IMMUNE NETWORK

The Korean Association of Immunobiologists (대한면역학회)
권호 표지
DOI QR코드

DOI QR Code

Cellular Mechanism of Newly Synthesized Indoledione Derivative-induced Immunological Death of Tumor Cell

  • Oh, Su-Jin (Office of Biomedical Science, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Ryu, Chung-Kyu (College of Pharmacy & Division of Life and Pharmaceutical Sciences, Ewha Womans University) ;
  • Baek, So-Young (Office of Biomedical Science, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Lee, Hyun-Ah (Office of Biomedical Science, Samsung Medical Center, Sungkyunkwan University School of Medicine)
  • Received : 2011.10.11
  • Accepted : 2011.11.08
  • Published : 2011.12.31
Download PDF
⟨ Previous Next ⟩

Abstract

Background: EY-6 is one of the newly synthesized indoledione derivatives to induce tumor cell-specific cell death. In this study, we investigated the mechanism of immunological death induced by EY-6 at mouse colon cancer cell as well as at the normal immune cell represented by dendritic cell. Methods: C57BL/6 mouse syngeneic colon cancer cell MC38 was treated with EY-6, and analyzed by MTT for viability test, flow cytometry for confirming surface expressing molecules and ELISA for detection of cytokine secretion. Normal myeloid-dendritic cell (DC) was ex vivo cultured from bone marrow hematopoietic stem cells of C57BL/6 mice with GM-CSF and IL-4 to analyze the DC uptake of dead tumor cells and to observe the effect of EY-6 on the normal DC. Results: EY-6 killed the MC38 tumor cells in a dose dependent manner (25, 50 and $100{\mu}M$) with carleticulin induction. And EY-6 induced the secretion of IFN-${\gamma}$ but not of TNF-${\alpha}$ from the MC38 tumor cells. EY-6 did not kill the ex-vivo cultured DCs at the dose killing tumor cells and did slightly but not significantly induced the DC maturation. The OVA-specific cross-presentation ability of DC was not induced by chemical treatment (both MHC II and MHC I-restricted antigen presentation). Conclusion: Data indicate that the EY-6 induced tumor cell specific and immunological cell death by modulation of tumor cell phenotype and cytokine secretion favoring induction of specific immunity eliminating tumor cells.

Keywords

References

  1. Obeid M, Panaretakis T, Tesniere A, Joza N, Tufi R, Apetoh L, Ghiringhelli F, Zitvogel L, Kroemer G: Leveraging the immune system during chemotherapy: moving calreticulin to the cell surface converts apoptotic death from "silent" to immunogenic. Cancer Res 67;7941-7944, 2007. https://doi.org/10.1158/0008-5472.CAN-07-1622
  2. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pag$\grave{e}$s C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohou$\grave{e}$ F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pagès F: Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313;1960-1964, 2006. https://doi.org/10.1126/science.1129139
  3. Apetoh L, Mignot G, Panaretakis T, Kroemer G, Zitvogel L: Immunogenicity of anthracyclines: moving towards more personalized medicine. Trends Mol Med 14;141-151, 2008. https://doi.org/10.1016/j.molmed.2008.02.002
  4. Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G: Immunological aspects of cancer chemotherapy. Nat Rev Immunol 8;59-73, 2008. https://doi.org/10.1038/nri2216
  5. Chan OT, Yang LX: The immunological effects of taxanes. Cancer Immunol Immunother 49;181-185, 2000. https://doi.org/10.1007/s002620000122
  6. Spreafico F, Vecchi A, Colotta F, Montovani A: Cancer chemotherapeutics as immunomodulators. Springer Semin Immunopathol 8;361-374, 1985. https://doi.org/10.1007/BF01857390
  7. North RJ: Cyclophosphamide-facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor-induced suppressor T cells. J Exp Med 155;1063-1074, 1982. https://doi.org/10.1084/jem.155.4.1063
  8. Nowak AK, Robinson BW, Lake RA: Gemcitabine exerts a selective effect on the humoral immune response: implications for combination chemo-immunotherapy. Cancer Res 62;2353-2358, 2002.
  9. Suzuki E, Kapoor V, Jassar AS, Kaiser LR, Albelda SM: Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res 11;6713- 6721, 2005. https://doi.org/10.1158/1078-0432.CCR-05-0883
  10. Machiels JP, Reilly RT, Emens LA, Ercolini AM, Lei RY, Weintraub D, Okoye FI, Jaffee EM: Cyclophosphamide, doxorubicin, and paclitaxel enhance the antitumor immune response of granulocyte/macrophage-colony stimulating factor-secreting whole-cell vaccines in HER-2/neu tolerized mice. Cancer Res 61;3689-3697, 2001.
  11. Zitvogel L, Kepp O, Senovilla L, Menger L, Chaput N, Kroemer G: Immunogenic tumor cell death for optimal anticancer therapy: the calreticulin exposure pathway. Clin Cancer Res 16;3100-3104, 2010. https://doi.org/10.1158/1078-0432.CCR-09-2891
  12. Panaretakis T, Kepp O, Brockmeier U, Tesniere A, Bjorklund AC, Chapman DC, Durchschlag M, Joza N, Pierron G, van Endert P, Yuan J, Zitvogel L, Madeo F, Williams DB, Kroemer G: Mechanisms of pre-apoptotic calreticulin exposure in immunogenic cell death. EMBO J 28;578-590, 2009. https://doi.org/10.1038/emboj.2009.1
  13. Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L, Perfettini JL, Castedo M, Mignot G, Panaretakis T, Casares N, Métivier D, Larochette N, van Endert P, Ciccosanti F, Piacentini M, Zitvogel L, Kroemer G: Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med 13;54-61, 2007. https://doi.org/10.1038/nm1523
  14. Ko JH, Yeon SW, Ryu JS, Kim TY, Song EH, You HJ, Park RE, Ryu CK: Synthesis and biological evaluation of 5-arylamino- 6-chloro-1H-indazole-4,7-diones as inhibitors of protein kinase B/Akt. Bioorg Med Chem Lett 16;6001-6005, 2006. https://doi.org/10.1016/j.bmcl.2006.08.120
  15. Chung KH, Hong SY, You HJ, Park RE, Ryu CK: Synthesis and biological evaluation of 5-arylamino-1H-benzo[d]imidazole- 4,7-diones as inhibitor of endothelial cell proliferation. Bioorg Med Chem 14;5795-5801, 2006. https://doi.org/10.1016/j.bmc.2006.05.059
  16. Kim JS, Rhee HK, Park HJ, Lee IK, Lee SK, Suh ME, Lee HJ, Ryu CK, Choo HY: Synthesis of 6-chloroisoquinoline- 5,8-diones and pyrido[3,4-b]phenazine-5,12-diones and evaluation of their cytotoxicity and DNA topoisomerase II inhibitory activity. Bioorg Med Chem 15;451-457, 2007. https://doi.org/10.1016/j.bmc.2006.09.040
  17. Seo JM, Jin YR, Ryu CK, Kim TJ, Han XH, Hong JT, Yoo HS, Lee CK, Yun YP: JM91, a newly synthesized indoledione derivative, inhibits rat aortic vascular smooth muscle cells proliferation and cell cycle progression through inhibition of ERK1/2 and Akt activations. Biochem Pharmacol 75;1331-1340, 2008. https://doi.org/10.1016/j.bcp.2007.11.013
  18. Esumi N, Hunt B, Itaya T, Frost P: Reduced tumorigenicity of murine tumor cells secreting gamma-interferon is due to nonspecific host responses and is unrelated to class I major histocompatibility complex expression. Cancer Res 51;1185- 1189, 1991
  19. Janelidze S, Bexell D, Badn W, Darabi A, Smith KE, Fritzell S, Gunnarsson S, Milos P, Bengzon J, Salford LG, Siesjo P, Visse E: Immunizations with IFNgamma secreting tumor cells can eliminate fully established and invasive rat gliomas. J Immunother 32;593-601, 2009. https://doi.org/10.1097/CJI.0b013e3181a95148

Cited by

  1. Induction of immunogenic cell death of tumors by newly synthesized heterocyclic quinone derivative vol.12, pp.3, 2017, https://doi.org/10.1371/journal.pone.0173121
  2. Vx3-Functionalized Alumina Nanoparticles Assisted Enrichment of Ubiquitinated Proteins from Cancer Cells for Enhanced Cancer Immunotherapy vol.29, pp.3, 2011, https://doi.org/10.1021/acs.bioconjchem.7b00578