Induction of Immunogenic Cell Death by Chemotherapeutic Platinum Complexes

  • Daniel Yuan Qiang WongEmail author
Part of the Springer Theses book series (Springer Theses)


There is growing evidence that conventional chemotherapeutics can modulate the immune system and trigger an immune response which sustains a long term durable therapeutic outcome.

Supplementary material


  1. 1.
    Galluzzi, L., Senovilla, L., Zitvogel, L., Kroemer, G.: The secret ally: immunostimulation by anticancer drugs. Nat. Rev. Drug Discov. 11, 215–233 (2012)CrossRefPubMedGoogle Scholar
  2. 2.
    Zitvogel, L., Galluzzi, L., Smyth, M.J., Kroemer, G.: Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity 39, 74–88 (2013)CrossRefPubMedGoogle Scholar
  3. 3.
    Mattarollo, S.R., Loi, S., Duret, H., Ma, Y., Zitvogel, L., Smyth, M.J.: Pivotal role of innate and adaptive immunity in anthracycline chemotherapy of established tumors. Cancer Res. 71, 4809–4820 (2011)CrossRefPubMedGoogle Scholar
  4. 4.
    Halama, N., Michel, S., Kloor, M., Zoernig, I., Benner, A., Spille, A., Pommerencke, T., von Knebel, D.M., Folprecht, G., Luber, B., Feyen, N., Martens, U.M., Beckhove, P., Gnjatic, S., Schirmacher, P., Herpel, E., Weitz, J., Grabe, N., Jaeger, D.: Localization and density of immune cells in the invasive margin of human colorectal cancer liver metastases are prognostic for response to chemotherapy. Cancer Res. 71, 5670–5677 (2011)CrossRefPubMedGoogle Scholar
  5. 5.
    Dieci, M.V., Criscitiello, C., Goubar, A., Viale, G., Conte, P., Guarneri, V., Ficarra, G., Mathieu, M.C., Delaloge, S., Curigliano, G., Andre, F.: Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study. Ann. Oncol. 25, 611–618 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Kroemer, G., Galluzzi, L., Kepp, O., Zitvogel, L.: Immunogenic cell death in cancer therapy. Annu. Rev. Immunol. 31, 51–72 (2013)CrossRefPubMedGoogle Scholar
  7. 7.
    Krysko, D.V., Garg, A.D., Kaczmarek, A., Krysko, O., Agostinis, P., Vandenabeele, P.: Immunogenic cell death and DAMPs in cancer therapy. Nat. Rev. Cancer 12, 860–875 (2012)CrossRefPubMedGoogle Scholar
  8. 8.
    Obeid, M., Tesniere, A., Ghiringhelli, F., Fimia, G.M., Apetoh, L., Perfettini, J.L., Castedo, M., Mignot, G., Panaretakis, T., Casares, N., Metivier, 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)CrossRefPubMedGoogle Scholar
  9. 9.
    Menger, L., Vacchelli, E., Adjemian, S., Martins, I., Ma, Y., Shen, S., Yamazaki, T., Sukkurwala, A. Q., Michaud, M., Mignot, G., Schlemmer, F., Sulpice, E., Locher, C., Gidrol, X., Ghiringhelli, F., Modjtahedi, N., Galluzzi, L.; André, F., Zitvogel, L., Kepp, O., Kroemer, G.: Cardiac glycosides exert anticancer effects by inducing immunogenic cell death. Sci. Transl. Med. 4, 143ra99 (2012)CrossRefPubMedGoogle Scholar
  10. 10.
    Kepp, O., Menger, L., Vacchelli, E., Locher, C., Adjemian, S., Yamazaki, T., Martins, I., Sukkurwala, A.Q., Michaud, M., Senovilla, L., Galluzzi, L., Kroemer, G., Zitvogel, L.: Crosstalk between ER stress and immunogenic cell death. Cytokine Growth Factor Rev. 24, 311–318 (2013)CrossRefPubMedGoogle Scholar
  11. 11.
    Chao, M.P., Jaiswal, S., Weissman-Tsukamoto, R., Alizadeh, A.A., Gentles, A.J., Volkmer, J., Weiskopf, K., Willingham, S.B., Raveh, T., Park, C.Y., Majeti, R., Weissman, I.L.: Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47. Sci. Transl. Med. 2, 63ra94 (2010)CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Tesniere, A., Schlemmer, F., Boige, V., Kepp, O., Martins, I., Ghiringhelli, F., Aymeric, L., Michaud, M., Apetoh, L., Barault, L., Mendiboure, J., Pignon, J.P., Jooste, V., van Endert, P., Ducreux, M., Zitvogel, L., Piard, F., Kroemer, G.: Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene 29, 482–491 (2009)CrossRefPubMedGoogle Scholar
  13. 13.
    Shah, N., Dizon, D.S.: New-generation platinum agents for solid tumors. Future Oncol. 5, 33–42 (2009)CrossRefPubMedGoogle Scholar
  14. 14.
    Park, G.Y., Wilson, J.J., Song, Y., Lippard, S.J.: Phenanthriplatin, a monofunctional DNA-binding platinum anticancer drug candidate with unusual potency and cellular activity profile. Proc. Natl. Acad. Sci. U. S. A. 109, 11987–11992 (2012)CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Bhargava, A., Vaishampayan, U.N.: Satraplatin: leading the new generation of oral platinum agents. Expert Opin. Investig. Drugs 18, 1787–1797 (2009)CrossRefPubMedGoogle Scholar
  16. 16.
    Holford, J., Sharp, S.Y., Murrer, B.A., Abrams, M., Kelland, L.R.: In vitro circumvention of cisplatin resistance by the novel sterically hindered platinum complex AMD473. Br. J. Cancer 77, 366–373 (1998)CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Zou, T., Lok, C.N., Fung, Y.M., Che, C.M.: Luminescent organoplatinum(II) complexes containing bis(N-heterocyclic carbene) ligands selectively target the endoplasmic reticulum and induce potent photo-toxicity. Chem. Commun. 49, 5423–5425 (2013)CrossRefGoogle Scholar
  18. 18.
    Hoffmann, P.R., deCathelineau, A.M., Ogden, C.A., Leverrier, Y., Bratton, D.L., Daleke, D.L., Ridley, A.J., Fadok, V.A., Henson, P.M.: Phosphatidylserine (PS) induces PS receptor-mediated macropinocytosis and promotes clearance of apoptotic cells. J. Cell Biol. 155, 649–659 (2001)CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Savill, J., Dransfield, I., Gregory, C., Haslett, C.: A blast from the past: clearance of apoptotic cells regulates immune responses. Nat. Rev. Immunol. 2, 965–975 (2002)CrossRefPubMedGoogle Scholar
  20. 20.
    Gardai, S.J., McPhillips, K.A., Frasch, S.C., Janssen, W.J., Starefeldt, A., Murphy-Ullrich, J.E., Bratton, D.L., Oldenborg, P.-A., Michalak, M., Henson, P.M.: Cell-Surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell 123, 321–334 (2005)CrossRefPubMedGoogle Scholar
  21. 21.
    Garg, A., Krysko, D., Vandenabeele, P., Agostinis, P.: Hypericin-based photodynamic therapy induces surface exposure of damage-associated molecular patterns like HSP70 and calreticulin. Cancer Immunol. Immunother. 61, 215–221 (2012)CrossRefPubMedGoogle Scholar
  22. 22.
    Garg, A.D., Krysko, D.V., Verfaillie, T., Kaczmarek, A., Ferreira, G.B., Marysael, T., Rubio, N., Firczuk, M., Mathieu, C., Roebroek, A.J.M., Annaert, W., Golab, J., de Witte, P., Vandenabeele, P., Agostinis, P.: A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death. EMBO J. 31, 1062–1079 (2012)CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Garg, A.D., Krysko, D.V., Vandenabeele, P., Agostinis, P.: The emergence of phox-ER stress induced immunogenic apoptosis. OncoImmunology 1, 786–788 (2012)CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Inoue, H., Tani, K.: Multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments. Cell Death Differ. 21, 39–49 (2014)CrossRefPubMedGoogle Scholar
  25. 25.
    Hempel, S.L., Buettner, G.R., O’Malley, Y.Q., Wessels, D.A., Flaherty, D.M.: Dihydrofluorescein diacetate is superior for detecting intracellular oxidants: comparison with 2′,7′-dichlorodihydrofluorescein diacetate, 5(and 6)-carboxy-2′,7′-dichlorodihydrofluorescein diacetate, and dihydrorhodamine 123. Free Radic. Biol. Med. 27, 146–159 (1999)CrossRefPubMedGoogle Scholar
  26. 26.
    Costes, S.V., Daelemans, D., Cho, E.H., Dobbin, Z., Pavlakis, G., Lockett, S.: Automatic and quantitative measurement of protein-protein colocalization in live cells. Biophys. J. 86, 3993–4003 (2004)CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Wang, X., Olberding, K.E., White, C., Li, C.: Bcl-2 proteins regulate ER membrane permeability to luminal proteins during ER stress-induced apoptosis. Cell Death Differ. 18, 38–47 (2011)CrossRefPubMedGoogle Scholar
  28. 28.
    Sukkurwala, A.Q., Adjemian, S., Senovilla, L., Michaud, M., Spaggiari, S., Vacchelli, E., Baracco, E.E., Galluzzi, L., Zitvogel, L., Kepp, O., Kroemer, G.: Screening of novel immunogenic cell death inducers within the NCI mechanistic diversity set. OncoImmunology 3, e28473 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Wong, D.Y.Q., Yeo, C.H.F., Ang, W.H.: Immuno-chemotherapeutic platinum(IV) prodrugs of cisplatin as multimodal anticancer agents. Angew. Chem. Int. Ed. 53, 6752–6756 (2014)CrossRefGoogle Scholar
  30. 30.
    Dhara, S.C.: A rapid method for the synthesis of cis-[Pt(NH3)2Cl2]. Indian J. Chem. 8, 193–194 (1970)Google Scholar
  31. 31.
    Pepels, A., Rauter, H., Schnebeck, R.D., Wissmann, F.: Process for the preparation of 1,2-diaminocyclohexane-platinum(II) complexes. In Google Patents (2007)Google Scholar
  32. 32.
    Chin, C.F., Tian, Q., Setyawati, M.I., Fang, W., Tan, E.S., Leong, D.T., Ang, W.H.: Tuning the activity of platinum(IV) anticancer complexes through asymmetric acylation. J. Med. Chem. 55, 7571–7582 (2012)CrossRefPubMedGoogle Scholar
  33. 33.
    Zhang, J.Z., Bonnitcha, P., Wexselblatt, E., Klein, A.V., Najajreh, Y., Gibson, D., Hambley, T.W.: Facile preparation of mono-, di- and mixed-carboxylato platinum(IV) complexes for versatile anticancer prodrug design. Chem. Eur. J. 19, 1672–1676 (2013)CrossRefPubMedGoogle Scholar
  34. 34.
    Battle, A.R., Choi, R., Hibbs, D.E., Hambley, T.W.: Platinum(IV) analogues of AMD473 (cis-[PtCl2(NH3)(2-picoline)]): preparative, structural, and electrochemical studies. Inorg. Chem. 45, 6317–6322 (2006)CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Department of ChemistryNational University of SingaporeSingaporeSingapore

Personalised recommendations