun Yat-sen University, Dongguan, Guangdong 523000, P.R. China, Guangzhou Nansha Central Hospital, Guangzhou, Guangdong 511400, P.R. China
Published online on: October 12, 2017 https://doi.org/10.3892/or.2017.6028
Pages: 3583-3591

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Abstract

Curcumol, a polyphenol compound derived from the rhizome of Curcuma, has been established as an antitumor compound against multiple types of cancer, including gastric (GC), lung, liver and breast cancer. However, the molecular mechanisms undelying its anticancer activity in GC are still unclear. In this study, the antitumor efficacy of curcumol was ascertained in human gastric adenocarcinoma MGC-803 cells. An MTT assay was used to assess the viability of the MGC-803 cells treated by curcumol. The results of the Annexin V/propidium iodide (PI) staining followed by fluorescence activated cell sorting (FACS) analysis demonstrated that the cell cycle was arrested in the G2/M phase by curcumol. Annexin V-FITC/PI double staining followed by FACS analysis revealed that curcumol induced apoptosis of MGC-803 cells. FACS analysis after the cells were loaded with a DFCH-DA probe revealed that the level of reactive oxygen species (ROS) increased after the cells were treated with curcumol. In adittion, FACS analysis after the cells were loaded with JC-1 revealed that the level of mitochondrial membrane potential (MMP) decreased after the cells were treated with curcumol. Furthermore, the downregulation of isocitrate dehydrogenase 1 (IDH1) was observed in the MGC-803 cells after being treated with curcumol as determined by western blotting and RT-qPCR. In conclusion, we elucidated the antitumor effect of curcumol on MGC-803 cells and the involved mechanisms related to the induction of apoptosis, the increase of ROS, the decrease of MMP and the downregulation of IDH1.

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1	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
2	Hudler P: Challenges of deciphering gastric cancer heterogeneity. World J Gastroenterol. 21:10510–10527. 2015. View Article : Google Scholar : PubMed/NCBI
3	Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI
4	Xu W, Yang Z and Lu N: Molecular targeted therapy for the treatment of gastric cancer. J Exp Clin Cancer Res. 35:12016. View Article : Google Scholar : PubMed/NCBI
5	Ko YC, Lien JC, Liu HC, Hsu SC, Ji BC, Yang MD, Hsu WH and Chung JG: Demethoxycurcumin induces the apoptosis of human lung cancer NCI-H460 cells through the mitochondrial-dependent pathway. Oncol Rep. 33:2429–2437. 2015. View Article : Google Scholar : PubMed/NCBI
6	Gomez-Martín C, Lopez-Rios F, Aparicio J, Barriuso J, García-Carbonero R, Pazo R, Rivera F, Salgado M, Salud A, Vázquez-Sequeiros E, et al: A critical review of HER2-positive gastric cancer evaluation and treatment: From trastuzumab, and beyond. Cancer Lett. 351:30–40. 2014. View Article : Google Scholar : PubMed/NCBI
7	Al-Batran SE, Ducreux M and Ohtsu A: mTOR as a therapeutic target in patients with gastric cancer. Int J Cancer. 130:491–496. 2012. View Article : Google Scholar : PubMed/NCBI
8	Zhang K, Cui J, Xi H, Bian S, Ma L, Shen W, Li J, Wang N, Wei B and Chen L: Serum HER2 is a potential surrogate for tissue HER2 status in gastric cancer: A systematic review and meta-analysis. PLoS One. 10:e01363222015. View Article : Google Scholar : PubMed/NCBI
9	Liu JS, He SC, Zhang ZL, Chen R, Fan L, Qiu GL, Chang S, Li L and Che XM: Anticancer effects of β-elemene in gastric cancer cells and its potential underlying proteins: A proteomic study. Oncol Rep. 32:2635–2647. 2014. View Article : Google Scholar : PubMed/NCBI
10	Cai XZ, Huang WY, Qiao Y, Du SY, Chen Y, Chen D, Yu S, Che RC, Liu N and Jiang Y: Inhibitory effects of curcumin on gastric cancer cells: A proteomic study of molecular targets. Phytomedicine. 20:495–505. 2013. View Article : Google Scholar : PubMed/NCBI
11	Cai LJ, Song SP, Lu B and Meng LN: Reversal effect of curcuma wenyujin extract on SGC-7901/VCR induced subcutaneous transplanted tumor in nude mice and its effect on the expression of P-glycoprotein. Zhongguo Zhong Xi Yi Jie He Za Zhi. 34:1347–1353. 2014.(In Chinese). PubMed/NCBI
12	Guo P, Wang YW, Weng BX, Li XK, Yang SL and Ye FQ: Synthesis, anti-tumor activity, and structure-activity relationships of curcumol derivatives. J Asian Nat Prod Res. 16:53–58. 2014. View Article : Google Scholar : PubMed/NCBI
13	Tang QL, Guo JQ, Wang QY, Lin HS, Yang ZP, Peng T, Pan XD, Liu B, Wang SJ and Zang LQ: Curcumol induces apoptosis in SPC-A-1 human lung adenocarcinoma cells and displays anti-neoplastic effects in tumor bearing mice. Asian Pac J Cancer Prev. 16:2307–2312. 2015. View Article : Google Scholar : PubMed/NCBI
14	Gao C, Ding Z, Liang B, Chen N and Cheng D: Study on the effects of curcumin on angiogenesis. Zhong Yao Cai. 26:499–502. 2003.(In Chinese). PubMed/NCBI
15	Lu JJ, Dang YY, Huang M, Xu WS, Chen XP and Wang YT: Anti-cancer properties of terpenoids isolated from Rhizoma Curcumae - a review. J Ethnopharmacol. 143:406–411. 2012. View Article : Google Scholar : PubMed/NCBI
16	Thani Abdullah NA, Sallis B, Nuttall R, Schubert FR, Ahsan M, Davies D, Purewal S, Cooper A and Rooprai HK: Induction of apoptosis and reduction of MMP gene expression in the U373 cell line by polyphenolics in Aronia melanocarpa and by curcumin. Oncol Rep. 28:1435–1442. 2012. View Article : Google Scholar : PubMed/NCBI
17	Fan H, Liang Y, Jiang B, Li X, Xun H, Sun J, He W, Lau HT and Ma X: Curcumin inhibits intracellular fatty acid synthase and induces apoptosis in human breast cancer MDA-MB-231 cells. Oncol Rep. 35:2651–2656. 2016. View Article : Google Scholar : PubMed/NCBI
18	Du Q, Hu B, An HM, Shen KP, Xu L, Deng S and Wei MM: Synergistic anticancer effects of curcumin and resveratrol in Hepa1-6 hepatocellular carcinoma cells. Oncol Rep. 29:1851–1858. 2013. View Article : Google Scholar : PubMed/NCBI
19	Zhao G, Han X, Zheng S, Li Z, Sha Y, Ni J, Sun Z, Qiao S and Song Z: Curcumin induces autophagy, inhibits proliferation and invasion by downregulating AKT/mTOR signaling pathway in human melanoma cells. Oncol Rep. 35:1065–1074. 2016. View Article : Google Scholar : PubMed/NCBI
20	Park EH, Bae WY, Eom SJ, Kim KT and Paik HD: Improved antioxidative and cytotoxic activities of chamomile (Matricaria chamomilla) florets fermented by Lactobacillus plantarum KCCM 11613P. J Zhejiang Univ Sci B. 18:152–160. 2017. View Article : Google Scholar : PubMed/NCBI
21	Narita Y and Muro K: Challenges in molecular targeted therapy for gastric cancer: Considerations for efficacy and safety. Expert Opin Drug Saf. 16:319–327. 2016. View Article : Google Scholar : PubMed/NCBI
22	Han J, Meng Q, Xi Q, Wang H and Wu G: PFKFB3 was overexpressed in gastric cancer patients and promoted the proliferation and migration of gastric cancer cells. Cancer Biomark. 18:249–256. 2017. View Article : Google Scholar : PubMed/NCBI
23	Kang Y, Hu W, Bai E, Zheng H, Liu Z, Wu J, Jin R, Zhao C and Liang G: Curcumin sensitizes human gastric cancer cells to 5-fluorouracil through inhibition of the NFκB survival-signaling pathway. Onco Targets Ther. 9:7373–7384. 2016. View Article : Google Scholar : PubMed/NCBI
24	Guo X, Zhang L, Fan Y, Zhang D, Qin L, Dong S and Li G: Oxysterol binding protein-related protein 8 inhibits gastric cancer growth through induction of ER stress, inhibition of Wnt signaling and activation of apoptosis. Oncol Res. 25:799–808. 2017. View Article : Google Scholar : PubMed/NCBI
25	Echizen K, Hirose O, Maeda Y and Oshima M: Inflammation in gastric cancer: Interplay of the COX-2/prostaglandin E2 and Toll-like receptor/MyD88 pathways. Cancer Sci. 107:391–397. 2016. View Article : Google Scholar : PubMed/NCBI
26	DeNicola GM, Karreth FA, Humpton TJ, Gopinathan A, Wei C, Frese K, Mangal D, Yu KH, Yeo CJ, Calhoun ES, et al: Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature. 475:106–109. 2011. View Article : Google Scholar : PubMed/NCBI
27	Ishikawa K, Takenaga K, Akimoto M, Koshikawa N, Yamaguchi A, Imanishi H, Nakada K, Honma Y and Hayashi J: ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science. 320:661–664. 2008. View Article : Google Scholar : PubMed/NCBI
28	Yee C, Yang W and Hekimi S: The intrinsic apoptosis pathway mediates the pro-longevity response to mitochondrial ROS in C. elegans. Cell. 157:897–909. 2014. View Article : Google Scholar : PubMed/NCBI
29	Zhao X, Xu L, Zheng L, Yin L, Qi Y, Han X, Xu Y and Peng J: Potent effects of dioscin against gastric cancer in vitro and in vivo. Phytomedicine. 23:274–282. 2016. View Article : Google Scholar : PubMed/NCBI
30	Wang SQ, Wang C, Wang JW, Yang DX, Wang R, Wang CJ, Li HJ, Shi HG, Ke Y and Liu HM: Geridonin, a novel derivative of oridonin, inhibits proliferation of MGC 803 cells both in vitro and in vivo through elevating the intracellular ROS. J Pharm Pharmacol. 69:213–221. 2017. View Article : Google Scholar : PubMed/NCBI
31	Shi XJ, Yu B, Wang JW, Qi PP, Tang K, Huang X and Liu HM: Structurally novel steroidal spirooxindole by241 potently inhibits tumor growth mainly through ROS-mediated mechanisms. Sci Rep. 6:316072016. View Article : Google Scholar : PubMed/NCBI
32	Zhou Y, Wei L, Zhang H, Dai Q, Li Z, Yu B, Guo Q and Lu N: FV-429 induced apoptosis through ROS-mediated ERK2 nuclear translocation and p53 activation in gastric cancer cells. J Cell Biochem. 116:1624–1637. 2015. View Article : Google Scholar : PubMed/NCBI
33	Huang XC, Jin L, Wang M, Liang D, Chen ZF, Zhang Y, Pan YM and Wang HS: Design, synthesis and in vitro evaluation of novel dehydroabietic acid derivatives containing a dipeptide moiety as potential anticancer agents. Eur J Med Chem. 89:370–385. 2015. View Article : Google Scholar : PubMed/NCBI
34	Ye MY, Yao GY, Pan YM, Liao ZX, Zhang Y and Wang HS: Synthesis and antitumor activities of novel α-aminophosphonate derivatives containing an alizarin moiety. Eur J Med Chem. 83:116–128. 2014. View Article : Google Scholar : PubMed/NCBI
35	Li JF, Huang RZ, Yao GY, Ye MY, Wang HS, Pan YM and Xiao JT: Synthesis and biological evaluation of novel aniline-derived asiatic acid derivatives as potential anticancer agents. Eur J Med Chem. 86:175–188. 2014. View Article : Google Scholar : PubMed/NCBI
36	Zhou Y, Tian L, Long L, Quan M, Liu F and Cao J: Casticin potentiates TRAIL-induced apoptosis of gastric cancer cells through endoplasmic reticulum stress. PLoS One. 8:e588552013. View Article : Google Scholar : PubMed/NCBI
37	Wu C, Wang C, Han T, Zhou X, Guo S and Zhang J: Insight into the cellular internalization and cytotoxicity of graphene quantum dots. Adv Healthc Mater. 2:1613–1619. 2013. View Article : Google Scholar : PubMed/NCBI
38	Qian X, Li J, Ding J, Wang Z, Duan L and Hu G: Glibenclamide exerts an antitumor activity through reactive oxygen species-c-jun NH2-terminal kinase pathway in human gastric cancer cell line MGC-803. Biochem Pharmacol. 76:1705–1715. 2008. View Article : Google Scholar : PubMed/NCBI
39	Chen CW, Chan YC, Hsiao M and Liu RS: Plasmon-enhanced photodynamic cancer therapy by upconversion nanoparticles conjugated with Au nanorods. ACS Appl Mater Interfaces. 8:32108–32119. 2016. View Article : Google Scholar : PubMed/NCBI
40	Liu L, Fu L, Jing T, Ruan Z and Yan L: pH-triggered polypeptides nanoparticles for efficient BODIPY imaging-guided near infrared photodynamic therapy. ACS Appl Mater Interfaces. 8:8980–8990. 2016. View Article : Google Scholar : PubMed/NCBI
41	Chou NH, Tsai CY, Tu YT, Wang KC, Kang CH, Chang PM, Li GC, Lam HC, Liu SI and Tsai KW: Isocitrate dehydrogenase 2 dysfunction contributes to 5-hydroxymethylcytosine depletion in gastric cancer cells. Anticancer Res. 36:3983–3990. 2016.PubMed/NCBI
42	Jiang L, Shestov AA, Swain P, Yang C, Parker SJ, Wang QA, Terada LS, Adams ND, McCabe MT, Pietrak B, et al: Reductive carboxylation supports redox homeostasis during anchorage-independent growth. Nature. 532:255–258. 2016. View Article : Google Scholar : PubMed/NCBI
43	Lian CG, Xu Y, Ceol C, Wu F, Larson A, Dresser K, Xu W, Tan L, Hu Y, Zhan Q, et al: Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma. Cell. 150:1135–1146. 2012. View Article : Google Scholar : PubMed/NCBI
44	IDH1 inhibitor shows promising early results. Cancer Discov. 5:42015.
45	Shi H, Tan B, Ji G, Lu L, Cao A, Shi S and Xie J: Zedoary oil (Ezhu You) inhibits proliferation of AGS cells. Chin Med. 8:132013. View Article : Google Scholar : PubMed/NCBI