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Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Morin Inhibits Ovarian Cancer Growth through the Inhibition of NF-κB Signaling Pathway

Author(s): Meimei Xu and Yan Zhang*

Volume 19, Issue 18, 2019

Page: [2243 - 2250] Pages: 8

DOI: 10.2174/1871521409666191014164742

Price: $65


Background & Objective: Ovarian cancer has the highest mortality in gynecological tumors without effective therapeutic drugs as a result of drug-resistance for long-term utilization. Morin has been reported to possess powerful anti-tumor effects in several cancers. The present study aims to investigate whether Morin could influence ovarian cancer growth and underlying mechanisms.

Methods: Morin was administered to cultured cells in vitro and formed tumors in vivo. MTT and colony formation assays were performed to explore the effects of Morin on the proliferation and colony formation of OVCAR3 and SKOV3 ovarian cancer cells. Western blot, RT-qPCR, immunofluorescence as well as ELISA were used to detect protein and mRNA expression of target factors. Tumor formation was performed to investigate tumorigenesis ability of drug-treated cells.

Results: The proliferation and colony size of OVCAR3 and SKOV3 were significantly decreased after Morin administration. The expression of NF-κB and inflammatory cytokine IL6/8 induced by TNF-α can be inhibited by Morin. Furthermore, Morin inhibited the volume of ovarian cancer tumors in nude mice.

Conclusion: Morin effectively alleviates ovarian cancer growth, inhibits the inflammatory response, and reduces tumor size via modulation of the NF-κB pathway.

Keywords: Morin, ovarian tumor, C/EBPβ, endoplasmic reticulum, NF-κB, mRNA expression.

Graphical Abstract
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2019. CA Cancer J. Clin., 2019, 69(1), 7-34.
[] [PMID: 30620402]
(a) Coleman, R.L.; Monk, B.J.; Sood, A.K.; Herzog, T.J. Latest research and treatment of advanced-stage epithelial ovarian cancer. Nat. Rev. Clin. Oncol., 2013, 10(4), 211-224.
[] [PMID: 23381004]
(b) Bookman, M.A.; Gilks, C.B.; Kohn, E.C.; Kaplan, K.O.; Huntsman, D.; Aghajanian, C.; Birrer, M.J.; Ledermann, J.A.; Oza, A.M.; Swenerton, K.D. Better therapeutic trials in ovarian cancer. J. Natl. Cancer Inst., 2014, 106(4) dju029
[] [PMID: 24627272]
Kim, Y.W.; Kim, E.Y.; Jeon, D.; Liu, J.L.; Kim, H.S.; Choi, J.W.; Ahn, W.S. Differential microRNA expression signatures and cell type-specific association with Taxol resistance in ovarian cancer cells. Drug Des. Devel. Ther., 2014, 8, 293-314.
[PMID: 24591819]
Fang, S-H.; Hou, Y-C.; Chang, W-C.; Hsiu, S-L.; Chao, P.D.; Chiang, B.L. Morin sulfates/glucuronides exert anti-inflammatory activity on activated macrophages and decreased the incidence of septic shock. Life Sci., 2003, 74(6), 743-756.
[] [PMID: 14654167]
Caselli, A.; Cirri, P.; Santi, A.; Paoli, P. Morin: A promising natural drug. Curr. Med. Chem., 2016, 23(8), 774-791.
[] [PMID: 26018232]
Ji, Y.; Jia, L.; Zhang, Y.; Xing, Y.; Wu, X.; Zhao, B.; Zhang, D.; Xu, X.; Qiao, X. Antitumor activity of the plant extract morin in tongue squamous cell carcinoma cells. Oncol. Rep., 2018, 40(5), 3024-3032.
[] [PMID: 30132559]
Jiang, W.; Wang, Y.; Sun, W.; Zhang, M. Morin suppresses astrocyte activation and regulates cytokine release in bone cancer pain rat models. Phytother. Res., 2017, 31(9), 1298-1304.
[] [PMID: 28618070]
Zhang, Q.; Zhang, F.; Thakur, K.; Wang, J.; Wang, H.; Hu, F.; Zhang, J.G.; Wei, Z.J. Molecular mechanism of anti-cancerous potential of Morin extracted from mulberry in Hela cells. Food Chem. Toxicol., 2018, 112, 466-475.
[] [PMID: 28689916]
Jiang, K.; Shi, J.; Shi, J. Morin alleviates vincristine-induced neuropathic pain via nerve protective effect and inhibition of NF-κB pathway in rats. Cell. Mol. Neurobiol., 2019, 39(6), 799-808.
[] [PMID: 31011938]
Bieg, D.; Sypniewski, D.; Nowak, E.; Bednarek, I. Morin decreases galectin-3 expression and sensitizes ovarian cancer cells to cisplatin. Arch. Gynecol. Obstet., 2018, 298(6), 1181-1194.
[] [PMID: 30267152]
Yan, X.Y.; Zhang, Y.; Zhang, J.J.; Zhang, L.C.; Liu, Y.N.; Wu, Y.; Xue, Y.N.; Lu, S.Y.; Su, J.; Sun, L.K. p62/SQSTM1 as an oncotarget mediates cisplatin resistance through activating RIP1-NF-κB pathway in human ovarian cancer cells. Cancer Sci., 2017, 108(7), 1405-1413.
[] [PMID: 28498503]
Qu, Y.; Liu, Y.; Li, R. FSTL1 promotes inflammatory reaction and cartilage catabolism through interplay with NFκB signaling pathways in an in vitro ONFH model. Inflammation, 2019, 42(4), 1491-1503.
[] [PMID: 31011927]
Cho, U.; Kim, B.; Kim, S.; Han, Y.; Song, Y.S. Pro-inflammatory M1 macrophage enhances metastatic potential of ovarian cancer cells through NF-κB activation. Mol. Carcinog., 2018, 57(2), 235-242.
[] [PMID: 29024042]
Hayakawa, K.; Nakajima, S.; Hiramatsu, N.; Okamura, M.; Huang, T.; Saito, Y.; Tagawa, Y.; Tamai, M.; Takahashi, S.; Yao, J.; Kitamura, M. ER stress depresses NF-kappaB activation in mesangial cells through preferential induction of C/EBP beta. J. Am. Soc. Nephrol., 2010, 21(1), 73-81.
[] [PMID: 19875812]
Zou, J.; Li, H.; Chen, X.; Zeng, S.; Ye, J.; Zhou, C.; Liu, M.; Zhang, L.; Yu, N.; Gan, X.; Zhou, H.; Xian, Z.; Chen, S.; Liu, P. C/EBPβ knockdown protects cardiomyocytes from hypertrophy via inhibition of p65-NFκB. Mol. Cell. Endocrinol., 2014, 390(1-2), 18-25.
[] [PMID: 24704266]
Dai, J.; Kumbhare, A.; Youssef, D.; Yao, Z.Q.; McCall, C.E.; El Gazzar, M. Expression of C/EBPβ in myeloid progenitors during sepsis promotes immunosuppression. Mol. Immunol., 2017, 91, 165-172.
[] [PMID: 28934717]
Foster, S.R.; Porrello, E.R.; Stefani, M.; Smith, N.J.; Molenaar, P.; dos Remedios, C.G.; Thomas, W.G.; Ramialison, M. Cardiac gene expression data and in silico analysis provide novel insights into human and mouse taste receptor gene regulation. Naunyn Schmiedebergs Arch. Pharmacol., 2015, 388(10), 1009-1027.
[] [PMID: 25986534]
Cao, Y.; Trillo-Tinoco, J.; Sierra, R.A.; Anadon, C.; Dai, W.; Mohamed, E.; Cen, L.; Costich, T.L.; Magliocco, A.; Marchion, D.; Klar, R.; Michel, S.; Jaschinski, F.; Reich, R.R.; Mehrotra, S.; Cubillos-Ruiz, J.R.; Munn, D.H.; Conejo-Garcia, J.R.; Rodriguez, P.C. ER stress-induced mediator C/EBP homologous protein thwarts effector T cell activity in tumors through T-bet repression. Nat. Commun., 2019, 10(1), 1280.
[] [PMID: 30894532]
(a) Sui, H.; Zhao, J.; Zhou, L.; Wen, H.; Deng, W.; Li, C.; Ji, Q.; Liu, X.; Feng, Y.; Chai, N.; Zhang, Q.; Cai, J.; Li, Q. Tanshinone IIA inhibits β-catenin/VEGF-mediated angiogenesis by targeting TGF-β1 in normoxic and HIF-1α in hypoxic microenvironments in human colorectal cancer. Cancer Lett., 2017, 403, 86-97.
[] [PMID: 28602978]
(b) Angius, F.; Floris, A. Liposomes and MTT cell viability assay: An incompatible affair. Toxicol. In Vitro, 2015, 29(2), 314-319.
(a) Tinzl, M.; Chen, B.; Chen, S.Y.; Semenas, J.; Abrahamsson, P.A.; Dizeyi, N. Interaction between c-jun and androgen receptor determines the outcome of taxane therapy in castration resistant prostate cancer. PLoS One, 2013, 8(11) e79573
[] [PMID: 24260253]
(b) Yano, S.; Takehara, K.; Tazawa, H.; Kishimoto, H.; Urata, Y.; Kagawa, S.; Fujiwara, T.; Hoffman, R.M. Cell-cycle-dependent drug-resistant quiescent cancer cells induce tumor angiogenesis after chemotherapy as visualized by real-time FUCCI imaging. Cell Cycle, 2017, 16(5), 406-414.
[] [PMID: 27715464]
(a) Chen, Y.; Wang, D.D.; Wu, Y.P.; Su, D.; Zhou, T.Y.; Gai, R.H.; Fu, Y.Y.; Zheng, L.; He, Q.J.; Zhu, H.; Yang, B. MDM2 promotes epithelial-mesenchymal transition and metastasis of ovarian cancer SKOV3 cells. Br. J. Cancer, 2017, 117(8), 1192-1201.
[] [PMID: 28817834]
(b) Chen, W.T.; Yang, Y.J.; Zhang, Z.D.; An, Q.; Li, N.; Liu, W.; Yang, B. MiR-1307 promotes ovarian cancer cell chemoresistance by targeting the ING5 expression. J. Ovarian Res., 2017, 10(1), 1.
[] [PMID: 28086946]
Edwards, M.R.; Mukaida, N.; Johnson, M.; Johnston, S.L. IL-1beta induces IL-8 in bronchial cells via NF-kappaB and NF-IL6 transcription factors and can be suppressed by glucocorticoids. Pulm. Pharmacol. Ther., 2005, 18(5), 337-345.
[] [PMID: 15939312]
Sinha, K.; Ghosh, J.; Sil, P.C. Morin and its role in chronic diseases. In: Anti-Inflammatory Nutraceuticals and Chronic Diseases; Gupta, S.C.; Prasad, S.; Aggarwal, B.B., Eds.; Springer International Publishing: Heidelberg, New York, 2016; pp. 453-471.
Shanmugam, M.K.; Rane, G.; Kanchi, M.M.; Arfuso, F.; Chinnathambi, A.; Zayed, M.E.; Alharbi, S.A.; Tan, B.K.; Kumar, A.P.; Sethi, G. The multifaceted role of curcumin in cancer prevention and treatment. Molecules, 2015, 20(2), 2728-2769.
[] [PMID: 25665066]
Pei, H.; Jin, Z.; Chen, S.; Sun, X.; Yu, J.; Guo, W. MiR-135b promotes proliferation and invasion of osteosarcoma cells via targeting FOXO1. Mol. Cell. Biochem., 2015, 400(1-2), 245-252.
[] [PMID: 25416447]
Li, Q.; Verma, I.M. NF-kappaB regulation in the immune system. Nat. Rev. Immunol., 2002, 2(10), 725-734.
[] [PMID: 12360211]
Mao, X.; Phanavanh, B.; Hamdan, H.; Moerman-Herzog, A.M.; Barger, S.W. NFκB-inducing kinase inhibits NFκB activity specifically in neurons of the CNS. J. Neurochem., 2016, 137(2), 154-163.
[] [PMID: 26778773]
Luft, F.C. C/EBPβ LIP induces a tumor menagerie making it an oncogene. J. Mol. Med. (Berl.), 2015, 93(1), 1-3.
[] [PMID: 25425057]
Li, J.; Shan, F.; Xiong, G.; Chen, X.; Guan, X.; Wang, J.M.; Wang, W.L.; Xu, X.; Bai, Y. EGF-induced C/EBPβ participates in EMT by decreasing the expression of miR-203 in esophageal squamous cell carcinoma cells. J. Cell Sci., 2014, 127(Pt 17), 3735-3744.
[] [PMID: 24994936]

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