IMMUNE NETWORK

  • 제16권1호
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  • Pages.75-84
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  • 2016
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  • 1598-2629(pISSN)
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  • 2092-6685(eISSN)
대한면역학회 (The Korean Association of Immunobiologists)
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DOI QR코드

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Immunogenic Cell Death Induced by Ginsenoside Rg3: Significance in Dendritic Cell-based Anti-tumor Immunotherapy

  • Keum-joo Son (R&D Center, Pharmicell Co. Ltd.) ;
  • Ki ryung Choi (R&D Center, Pharmicell Co. Ltd.) ;
  • Seog Jae Lee (Department of Thoracic and Cardiovascular Surgery, Jeju National University School of Medicine) ;
  • Hyunah Lee (R&D Center, Pharmicell Co. Ltd.)
  • 투고 : 2015.11.27
  • 심사 : 2016.01.29
  • 발행 : 2016.02.29
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초록

Cancer is one of the leading causes of morbidity and mortality worldwide; therefore there is a need to discover new therapeutic modules with improved efficacy and safety. Immune-(cell) therapy is a promising therapeutic strategy for the treatment of intractable cancers. The effectiveness of certain chemotherapeutics in inducing immunogenic tumor cell death thus promoting cancer eradication has been reported. Ginsenoside Rg3 is a ginseng saponin that has antitumor and immunomodulatory activity. In this study, we treated tumor cells with Rg3 to verify the significance of inducing immunogenic tumor cell death in antitumor therapy, especially in DC-based immunotherapy. Rg3 killed the both immunogenic (B16F10 melanoma cells) and non-immunogenic (LLC: Lewis Lung Carcinoma cells) tumor cells by inducing apoptosis. Surface expression of immunogenic death markers including calreticulin and heat shock proteins and the transcription of relevant genes were increased in the Rg3-dying tumor. Increased calreticulin expression was directly related to the uptake of dying tumor cells by dendritic cells (DCs): the proportion of CRT+CD11c+cells was increased in the Rg3-treated group. Interestingly, tumor cells dying by immunogenic cell death secreted IFN-γ, an effector molecule for antitumor activity in T cells. Along with the Rg3-induced suppression of pro-angiogenic (TNF-α) and immunosuppressive cytokine (TGF-β) secretion, IFN-γ production from the Rg3-treated tumor cells may also indicate Rg3 as an effective anticancer immunotherapeutic strategy. The data clearly suggests that Rg3-induced immunogenic tumor cell death due its cytotoxic effect and its ability to induce DC function. This indicates that Rg3 may be an effective immunotherapeutic strategy.

키워드

과제정보

The authors sincerely thank to Dr. Sung Ho Son at the Vitrosys Inc., Yeongju, Korea for providing ginsenoside Rg3. This study was supported by the grant from the National Research Foundation of Korea (#2014-055-842).

참고문헌

  1. Kim, J. W., S. Y. Jung, Y. H. Kwon, J. H. Lee, Y. M. Lee, B. Y. Lee, and S. M. Kwon. 2012. Ginsenoside Rg3 attenuates tumor angiogenesis via inhibiting bioactivities of endothelial progenitor cells. Cancer Biol. Ther. 13: 504-515. https://doi.org/10.4161/cbt.19599
  2. Nam, K. Y., J. E. Choi, S. C. Hong, K. M. Pyo, and J. D. Park. 2014. Recent Progress in Research on Anticancer Activities of Ginsenoside-Rg3. Kor. J. Pharm. 45: 1-10.
  3. Cirone, M., R. L. Di, L. V. Lotti, V. Conte, P. Trivedi, R. Santarelli, R. Gonnella, L. Frati, and A. Faggioni. 2012. Activation of dendritic cells by tumor cell death. Oncoimmunology 1: 1218-1219. https://doi.org/10.4161/onci.20428
  4. Fucikova, J., P. Kralikova, A. Fialova, T. Brtnicky, L. Rob, J. Bartunkova, and R. Spisek. 2011. Human tumor cells killed by anthracyclines induce a tumor-specific immune response. Cancer Res. 71: 4821-4833. https://doi.org/10.1158/0008-5472.CAN-11-0950
  5. Zitvogel, L., O. Kepp, L. Senovilla, L. Menger, N. Chaput, and G. Kroemer. 2010. Immunogenic tumor cell death for optimal anticancer therapy: the calreticulin exposure pathway. Clin. Cancer Res. 16: 3100-3104. https://doi.org/10.1158/1078-0432.CCR-09-2891
  6. Panaretakis, T., O. Kepp, U. Brockmeier, A. Tesniere, A. C. Bjorklund, D. C. Chapman, M. Durchschlag, N. Joza, G. Pierron, E. P. van, J. Yuan, L. Zitvogel, F. Madeo, D. B. Williams, and G. Kroemer. 2009. Mechanisms of pre-apoptotic calreticulin exposure in immunogenic cell death. EMBO J. 28: 578-590. https://doi.org/10.1038/emboj.2009.1
  7. Obeid, M., A. Tesniere, F. Ghiringhelli, G. M. Fimia, L. Apetoh, J. L. Perfettini, M. Castedo, G. Mignot, T. Panaretakis, N. Casares, D. Metivier, N. Larochette, E. P. van, F. Ciccosanti, M. Piacentini, L. Zitvogel, and G. Kroemer. 2007. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat. Med. 13: 54-61. https://doi.org/10.1038/nm1523
  8. Cragg, G. M., D. J. Newman, and K. M. Snader. 1997. Natural products in drug discovery and development. J. Nat. Prod. 60: 52-60. https://doi.org/10.1021/np9604893
  9. Joo, E. J., Y. W. Ha, H. Shin, S. H. Son, and Y. S. Kim. 2009. Generation and characterization of monoclonal antibody to ginsenoside rg3. Biol. Pharm. Bull. 32: 548-552. https://doi.org/10.1248/bpb.32.548
  10. Gao, J. L., G. Y. Lv, B. C. He, B. Q. Zhang, H. Zhang, N. Wang, C. Z. Wang, W. Du, C. S. Yuan, and T. C. He. 2013. Ginseng saponin metabolite 20(S)-protopanaxadiol inhibits tumor growth by targeting multiple cancer signaling pathways. Oncol. Rep. 30: 292-298. https://doi.org/10.3892/or.2013.2438
  11. Wang, C. Z., H. H. Aung, M. Ni, J. A. Wu, R. Tong, S. Wicks, T. C. He, and C. S. Yuan. 2007. Red American ginseng: ginsenoside constituents and antiproliferative activities of heat-processed Panax quinquefolius roots. Planta Med. 73: 669-674. https://doi.org/10.1055/s-2007-981524
  12. Liu, T. G., Y. Huang, D. D. Cui, X. B. Huang, S. H. Mao, L. L. Ji, H. B. Song, and C. Yi. 2009. Inhibitory effect of ginsenoside Rg3 combined with gemcitabine on angiogenesis and growth of lung cancer in mice. BMC Cancer 9: 250.
  13. Zhang, Q., X. Kang, and W. Zhao. 2006. Antiangiogenic effect of low-dose cyclophosphamide combined with ginsenoside Rg3 on Lewis lung carcinoma. Biochem. Biophys. Res. Commun. 342: 824-828. https://doi.org/10.1016/j.bbrc.2006.02.044
  14. Yi, C., X. B. Huang, and M. Hou. 2005. [Experimental study on effect of chemotherapy combined ginsengnoside Rg3 in treating pulmonary carcinoma]. Zhongguo Zhong. Xi. Yi. Jie. He. Za Zhi. 25: 58-59.
  15. Hu, S. S., L. K. Zhou, Y. Ba, H. I. Li, and C. H. Zhu. 2011. A meta-analysis of Ginsenoside Rg3 for non- small cell lung cancer. Clin. Oncol. Cancer Res. 8: 175-180. https://doi.org/10.1007/s11805-011-0578-4
  16. Liu, J. W., J. X. Chen, L. H. Yu, Y. X. Tian, X. Y. Cui, Q. Yan, and L. Fu. 2004. [Inhibitory effect of ginsenoside-Rg3 on lung metastasis of mouse melanoma transfected with ribonuclease inhibitor]. Zhonghua Zhong. Liu Za Zhi. 26: 722-725.
  17. Xu, T. M., M. H. Cui, Y. Xin, L. P. Gu, X. Jiang, M. M. Su, D. D. Wang, and W. J. Wang. 2008. Inhibitory effect of ginsenoside Rg3 on ovarian cancer metastasis. Chin. Med. J. (Engl.) 121: 1394-1397. https://doi.org/10.1097/00029330-200808010-00012
  18. Kim, Y. J., W. I. Choi, B. N. Jeon, K. C. Choi, K. Kim, T. J. Kim, J. Ham, H. J. Jang, K. S. Kang, and H. Ko. 2014. Stereospecific effects of ginsenoside 20-Rg3 inhibits TGF-beta1-induced epithelial-mesenchymal transition and suppresses lung cancer migration, invasion and anoikis resistance. Toxicology 322: 23-33. https://doi.org/10.1016/j.tox.2014.04.002
  19. Lee, S. G., B. S. Kim, and J. O. Nam. 2014. Ginsenoside Rg3 induces apoptosis in B16F10 melonoma cells. J. Life Sci. 24: 1001-1005. https://doi.org/10.5352/JLS.2014.24.9.1001
  20. Oh, S. J., C. K. Ryu, S. Y. Baek, and H. Lee. 2011. Cellular mechanism of newly synthesized indoledione derivative-induced immunological death of tumor cell. Immune Netw. 11: 383-389. https://doi.org/10.4110/in.2011.11.6.383
  21. Park, D., D. K. Bae, J. H. Jeon, J. Lee, N. Oh, G. Yang, Y. H. Yang, T. K. Kim, J. Song, S. H. Lee, B. S. Song, T. H. Jeon, S. J. Kang, S. S. Joo, S. U. Kim, and Y. B. Kim. 2011. Immuno-potentiation and antitumor effects of a ginsenoside Rg(3)-fortified red ginseng preparation in mice bearing H460 lung cancer cells. Environ. Toxicol. Pharmacol. 31: 397-405. https://doi.org/10.1016/j.etap.2011.01.008