Login Register Cart 0
Generic placeholder image

Recent Patents on Anti-Cancer Drug Discovery

Editor-in-Chief

ISSN (Print): 1574-8928
ISSN (Online): 2212-3970

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Effect of PI3K/AKT/mTOR Signaling Pathway on Regulating and Controlling the Anti-Invasion and Metastasis of Hepatoma Cells by Bufalin

Author(s): Xia Sheng, Pengfei Zhu, Yi Zhao, Jinwei Zhang, Haijia Li, Huan Zhao and Jianmin Qin*

Volume 16, Issue 1, 2021

Published on: 01 February, 2021

Page: [54 - 65] Pages: 12

DOI: 10.2174/1574892816666210201120324

Price: $65

Abstract

Background: Autophagy plays a “double-edged sword” in the process of tumorigenesis, development and metastasis.

Objective: In this study, we explored the effect of PI3K/AKT/mTOR autophagy-related signaling pathway on regulating and controlling the invasion and metastasis of liver cancer cells by Bufalin.

Methods: The cell counting, migration, adhesion and invasion assay were used to evaluate the effect of Bufalin on cell proliferation, invasion and metastasis. The protein expression of PI3K/AKT/ mTOR signaling pathway were detected by the Western Blotting technique.

Results: After inhibiting autophagy of HCC-LM3 cells, the inhibitory effect of Bufalin on adhesion, migration and invasion of HCC-LM3 cells was significantly enhanced. Synergistic inhibition was strongest when different autophagy inhibitors were combined with 3MA and CQ. After inhibiting autophagy, Bufalin significantly inhibited the protein expression of P-AKT, Cyclin D1, MMP- 2, MMP-9 and VEGF in HCC-LM3 cells. The protein expression of PTEN and E-Cadherin in HCC-LM3 cells was significantly increased.

Conclusion: The present study shows that the anti-tumor effect of Bufalin mainly inhibit proliferation, extracellular matrix degradation and angiogenesis of HCC by influencing autophagy. These findings confirm the capability of Bufalin in inhibiting metastasis of HCC and in parallel to current patents, could be applied as a novel therapeutic strategy in the prevention of metastasis of HCC.

Keywords: Autophagy, bufalin, hepatocellular carcinoma, HCC-LM3 cells, invasion and metastasis, PI3K/AKT/mTOR signaling pathway.

« Previous Next »
[1]
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin 2015; 65(2): 87-108.
[http://dx.doi.org/10.3322/caac.21262] [PMID: 25651787]
[2]
Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet 2012; 379(9822): 1245-55.
[http://dx.doi.org/10.1016/B978-1-4377-1454-8.00080-1]
[3]
Steeg PS. Tumor metastasis: Mechanistic insights and clinical challenges. Nat Med 2006; 12(8): 895-904.
[http://dx.doi.org/10.1038/nm1469] [PMID: 16892035]
[4]
Yang F, Jin C, Jiang YJ, Li J, Di Y, Fu DL. Potential role of soluble VEGFR-1 in antiangiogenesis therapy for cancer. Expert Rev Anticancer Ther 2011; 11(4): 541-9.
[http://dx.doi.org/10.1586/era.10.171] [PMID: 21504321]
[5]
Van den Bossche J, Van Ginderachter JA. E-cadherin: From epithelial glue to immunological regulator. Eur J Immunol 2013; 43(1): 34-7.
[http://dx.doi.org/10.1002/eji.201243168] [PMID: 23229729]
[6]
Ghajar CM. Metastasis prevention by targeting the dormant niche. Nat Rev Cancer 2015; 15(4): 238-47.
[http://dx.doi.org/10.1038/nrc3910] [PMID: 25801619]
[7]
Levine B, Mizushima N, Virgin HW. Autophagy in immunity and inflammation. Nature 2011; 469(7330): 323-35.
[http://dx.doi.org/10.1038/nature09782] [PMID: 21248839]
[8]
White E. Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer 2012; 12(6): 401-10.
[http://dx.doi.org/10.1038/nrc3262] [PMID: 22534666]
[9]
Zhang XH, Wang Q, Gerald W, et al. Latent bone metastasis in breast cancer tied to Src-dependent survival signals. Cancer Cell 2009; 16(1): 67-78.
[http://dx.doi.org/10.1016/j.ccr.2009.05.017] [PMID: 19573813]
[10]
Kenific CM, Thorburn A, Debnath J. Autophagy and metastasis: Another double-edged sword. Curr Opin Cell Biol 2010; 22(2): 241-5.
[http://dx.doi.org/10.1016/j.ceb.2009.10.008] [PMID: 19945838]
[11]
Lu Z, Luo RZ, Lu Y, et al. The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in human ovarian cancer cells. J Clin Invest 2008; 118(12): 3917-29.
[http://dx.doi.org/10.1172/JCI35512] [PMID: 19033662]
[12]
Apel A, Herr I, Schwarz H, Rodemann HP, Mayer A. Blocked autophagy sensitizes resistant carcinoma cells to radiation therapy. Cancer Res 2008; 68(5): 1485-94.
[13]
Miao Q, Bi LL, Li X, et al. Anticancer effects of bufalin on human hepatocellular carcinoma HepG2 cells: Roles of apoptosis and autophagy. Int J Mol Sci 2013; 14(1): 1370-82.
[http://dx.doi.org/10.3390/ijms14011370] [PMID: 23344047]
[14]
Li D, Qu X, Hou K, Zhang Y, Dong Q, Teng Y. PI3K/Akt is involved in Bufalin-induced apoptosis in gastric cancer cells. Anticancer Drugs 2009; 20(1): 59-64.
[15]
Yin P, Wang Y, Qiu Y, et al. Bufalin-loaded mPEG-PLGA-PLL-cRGD nanoparticles: Preparation, cellular uptake, tissue distribution, and anticancer activity. Int J Nanomedicine 2012; 7(13): 3961-9.
[http://dx.doi.org/10.2147/IJN.S32063] [PMID: 22888239]
[16]
Han KQ, Huang G, Gu W, Su YH, Huang XQ, Ling CQ. Anti-tumor activities and apoptosis-regulated mechanisms of bufalin on the orthotopic transplantation tumor model of human hepatocellular carcinoma in nude mice. World J Gastroenterol 2007; 13(24): 3374-9.
[http://dx.doi.org/10.3748/wjg.v13.i24.3374] [PMID: 17659679]
[17]
Sheng X, Zhu P, Qin J, Li Q. The biological role of autophagy in regulating and controlling the proliferation of liver cancer cells induced by bufalin. Oncol Rep 2018; 39(6): 2931-41.
[http://dx.doi.org/10.3892/or.2018.6365] [PMID: 29658591]
[18]
Gai JQ, Qin JM, Fan YZ. Experimental study on Bufalin inhibiting hepatocellular carcinoma proliferation and invasion. World Chin J Digestology 2014; 22(14): 1921-7.
[http://dx.doi.org/10.11569/wcjd.v22.i14.1921]
[19]
Sheng X, Sun X, Sun K, Sui H, Qin J, Li Q. Inhibitory effect of bufalin combined with Hedgehog signaling pathway inhibitors on proliferation and invasion and metastasis of liver cancer cells. Int J Oncol 2016; 49(4): 1513-24.
[http://dx.doi.org/10.3892/ijo.2016.3667] [PMID: 27634330]
[20]
Gai JQ, Sheng X, Qin JM, Sun K, Zhao W, Ni L. The effect and mechanism of bufalin on regulating hepatocellular carcinoma cell invasion and metastasis via Wnt/β-catenin signaling pathway. Int J Oncol 2016; 48(1): 338-48.
[http://dx.doi.org/10.3892/ijo.2015.3250] [PMID: 26648168]
[21]
Levine B. Eating oneself and uninvited guests: Autophagy-related pathways in cellular defense. Cell 2005; 120(2): 159-62.
[http://dx.doi.org/10.1016/j.cell.2005.01.005] [PMID: 15680321]
[22]
Zhu PF, Qin JM. Biological function of autophagy in occurrence and prevention of primary liver cancer. Chin Med Pharm 2015; 5(1): 24-8.
[23]
Kovács AL, Molnár K, Seglen PO. Inhibition of autophagic sequestration and endogenous protein degradation in isolated rat hepatocytes by methylated adenosine derivatives. FEBS Lett 1981; 134(2): 194-6.
[http://dx.doi.org/10.1016/0014-5793(81)80600-X] [PMID: 7308488]
[24]
Zhou ZW, Li XX, He ZX, et al. Induction of apoptosis and autophagy via sirtuin1- and PI3K/Akt/mTOR-mediated pathways by plumbagin in human prostate cancer cells. Drug Des Devel Ther 2015; 9(9): 1511-54.
[http://dx.doi.org/10.2147/DDDT.S75976] [PMID: 25834399]
[25]
Gonzalez-Angulo AM, Blumenschein GR Jr. Defining biomarkers to predict sensitivity to PI3K/Akt/mTOR pathway inhibitors in breast cancer. Cancer Treat Rev 2013; 39(4): 313-20.
[http://dx.doi.org/10.1016/j.ctrv.2012.11.002] [PMID: 23218708]
[26]
Guha M, Mackman N. The phosphatidylinositol 3-kinase-Akt pathway limits lipopolysaccharide activation of signaling pathways and expression of inflammatory mediators in human monocytic cells. J Biol Chem 2002; 277(35): 32124-32.
[http://dx.doi.org/10.1074/jbc.M203298200] [PMID: 12052830]
[27]
Fang Z, Tang Y, Jiao W, et al. Nitidine chloride induces apoptosis and inhibits tumor cell proliferation via suppressing ERK signaling pathway in renal cancer. Food Chem Toxicol 2014; 66(4): 210-6.
[http://dx.doi.org/10.1016/j.fct.2014.01.049] [PMID: 24508476]
[28]
Zhiyong C, Wentong L, Xiaoyang Y, Ling P. PTEN’s regulation of VEGF and VEGFR1 expression and its clinical significance in myeloid leukemia. Med Oncol 2012; 29(2): 1084-92.
[http://dx.doi.org/10.1007/s12032-011-9867-2] [PMID: 21360018]
[29]
Duan YJ, Qu HT. Somatic mutation of PTEN in prostate cancer. Nanhua University 2001; 29(5): 243-5.
[30]
Noë V, Fingleton B, Jacobs K, et al. Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1. J Cell Sci 2001; 114(Pt 1): 111-8.
[PMID: 11112695]
[31]
Gould Rothberg BE, Bracken MB. E-cadherin immunohistochemical expression as a prognostic factor in infiltrating ductal carcinoma of the breast: A systematic review and meta-analysis. Breast Cancer Res Treat 2006; 100(2): 139-48.
[http://dx.doi.org/10.1007/s10549-006-9248-2] [PMID: 16791476]
[32]
Lei J, Shao JH. Research progress on the relationship between CyclinD1 and malignant tumor. Pract Clin Med 2007; 8(3): 127-9.
[33]
Buccione R, Caldieri G, Ayala I. Invadopodia: Specialized tumor cell structures for the focal degradation of the extracellular matrix. Cancer Metastasis Rev 2009; 28(1-2): 137-49.
[http://dx.doi.org/10.1007/s10555-008-9176-1] [PMID: 19153671]
[34]
Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2002; 2(3): 161-74.
[http://dx.doi.org/10.1038/nrc745] [PMID: 11990853]
[35]
Park CM, Park MJ, Kwak HJ, Lee HC, Kim MS, Lee SH. Ionizing radiation enhances matrix metalloproteinase-2 secretion and invasion of glioma cells through Src/epidermal growth factor receptor-mediated p38/Akt and phosphatidylinositol 3-kinase/Akt signaling pathways. Cancer Res 2006; 66(17): 8511-9.
[36]
Fukao T, Koyasu S. PI3K and negative regulation of TLR signaling. Trends Immunol 2003; 24(7): 358-63.
[http://dx.doi.org/10.1016/S1471-4906(03)00139-X] [PMID: 12860525]
[37]
Cao Z, Liu LZ, Dixon DA, Zheng JZ, Chandran B, Jiang BH. Insulin-like growth factor-I induces cyclooxygenase-2 expression via PI3K, MAPK and PKC signaling pathways in human ovarian cancer cells. Cell Signal 2007; 19(7): 1542-53.
[http://dx.doi.org/10.1016/j.cellsig.2007.01.028] [PMID: 17341442]
[38]
Li DF, Zheng QS, Pan ZH, Chen XY, Liu XN, Ye L. Application and preparation of Bufalin as an anti-malignant melanoma drug. CN108743594, 2018.
[39]
Su YH, Ling CQ, Gu W. Preparation of Bufalin albumin nanoparticles and its preparation method. CN1302809, 2007.
[40]
Jiang RW, Tang HJ, Tian HY, Cao W, Ye WC. The glycosylation of Bufalin and its preparation and its application in the preparation of anti-tumor drugs. CN103288911, 2013.
[41]
Zhao CG, Yang LH, Dai XX, Xiang YQ, Zhou B, Hu WL. Application of acetylBufalin in the preparation of anti-tumor drugs. CN108354939, 2018.
[42]
Cavallo KDM, Cavallo DMF, Cavallo MDF, Pacheco ODC, Moore RCD. The use of Toadosin as an analgesic in the treatment of acute and chronic pain, the composition containing toadosin and its use. BR102448465, 2012.
[43]
Wong Y, Wang YH, Wen AD, Xi MM, Yang ZF, Duan JL. Application of toad venom extract in the preparation of drugs for the treatment of human glioma. CN105687251, 2016.

Rights & Permissions Print Cite
Article Metrics
73
1
© 2024 Bentham Science Publishers | Privacy Policy