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Lycorine inhibits breast cancer growth and metastasis via inducing apoptosis and blocking Src/FAK-involved pathway

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Abstract

Breast cancer is the most commonly diagnosed cancer type worldwide among women and more than 90% of patients die from tumor metastasis. Lycorine, a natural alkaloid, has been widely reported possessing potential efficacy against cancer proliferation and metastasis. In our study, the anti-tumor potency on breast cancer was evaluated in vitro and in vivo for the first time. Our results indicated that lycorine inhibited breast cancer cells growth, migration and invasion as well as induced their apoptosis. In in vivo study, lycorine not only suppressed breast tumor growth in xenograft models and inhibited breast tumor metastasis in MDA-MB-231 tail vein model. More importantly, we found lycorine had less toxicity than first-line chemotherapy drug paclitaxel at the same effective dose in vivo. Furthermore, on mechanism, lycorine inhibited tumor cell migration and invasion via blocking the Src/FAK (focal adhesion kinase)-involved pathway. In conclusion, our study implied lycorine was a potential candidate for the treatment of breast cancer by inhibition of tumor growth and metastasis.

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References

  • Alimova, I.N., Liu, B., Fan, Z., Edgerton, S.M., Dillon, T., Lind, S.E., and Thor, A.D. (2009). Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro. Cell Cycle 8, 909–915.

    Article  CAS  PubMed  Google Scholar 

  • Amiri-Kordestani, L., Basseville, A., Kurdziel, K., Fojo, A.T., and Bates, S.E. (2012). Targeting MDR in breast and lung cancer: discriminating its potential importance from the failure of drug resistance reversal studies. Drug Resist Updates 15, 50–61.

    Article  CAS  Google Scholar 

  • Bauvois, B. (2012). New facets of matrix metalloproteinases MMP-2 and MMP-9 as cell surface transducers: outside-in signaling and relationship to tumor progression. Biochim Biophys Acta 1825, 29–36.

    CAS  PubMed  Google Scholar 

  • Berardi, R., Caramanti, M., Savini, A., Chiorrini, S., Pierantoni, C., Onofri, A., Ballatore, Z., De Lisa, M., Mazzanti, P., and Cascinu, S. (2013). State of the art for cardiotoxicity due to chemotherapy and to targeted therapies: a literature review. Crit Rev Oncol Hematol 88, 75–86.

    Article  PubMed  Google Scholar 

  • Bevers, T.B., Anderson, B.O., Bonaccio, E., Buys, S., Daly, M.B., Dempsey, P.J., Farrar, W.B., Fleming, I., Garber, J.E., Harris, R.E., Heerdt, A.S., Helvie, M., Huff, J.G., Khakpour, N., Khan, S.A., Krontiras, H., Lyman, G., Rafferty, E., Shaw, S., Smith, M.L., Tsangaris, T.N., Williams, C., and Yankeelov, T. (2009). NCCN clinical practice guidelines in oncology: breast cancer screening and diagnosis. J Natl Compr Canc Netw 7, 1060–1096.

    Article  PubMed  Google Scholar 

  • Cance, W.G., and Golubovskaya, V.M. (2008). Focal adhesion kinase versus p53: apoptosis or survival? Sci Signal 1, pe22–pe22.

    Article  PubMed  PubMed Central  Google Scholar 

  • Canel, M., Serrels, A., Frame, M.C., and Brunton, V.G. (2013). E-cadherin-integrin crosstalk in cancer invasion and metastasis. J Cell Sci 126, 393–401.

    Article  CAS  PubMed  Google Scholar 

  • Cao, Z., Yu, D., Fu, S., Zhang, G., Pan, Y., Bao, M., Tu, J., Shang, B., Guo, P., Yang, P., and Zhou, Q. (2013). Lycorine hydrochloride selectively inhibits human ovarian cancer cell proliferation and tumor neovascularization with very low toxicity. Toxicol Lett 218, 174–185.

    Article  CAS  PubMed  Google Scholar 

  • Chaffer, C.L., and Weinberg, R.A. (2011). A perspective on cancer cell metastasis. Science 331, 1559–1564.

    Article  CAS  PubMed  Google Scholar 

  • Chung, J., Yoon, Y.O., Lee, J.S., Ha, T.K., Ryu, S.M., Kim, K.H., Jeong, M.H., Yoon, T.R., and Kim, H.K. (2011). Inulin induces dendritic cells apoptosis through the caspase-dependent pathway and mitochondrial dysfunction. Biol Pharm Bull 34, 495–500.

    Article  CAS  PubMed  Google Scholar 

  • Çitoğlu, G.S., Bahadır Acıkara, Ö., Sever Yılmaz, B., and Özbek, H. (2012). Evaluation of analgesic, anti-inflammatory and hepatoprotective effects of lycorine from Sternbergia fisheriana (Herbert) Rupr. Fitoterapia 83, 81–87.

    Article  PubMed  Google Scholar 

  • Coley, H.M. (2008). Mechanisms and strategies to overcome chemotherapy resistance in metastatic breast cancer. Cancer Treat Rev 34, 378–390.

    Article  CAS  PubMed  Google Scholar 

  • Cory, S., Huang, D.C.S., and Adams, J.M. (2003). The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene 22, 8590–8607.

    Article  CAS  PubMed  Google Scholar 

  • Dasari, R., Banuls, L.M.Y., Masi, M., Pelly, S.C., Mathieu, V., Green, I.R., van Otterlo, W.A.L., Evidente, A., Kiss, R., and Kornienko, A. (2014). C1,C2-ether derivatives of the Amaryllidaceae alkaloid lycorine: retention of activity of highly lipophilic analogues against cancer cells. Bioorg Med Chem Lett 24, 923–927.

    Article  CAS  PubMed  Google Scholar 

  • Dumont, P., Ingrassia, L., Rouzeau, S., Ribaucour, F., Thomas, S., Roland, I., Darro, F., Lefranc, F., and Kiss, R. (2007). The Amaryllidaceae isocarbostyril narciclasine induces apoptosis by activation of the death receptor and/or mitochondrial pathways in cancer cells but not in normal fibroblasts. Neoplasia 9, 766–776.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Esposito, M.T., Zhao, L., Fung, T.K., Rane, J.K., Wilson, A., Martin, N., Gil, J., Leung, A.Y., Ashworth, A., and Eric So, C.W. (2015). Synthetic lethal targeting of oncogenic transcription factors in acute leukemia by PARP inhibitors. Nat Med 21, 1481–1490.

    Article  CAS  PubMed  Google Scholar 

  • Fiandalo, M.V., and Kyprianou, N. (2012). Caspase control: protagonists of cancer cell apoptosis. Exp Oncol 34, 165–175.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fulda, S., and Vucic, D. (2012). Targeting IAP proteins for therapeutic intervention in cancer. Nat Rev Drug Discov 11, 109–124.

    Article  CAS  PubMed  Google Scholar 

  • Gupta, G.P., and Massagué, J. (2006). Cancer metastasis: building a framework. Cell 127, 679–695.

    Article  CAS  PubMed  Google Scholar 

  • Hu, M., Peng, S., He, Y., Qin, M., Cong, X., Xing, Y., Liu, M., and Yi, Z. (2015). Lycorine is a novel inhibitor of the growth and metastasis of hormone-refractory prostate cancer. Oncotarget 6, 15348–15361.

    Article  PubMed  PubMed Central  Google Scholar 

  • Huang, L.Y.L., Chang, C.C., Lee, Y.S., Chang, J.M., Huang, J.J., Chuang, S.H., Kao, K.J., Lau, G.M.G., Tsai, P.Y., Liu, C.W., Lin, H.S., and Lau, J.Y.N. (2014). Activity of a novel Hec1-targeted anticancer compound against breast cancer cell lines in vitro and in vivo. Mol Cancer Ther 13, 1419–1430.

    Article  CAS  PubMed  Google Scholar 

  • Llić, D.Â., Furuta, Y., Kanazawa, S., Takeda, N., Sobue, K., Nakatsuji, N., Nomura, S., Fujimoto, J., Okada, M., Yamamoto, T., and Aizawa, S. (1995). Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice. Nature 377, 539–544.

    Article  Google Scholar 

  • Kessenbrock, K., Plaks, V., and Werb, Z. (2010). Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141, 52–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lamoral-Theys, D., Andolfi, A., Van Goietsenoven, G., Cimmino, A., Le Calvé, B., Wauthoz, N., Mégalizzi, V., Gras, T., Bruyère, C., Dubois, J., Mathieu, V., Kornienko, A., Kiss, R., and Evidente, A. (2009). Lycorine, the main phenanthridine Amaryllidaceae alkaloid, exhibits significant antitumor activity in cancer cells that display resistance to proapoptotic stimuli: an investigation of structure-activity relationship and mechanistic insight. J Med Chem 52, 6244–6256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lamoral-Theys, D., Decaestecker, C., Mathieu, V., Dubois, J., Kornienko, A., Kiss, R., Evidente, A., and Pottier, L. (2010). Lycorine and its derivatives for anticancer drug design. Mini Rev Med Chem 10, 41–50.

    Article  CAS  PubMed  Google Scholar 

  • Liu, X., Jiang, J., Jiao, X., Wu, Y., Lin, J., and Cai, Y. (2009). Lycorine induces apoptosis and down-regulation of Mcl-1 in human leukemia cells. Cancer Lett 274, 16–24.

    Article  CAS  PubMed  Google Scholar 

  • Lowe, S.W., and Lin, A.W. (2000). Apoptosis in cancer. Carcinogenesis 21, 485–495.

    Article  CAS  PubMed  Google Scholar 

  • Luo, Y., Roy, M., Xiao, X., Sun, S., Liang, L., Chen, H., Fu, Y., Sun, Y., Zhu, M., Ye, M., and Liu, J. (2015). Lycorine induces programmed necrosis in the multiple myeloma cell line ARH-77. Tumor Biol 36, 2937–2945.

    Article  CAS  Google Scholar 

  • McLachlan, A., Kekre, N., McNulty, J., and Pandey, S. (2005). Pancratistatin: a natural anti-cancer compound that targets mitochondria specifically in cancer cells to induce apoptosis. Apoptosis 10, 619–630.

    Article  CAS  PubMed  Google Scholar 

  • Minn, A.J., Kang, Y., Serganova, I., Gupta, G.P., Giri, D.D., Doubrovin, M., Ponomarev, V., Gerald, W.L., Blasberg, R., and Massagué, J. (2005). Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors. J Clin Invest 115, 44–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mitra, S.K., Hanson, D.A., and Schlaepfer, D.D. (2005). Focal adhesion kinase: in command and control of cell motility. Nat Rev Mol Cell Biol 6, 56–68.

    Article  CAS  PubMed  Google Scholar 

  • Nair, J.J., and van Staden, J. (2014). Cytotoxicity studies of lycorine alkaloids of the Amaryllidaceae. Nat Prod Commun 9, 1193–1210.

    CAS  PubMed  Google Scholar 

  • Niu, J., Xue, A., Chi, Y., Xue, J., Wang, W., Zhao, Z., Fan, M., Yang, C.H., Shao, Z.M., Pfeffer, L.M., Wu, J., and Wu, Z.H. (2016). Induction of miRNA-181a by genotoxic treatments promotes chemotherapeutic resistance and metastasis in breast cancer. Oncogene 35, 1302–1313.

    Article  CAS  PubMed  Google Scholar 

  • Ouyang, L., Shi, Z., Zhao, S., Wang, F.T., Zhou, T.T., Liu, B., and Bao, J.K. (2012). Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis. Cell Prolif 45, 487–498.

    Article  CAS  PubMed  Google Scholar 

  • Panis, C., Lemos, L.G.T., Victorino, V.J., Herrera, A.C.S.A., Campos, F.C., Colado Simão, A.N., Pinge-Filho, P., Cecchini, A.L., and Cecchini, R. (2012). Immunological effects of Taxol and Adryamicin in breast cancer patients. Cancer Immunol Immunother 61, 481–488.

    Article  CAS  PubMed  Google Scholar 

  • Roth, W., and Reed, J.C. (2002). Apoptosis and cancer: when BAX is TRAILing away. Nat Med 8, 216–218.

    Article  CAS  PubMed  Google Scholar 

  • Schroeder, A., Heller, D.A., Winslow, M.M., Dahlman, J.E., Pratt, G.W., Langer, R., Jacks, T., and Anderson, D.G. (2011). Treating metastatic cancer with nanotechnology. Nat Rev Cancer 12, 39–50.

    Article  PubMed  Google Scholar 

  • Sein, T.T., Thant, A.A., Hiraiwa, Y., Amin, A.R., Sohara, Y., Liu, Y., Matsuda, S., Yamamoto, T., and Hamaguchi, M. (2000). A role for FAK in the Concanavalin A-dependent secretion of matrix metalloproteinase-2 and-9. Oncogene 19, 5539–5542.

    Article  CAS  PubMed  Google Scholar 

  • Shibue, T., Brooks, M.W., Inan, M.F., Reinhardt, F., and Weinberg, R.A. (2012). The outgrowth of micrometastases is enabled by the formation of filopodium-like protrusions. Cancer Discov 2, 706–721.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siegel, R.L., Miller, K.D., and Jemal, A. (2016). Cancer statistics, 2016. CA Cancer J Clin 66, 7–30.

    Article  PubMed  Google Scholar 

  • Siesser, P.M.F., and Hanks, S.K. (2006). The signaling and biological implications of FAK overexpression in cancer. Clin Cancer Res 12, 3233–3237.

    Article  CAS  PubMed  Google Scholar 

  • Skehan, P., Storeng, R., Scudiero, D., Monks, A., McMahon, J., Vistica, D., Warren, J.T., Bokesch, H., Kenney, S., and Boyd, M.R. (1990). New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst 82, 1107–1112.

    Article  CAS  PubMed  Google Scholar 

  • Steeg, P.S. (2006). Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 12, 895–904.

    Article  CAS  PubMed  Google Scholar 

  • Sulzmaier, F.J., Jean, C., and Schlaepfer, D.D. (2014). FAK in cancer: mechanistic findings and clinical applications. Nat Rev Cancer 14, 598–610.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tai, Y.L., Chen, L.C., and Shen, T.L. (2015). Emerging roles of focal adhesion kinase in cancer. BioMed Res Int 2015, 1–13.

    Google Scholar 

  • Tamura, K. (2015). Development of cell-cycle checkpoint therapy for solid tumors. Jpn J Clin Oncol 45, hyv131.

    Article  Google Scholar 

  • Trimmer, C., Whitaker-Menezes, D., Bonuccelli, G., Milliman, J.N., Daumer, K.M., Aplin, A.E., Pestell, R.G., Sotgia, F., Lisanti, M.P., and Capozza, F. (2010). CAV1 inhibits metastatic potential in melanomas through suppression of the integrin/Src/FAK signaling pathway. Cancer Res 70, 7489–7499.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Volk-Draper, L., Hall, K., Griggs, C., Rajput, S., Kohio, P., DeNardo, D., and Ran, S. (2014). Paclitaxel therapy promotes breast cancer metastasis in a TLR4-dependent manner. Cancer Res 74, 5421–5434.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang, P., Yuan, H.H., Zhang, X., Li, Y.P., Shang, L.Q., and Yin, Z. (2014). Novel lycorine derivatives as anticancer agents: synthesis and in vitro biological evaluation. Molecules 19, 2469–2480.

    Article  PubMed  Google Scholar 

  • Wang, S.C. (2014). PCNA: a silent housekeeper or a potential therapeutic target? Trends Pharmacol Sci 35, 178–186.

    Article  PubMed  Google Scholar 

  • Xu, Y., Liu, J.B., Wu, Y.L., Guo, Q.L., Sun, H.D., and Chen, G.Q. (2015). Natural products against hematological malignancies and identification of their targets. Sci China Life Sci 58, 1191–1201.

    Article  CAS  PubMed  Google Scholar 

  • Zhang, S., Liu, X., Bawa-Khalfe, T., Lu, L.S., Lyu, Y.L., Liu, L.F., and Yeh, E.T.H. (2012). Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med 18, 1639–1642.

    Article  PubMed  Google Scholar 

  • Zhang, T., Chen, Y., Li, J., Yang, F., Wu, H., Dai, F., Hu, M., Lu, X., Peng, Y., Liu, M., Zhao, Y., and Yi, Z. (2014). Antitumor action of a novel histone deacetylase inhibitor, YF479, in breast cancer. Neoplasia 16, 665–677.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao, X., and Guan, J.L. (2011). Focal adhesion kinase and its signaling pathways in cell migration and angiogenesis. Adv Drug Deliver Rev 63, 610–615.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by National Natural Science Foundation of China (81272463, 81472788), and Major State Basic Research Development Program of China (2015CB910400).

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Authors and Affiliations

  1. Department of General Surgery, Shanghai Jiaotong University Affiliated Sixth People’s Hospital, Shanghai, 200233, China

    Xuexiang Ying & Pingqing He

  2. Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China

    Anling Huang, Yajing Xing, Liping Lan & Zhengfang Yi

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  1. Xuexiang Ying
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Correspondence to Pingqing He.

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Ying, X., Huang, A., Xing, Y. et al. Lycorine inhibits breast cancer growth and metastasis via inducing apoptosis and blocking Src/FAK-involved pathway. Sci. China Life Sci. 60, 417–428 (2017). https://doi.org/10.1007/s11427-016-0368-y

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