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A novel matrine derivative WM622 inhibits hepatocellular carcinoma by inhibiting PI3K/AKT signaling pathways

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Abstract

Hepatocellular carcinoma (HCC) is among the most common lethal cancers of the digestive system with poor prognosis rates and ineffective therapeutic options. Matrine, a traditional Chinese medicine found in the roots of sophora species, has been used in the clinical treatment of liver fibrosis, chronic hepatitis B and other diseases. We have synthesized a matrine derivatives named WM622 (C26H35ON3S2) with a significant inhibitory effect on transplanted tumors in vivo. The half inhibitory concentration (IC50) of WM622 is 34 µM, which is much lower than matrine. WM622 inhibited the proliferation and promoted apoptosis of hepatocellular carcinoma cells significantly, and the cell cycle was blocked in G0/G1 phase. The protein phosphorylation levels of EGFR, AKT, PI3K and GSK3β (p-EGFR, p-AKT, p-PI3K, and p-GSK3β) were also decreased by WM622 treatment dose dependently. In tumor-bearing mice, WM622 could reduce the tumor volumes. In conclusion, the study demonstrated that WM622 could inhibit the proliferation of the hepatocellular carcinoma both in vivo and in vitro by inducing apoptosis, blocking cell cycle in G0/G1 phase and inhibiting the PI3K/AKT signal pathways.

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References

  1. Wei KR, Yu X, Zheng RS, Peng XB, Zhang SW, Ji MF, Liang ZH, Ou ZX, Chen WQ (2014) Incidence and mortality of liver cancer in China, 2010. Chin J Cancer 33(8):388. https://doi.org/10.5732/cjc.014.10088

    Article  PubMed  PubMed Central  Google Scholar 

  2. Ang C, O’Reilly EM, Abou-Alfa GK (2013) Targeted agents and systemic therapy in hepatocellular carcinoma. Recent Results Cancer Res 190:225–246. https://doi.org/10.1007/978-3-642-16037-0_15

    Article  PubMed  Google Scholar 

  3. Liu Y, Xu Y, Ji W, Li X, Sun B, Gao Q, Su C (2014) Anti-tumor activities of matrine and oxymatrine: literature review. Tumour Biol 35(6):5111–5119. https://doi.org/10.1007/s13277-014-1680-z

    Article  CAS  PubMed  Google Scholar 

  4. Chai NL, Fu Q, Shi H, Cai CH, Wan J, Xu SP, Wu BY (2012) Oxymatrine liposome attenuates hepatic fibrosis via targeting hepatic stellate cells. World J Gastroenterol 18(31):4199. https://doi.org/10.3748/wjg.v18.i31.4199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yang Y, Xiu J, Zhang X, Zhang L, Yan K, Qin C, Liu J (2012) Antiviral effect of matrine against human enterovirus 71. Molecules 17(9):10370–10376. https://doi.org/10.3390/molecules170910370

    Article  CAS  PubMed  Google Scholar 

  6. Zhang Y, Wang S, Li Y, Xiao Z, Hu Z, Zhang J (2008) Sophocarpine and matrine inhibit the production of TNF-alpha and IL-6 in murine macrophages and prevent cachexia-related symptoms induced by colon26 adenocarcinoma in mice. Int Immunopharmacol 8(13–14):1767–1772. https://doi.org/10.1016/j.intimp.2008.08.008

    Article  CAS  PubMed  Google Scholar 

  7. Liu XY1, Fang H, Yang ZG, Wang XY, Ruan LM, Fang DR, Ding YG, Wang YN, Zhang Y, Jiang XL, Chen HC (2008) Matrine inhibits invasiveness and metastasis of human malignant melanoma cell line A375 in vitro. Int J Dermatol 47(5):448–456. https://doi.org/10.1111/j.1365-4632.2008.03627.x

    Article  CAS  PubMed  Google Scholar 

  8. Qian L, Liu Y, Xu Y, Ji W, Wu Q, Liu Y, Gao Q, Su C (2015) Matrine derivative WM130 inhibits hepatocellular carcinoma by suppressing EGFR/ERK/MMP-2 and PTEN/AKT signaling pathways. Cancer Lett 368(1):126–34. https://doi.org/10.1016/j.canlet.2015.07.035

    Article  CAS  PubMed  Google Scholar 

  9. Liu Y, Qi Y, Bai ZH, Ni CX, Ren QH, Xu WH, Xu J, Hu HG, Qiu L, Li JZ, He ZG, Zhang JP (2016) A novel matrine derivate inhibits differentiated human hepatoma cells and hepatic cancer stem-like cells by suppressing PI3K/AKT signaling pathways. Acta Pharmacol Sin 38(1):120–132. https://doi.org/10.1038/aps.2016.104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zhang LP, Jiang JK, Tam JW, Zhang Y, Liu XS, Xu XR, Liu BZ, He YJ (2001) Effects of matrine on proliferation and differentiation in K-562 cells. Leuk Res 25(9):793–800

    Article  CAS  PubMed  Google Scholar 

  11. Zhang L, Wang T, Wen X, Wei Y, Peng X, Li H, Wei L (2007) Effect of matrine on HeLa cell adhesion and migration. Eur J Pharmacol 563(1–3):69–76

    Article  CAS  PubMed  Google Scholar 

  12. Liu XS, Jiang J, Jiao XY, Wu YE, Lin JH (2006) Matrine-induced apoptosis in leukemia U937 cells: involvement of caspases activation and MAPK-independent pathways. Planta Med 72(6):501–506

    Article  CAS  PubMed  Google Scholar 

  13. Jiang H, Hou C, Zhang S, Xie H, Zhou W, Jin Q, Cheng X, Qian R, Zhang X. (2007) Matrine upregulates the cell cycle protein E2F-1 and triggers apoptosis via the mitochondrial pathway in K562 cells. Eur J Pharmacol 559(2–3):98–108

    Article  CAS  PubMed  Google Scholar 

  14. Zhang S, Qi J, Sun L, Cheng B, Pan S, Zhou M, Sun X (2009) Matrine induces programmed cell death and regulates expression of relevant genes based on PCR array analysis in C6 glioma cells. Mol Biol Rep 36(4):791–799. https://doi.org/10.1007/s11033-008-9247-y

    Article  CAS  PubMed  Google Scholar 

  15. Manning BD, Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell 129(7):1261–1274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cheng GZ, Park S, Shu S, He L, Kong W, Zhang W, Yuan Z, Wang LH, Cheng JQ (2008) Advances of AKT pathway in human oncogenesis and as a target for anti-cancer drug discovery. Curr Cancer Drug Targets 8(1):2–6

    Article  CAS  PubMed  Google Scholar 

  17. Voigt P, Brock C, Nürnberg B, Schaefer M (2005) Assigning functional domains within the p101 regulatory subunit of phosphoinositide 3-kinase gamma. J Biol Chem 280(6):5121–5127

    Article  CAS  PubMed  Google Scholar 

  18. Embi N, Rylatt DB, Cohen P (1980) Glycogen synthase kinase-3 from rabbit skeletal muscle. Separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase. Eur J Biochem 107(2):519–527

    Article  CAS  PubMed  Google Scholar 

  19. Primot A, Baratte B, Gompel M, Borgne A, Liabeuf S, Romette JL, Jho EH, Costantini F, Meijer L (2000) Purification of GSK-3 by affinity chromatography on immobilized axin. Protein Expr Purif 20(3):394–404

    Article  CAS  PubMed  Google Scholar 

  20. Crowder RJ, Freeman RS (2000) Glycogen synthase kinase-3 beta activity is critical for neuronal death caused by inhibiting phosphatidylinositol 3-kinase or Akt but not for death caused by nerve growth factor withdrawal. J Biol Chem 275(44):34266–34271

    Article  CAS  PubMed  Google Scholar 

  21. Bianchi M, De Lucchini S, Marin O, Turner DL, Hanks SK, Villa-Moruzzi E (2005) Regulation of FAK Ser-722 phosphorylation and kinase activity by GSK3 and PP1 during cell spreading and migration. Biochem J 391(Pt 2):359–370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Liang J, Slingerland JM (2003) Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle 2(4):339–345

    Article  CAS  PubMed  Google Scholar 

  23. Li Y, Dowbenko D, Lasky LA (2001) AKT/PKB phosphorylation of p21Cip/WAF1 enhances protein stability of p21Cip/WAF1 and promotes cell survival. J Biol Chem 277(13):11352–11361

    Article  PubMed  Google Scholar 

  24. Hwangbo W, Lee JH, Ahn S, Kim S, Park KH, Kim CH, Kim I (2013) EGFR gene amplification and protein expression in invasive ductal carcinoma of the breast. Korean J Pathol 47(2):107. https://doi.org/10.4132/KoreanJPathol.2013.47.2.107

    Article  PubMed  PubMed Central  Google Scholar 

  25. Kalman B, Szep E, Garzuly F, Post DE (2013) Epidermal growth factor receptor as a therapeutic target in glioblastoma. Neuromolecular Med 15(2):420–434. https://doi.org/10.1007/s12017-013-8229-y

    Article  CAS  PubMed  Google Scholar 

  26. Colakoglu T, Yildirim S, Kayaselcuk F, Nursal TZ, Ezer A, Noyan T, Karakayali H, Haberal M (2008) Clinicopathological significance of PTEN loss and the phosphoinositide 3-kinase/Akt pathway in sporadic colorectal neoplasms: is PTEN loss predictor of local recurrence? Am J Surg 195(6):719–725. https://doi.org/10.1016/j.amjsurg.2007.05.061

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The work was supported by the National Natural Science Foundation of China (Nos. 21502225 and 30872120/H2603) and The Shanghai Pujiang Talent program (No. 17PJD042).

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    Authors and Affiliations

    1. Department of Cell Biology, Second Military Medical University, Shanghai, 200433, People’s Republic of China

      Xiao Sun & Yi-ping Hu

    2. Department of Organic Chemistry, Second Military Medical University, Shanghai, 200433, People’s Republic of China

      Xiao-bin Zhuo & Qing-jie Zhao

    3. Clinical Nutrition Department, Changhai Hospital, Second Military Medical University, Shanghai, 200433, People’s Republic of China

      Xuan Zheng

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    1. Xiao Sun
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    Correspondence to Xuan Zheng or Qing-jie Zhao.

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    Xiao Sun and Xiao-bin Zhuo have contributed equally to this work and should be considered co-first authors.

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    Sun, X., Zhuo, Xb., Hu, Yp. et al. A novel matrine derivative WM622 inhibits hepatocellular carcinoma by inhibiting PI3K/AKT signaling pathways. Mol Cell Biochem 449, 47–54 (2018). https://doi.org/10.1007/s11010-018-3341-9

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    • DOI: https://doi.org/10.1007/s11010-018-3341-9

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