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Journal of Molecular and Clinical Medicine   2018, Vol. 1 Issue (4): 205-212    DOI: 10.31083/j.jmcm.2018.04.403
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Novel aspects of the preclinical pharmacology of platinum compounds
Cristina Corno1, Paola Perego1, *()
1 Molecular Pharmacology Unit, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, 20133, Milan, Italy
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Abstract  

Platinum compounds are widely used antitumor agents known to interfere with DNA function by forming DNA crosslinks and DNA-protein crosslinks. Because of their electrophilicity, platinum compounds can interact with nucleophilic residues of all macromolecules. Consequently, this cross-linking inhibits DNA replication in cancer cells. Immunogenic and immunomodulating effects have been ascribed to platinum drugs, with differences and similarities among cisplatin, carboplatin and oxaliplatin. On the one hand, cisplatin is generally unable to induce immunogenic cell death; on the other hand, oxaliplatin appears to be a good inducer, thanks to its capability to efficiently trigger calreticulin exposure to the tumor cell plasma membrane. Conversely, cisplatin, carboplatin and oxaliplatin can relieve immunosuppressive networks e.g., by decreasing PDL-1 and PDL-2 in dendritic and tumor cells. Such drugs are also capable of modulating MHC molecules via IFN-β production and T-cell mediated lysis. The concentrations appear to be key in determining the immunomodulatory properties of these cytotoxic agents, with low in vivo doses usually playing stimulatory effects. As predicted from preclinical models, supportive results have emerged from clinical studies, particularly those based on chemotherapeutic regimens of platinum compounds combined with immunotherapeutics. Future therapeutic interventions are expected to benefit from a better definition of the molecular effects of platinum compounds on the immune system.

Key words:  Cisplatin      Carboplatin      Oxaliplatin      Immunogenic cell death      Immunostimulation     
Revised:  12 November 2018      Accepted:  02 December 2018      Published:  20 December 2018     
*Corresponding Author(s):  Perego Paola     E-mail:  paola.perego@istitutotumori.mi.it

Cite this article: 

Cristina Corno,Paola Perego. Novel aspects of the preclinical pharmacology of platinum compounds. Journal of Molecular and Clinical Medicine , 2018, 1(4): 205-212.

URL: 

https://jmcm.imrpress.com/EN/10.31083/j.jmcm.2018.04.403     OR     https://jmcm.imrpress.com/EN/Y2018/V1/I4/205

Fig. 1.  Structures of the most commonly used platinum compounds. The dates of approval for clinical use are indicated together with the mechanism of action and cell response.

Fig. 2.  Schematic representation of platinum drug-induced immunogenic cell death. Examples of modes to render cisplatin capable to trigger immunogenic cell death (ICD) are shown in the box. The key players of ICD are also shown. Abbreviations: ER = endoplasmic reticulum; Zn= zinc; Hsp70/90 = Heat shock protein 70/90; ATP = adenosine triphosphate; HGMB1 = high-mobility group box protein 1; DAMPs = damage-associated molecular patterns; DC = dendritic cell; IL-β 1 = interleukin 1-beta; IFN-γ = interferon gamma.

Fig. 3.  Immunomodulatory activity of platinum compounds. The main recently reported aspects of the immunomodulatory activity of platinum compounds are shown.

[1] Kelland L. The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer, 2007; 7(8): 573-584.
[2] Cossa G, Gatti L, Zunino F, Perego P. Strategies to improve the efficacy of platinum compounds. Curr Med Chem, 2009; 16(19): 2355-2365.
doi: 10.2174/092986709788682083 pmid: 19601785
[3] Isakoff SJ. Triple-negative breast cancer: Role of specific chemotherapy agents. Cancer J., 2010; 16(1): 53-61.
doi: 10.1097/PPO.0b013e3181d24ff7
[4] Wahba HA, El-Hadaad HA. Current approaches in treatment of triplenegative breast cancer. Cancer Biol Med., 2015; 12(2): 106-116.
doi: 10.7497/j.issn.2095-3941.2015.0030 pmid: 4493381
[5] Aparicio AM, Harzstark AL, Corn PG, Wen S, Araujo JC, Tu SM et al. Platinum-based chemotherapy for variant castrate-resistant prostate cancer. Clin Cancer Res, 2013; 19(13): 3621-3630.
doi: 10.1158/1078-0432.CCR-12-3791 pmid: 23649003
[6] Perego P, Robert J. Oxaliplatin in the era of personalized medicine: From mechanistic studies to clinical efficacy. Cancer Chemother Pharmacol, 2016; 77(1): 5-18.
doi: 10.1007/s00280-015-2901-x pmid: 26589793
[7] Dilruba S, Kalayda GV. Platinum-based drugs: Past, present and future. Cancer Chemother Pharmacol, 2016; 77(6): 1103-1124.
doi: 10.1007/s00280-016-2976-z pmid: 26886018
[8] Monneret C. Platinum anticancer drugs. from serendipity to rational design. Ann Pharm Fr, 2011; 69(6): 286-295.
doi: 10.1016/j.pharma.2011.10.001 pmid: 22115131
[9] Johnstone TC, Suntharalingam K, Lippard SJ. The next generation of platinum drugs: Targeted pt(II) agents, nanoparticle delivery, and pt(IV) prodrugs. Chem Rev, 2016; 116(5): 3436-3486.
doi: 10.1021/acs.chemrev.5b00597 pmid: 26865551
[10] Doshi G, Sonpavde G, Sternberg CN. Clinical and pharmacokinetic evaluation of satraplatin. Expert Opin Drug Metab Toxicol, 2012; 8(1): 103-111.
doi: 10.1517/17425255.2012.636352 pmid: 22098065
[11] Gatti L, Cassinelli G, Zaffaroni N, Lanzi C, Perego P. New mechanisms for old drugs: Insights into DNA-unrelated effects of platinum compounds and drug resistance determinants. Drug Resist Updat, 2015; 20: 1-11.
doi: 10.1016/j.drup.2015.04.001 pmid: 26003720
[12] de Klerk DJ, Honeywell RJ, Jansen G, Peters GJ. Transporter and lysosomal mediated (multi)drug resistance to tyrosine kinase inhibitors and potential strategies to overcome resistance. Cancers (Basel), 2018; 10(12): 1-27.
[13] O’Neill CP, Gilligan KE, Dwyer RM. Role of extracellular vesicles (EVs) in cell stress response and resistance to cancer therapy. Cancers (Basel), 2019; 11: 1-14.
[14] Pennati M, Cimino-Reale G, Gatti L, Cassinelli G. Strategies to strike survival networks in cancer. Crit Rev Oncog, 2016; 21(3-4): 269-308.
doi: 10.1615/CritRevOncog.v21.i3-4
[15] Phillips RM. Targeting the hypoxic fraction of tumours using hypoxiaactivated prodrugs. Cancer Chemother Pharmacol, 2016; 77(3): 441-57.
doi: 10.1007/s00280-015-2920-7 pmid: 4767869
[16] Yeldag G, Rice A, Del Rio Hernandez A. Chemoresistance and the self-maintaining tumor microenvironment. Cancers (Basel), 2018; 10(12): 471.
doi: 10.3390/cancers10120471
[17] Casares N, Pequignot MO, Tesniere A, Ghiringhelli F, Roux S, Chaput N, et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J Exp Med, 2005; 202(12): 1691-1701.
doi: 10.1084/jem.20050915 pmid: 16365148
[18] Martins I, Kepp O, Schlemmer F, Adjemian S, Tailler M, Shen S, et al. Restoration of the immunogenicity of cisplatin-induced cancer cell death by endoplasmic reticulum stress. Oncogene, 2011; 30(10): 1147-1158.
doi: 10.1038/onc.2010.500 pmid: 21151176
[19] Galluzzi L, Buque A, Kepp O, Zitvogel L, Kroemer G. Immunogenic cell death in cancer and infectious disease. Nat Rev Immunol, 2017; 17(2): 97-111.
doi: 10.1038/nri.2016.107 pmid: 27748397
[20] Obeid M, Tesniere A ,Panaretakis T,ufi R, Joza N, van Endert P, et al. Ecto-calreticulin in immunogenic chemotherapy. Immunol Rev , 2007; 220: 22-34.
doi: 10.1111/j.1600-065X.2007.00567.x pmid: 17979837
[21] Ghiringhelli F, Apetoh L, Tesniere A, Aymeric L, Ma Y, Ortiz C, et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat Med, 2009; 15(10): 1170-1178.
[22] Michaud M, Sukkurwala AQ, Di Sano F, Zitvogel L, Kepp O, Kroemer G. Synthetic induction of immunogenic cell death by genetic stimulation of endoplasmic reticulum stress. Oncoimmunology, 2014; 3: e28276.
doi: 10.4161/onci.28276 pmid: 4063145
[23] Kopecka J, Salaroglio IC, Righi L, Libener R, Orecchia S, Grosso F, et al. Loss of C/EBP-beta LIP drives cisplatin resistance in malignant pleural mesothelioma. Lung Cancer, 2018; 120: 34-45.
doi: 10.1016/j.lungcan.2018.03.022 pmid: 29748013
[24] Cirone M, Garufi A, Di Renzo L, Granato M, Faggioni A, D’Orazi G . Zinc supplementation is required for the cytotoxic and immunogenic effects of chemotherapy in chemoresistant p53-functionally deficient cells. Oncoimmunology, 2013; 2(9): e26198.
doi: 10.4161/onci.26198 pmid: 3820813
[25] Aranda F, Bloy N, Pesquet J, Petit B, Chaba K, Sauvat A, et al. Immune-dependent antineoplastic effects of cisplatin plus pyridoxine in non-small-cell lung cancer. Oncogene, 2015; 34(23): 3053-3062.
doi: 10.1038/onc.2014.234 pmid: 25065595
[26] Mandic A, Hansson J, Linder S, Shoshan MC. Cisplatin induces endoplasmic reticulum stress and nucleus-independent apoptotic signaling. J Biol Chem, 2003; 278(11): 9100-9106.
doi: 10.1074/jbc.M210284200 pmid: 12509415
[27] Beyranvand Nejad E, van der Sluis TC, van Duikeren S, van der Burg SH. Tumor eradication by cisplatin is sustained by CD80/86-mediated costimulation of CD8+ T cells. Cancer Res, 2016; 76(20): 6017-6029.
doi: 10.1158/0008-5472.CAN-16-0881 pmid: 27569212
[28] Mali B, Miklavcic D, Campana LG, et al. Tumor size and effectiveness of electrochemotherapy. Radiol Oncol, 2013; 47(1): 32-41.
doi: 10.2478/raon-2013-0002 pmid: 23450195
[29] Seyed Jafari SM, Jabbary Lak F, Gazdhar A, Shafighi M, Borradori L, Hunger RE. Application of electrochemotherapy in the management of primary and metastatic cutaneous malignant tumours: A systematic review and meta-analysis. Eur J Dermatol, 2018; 28(3): 287-313.
[30] Ursic K, Kos S, Kamensek U, Cemazar M, Scancar J, Bucek S, et al. Comparable effectiveness and immunomodulatory actions of oxaliplatin and cisplatin in electrochemotherapy of murine melanoma. Bioelectro-chemistry, 2018; 119: 161-171.
doi: 10.1016/j.bioelechem.2017.09.009 pmid: 29024870
[31] Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science, 2017; 357(6349): 409-413.
doi: 10.1126/science.aan6733 pmid: 5576142
[32] Aebi S, Fink D, Gordon R, Kim HK, Zheng H, Fink JL, et al. Resistance to cytotoxic drugs in DNA mismatch repair-deficient cells. Clin Cancer Res, 1997; 3(10): 1763-1767.
[33] Manic S, Gatti L, Carenini N, Fumagalli G, Zunino F, Perego P. Mechanisms controlling sensitivity to platinum complexes: Role of p53 and DNA mismatch repair. Curr Cancer Drug Targets, 2003; 3(1): 21-29.
doi: 10.2174/1568009033333727 pmid: 12570658
[34] Anthoney DA, McIlwrath AJ, Gallagher WM, Edlin AR, Brown R . Microsatellite instability, apoptosis, and loss of p53 function in drugresistant tumor cells. Cancer Res, 1996; 56(6): 1374-1381.
[35] de Biasi AR, Villena-Vargas J, Adusumilli PS. Cisplatin-induced antitumor immunomodulation: A review of preclinical and clinical evidence. Clin Cancer Res, 2014; 20(21): 5384-5391.
doi: 10.1158/1078-0432.CCR-14-1298 pmid: 4216745
[36] Hato SV, Khong A, de Vries IJ, Lesterhuis WJ. Molecular pathways: The immunogenic effects of platinum-based chemotherapeutics. Clin Cancer Res, 2014; 20(11): 2831-2837.
doi: 10.1158/1078-0432.CCR-13-3141 pmid: 24879823
[37] Lesterhuis WJ, Punt CJ, Hato SV, Eleveld-Trancikova D, Jansen BJ, Nierkens S, et al. Platinum-based drugs disrupt STAT6-mediated suppression of immune responses against cancer in humans and mice. J Clin Invest, 2011; 121(8): 3100-3108.
doi: 10.1172/JCI43656 pmid: 3148725
[38] Wan S, Pestka S, Jubin RG, Lyu YL, Tsai YC, Liu LF. Chemotherapeutics and radiation stimulate MHC class I expression through elevated interferon-beta signaling in breast cancer cells. PLoS One, 2012; 7(3): e32542.
doi: 10.1371/journal.pone.0032542 pmid: 3291570
[39] Gameiro SR, Caballero JA, Hodge JW. Defining the molecular signature of chemotherapy-mediated lung tumor phenotype modulation and increased susceptibility to T-cell killing. Cancer Biother Radiopharm, 2012; 27(1): 23-35.
doi: 10.1089/cbr.2012.1203 pmid: 22316209
[40] Nagai N, Ogata H, Wada Y, Tsujino D, Someya K, Ohno T, et al. Population pharmacokinetics and pharmacodynamics of cisplatin in patients with cancer: Analysis with the NONMEM program. J Clin Pharmacol, 1998; 38(11): 1025-1034.
doi: 10.1177/009127009803801107 pmid: 9824784
[41] Merritt RE, Mahtabifard A, Yamada RE, Crystal RG, Korst RJ. Cisplatin augments cytotoxic T-lymphocyte-mediated antitumor immunity in poorly immunogenic murine lung cancer. J Thorac Cardiovasc Surg, 2003; 126(5): 1609-1617.
doi: 10.1016/S0022-5223(03)00707-4 pmid: 14666041
[42] Dijkgraaf EM, Heusinkveld M, Tummers B, Vogelpoel LT, Goedemans R, Jha V, et al. Chemotherapy alters monocyte differentiation to favor generation of cancer-supporting M2 macrophages in the tumor microenvironment. Cancer Res, 2013; 73(8): 2480-2492.
doi: 10.1158/0008-5472.CAN-12-3542 pmid: 23436796
[43] Perrotta C, Cervia D, Di Renzo I, Moscheni C, Bassi MT, Campana L, et al. Nitric oxide generated by tumor-associated macrophages is responsible for cancer resistance to cisplatin and correlated with syntaxin 4 and acid sphingomyelinase inhibition. Front Immunol, 2018; 9: 1186.
[44] Liu C, Workman CJ, Vignali DA. Targeting regulatory T cells in tumors. FEBS J., 2016; 283(14): 2731-2748.
doi: 10.1111/febs.13656 pmid: 26787424
[45] Scharovsky OG, Mainetti LE, Rozados VR. Metronomic chemotherapy: Changing the paradigm that more is better. Curr Oncol, 2009; 16(2): 7-15.
doi: 10.3747/co.v16i2.420 pmid: 2669231
[46] Tseng CW, Hung CF, Alvarez RD, Trimble C, Huh WK, Kim D, et al. Pretreatment with cisplatin enhances E7-specific CD8+ T-cell-mediated antitumor immunity induced by DNA vaccination. Clin Cancer Res, 2008; 14(10): 3185-3192.
doi: 10.1158/1078-0432.CCR-08-0037 pmid: 18483387
[47] Chang CL, Hsu YT, Wu CC, et al. Dose-dense chemotherapy improves mechanisms of antitumor immune response. Cancer Res, 2013; 73(1): 119-127.
doi: 10.1158/0008-5472.can-12-2225 pmid: 23108141
[48] Tanaka H, Matsushima H, Mizumoto N, Takashima A. Classification of chemotherapeutic agents based on their differential in vitro effects on dendritic cells. Cancer Res, 2009; 69(17): 6978-6986.
doi: 10.1158/0008-5472.CAN-09-1101
[49] Dai M, Hellstrom I, Yip YY, Sjogren HO, Hellstrom KE. Tumor regression and cure depends on sustained Th1 responses. J Immunother, 2018; 41(8): 369-378.
doi: 10.1097/CJI.0000000000000231 pmid: 29912725
[50] Matsuzaki I, Suzuki H, Kitamura M, Minamiya Y, Kawai H, Ogawa J. Cisplatin induces fas expression in esophageal cancer cell lines and enhanced cytotoxicity in combination with LAK cells. Oncology, 2000; 59(4): 336-343.
doi: 10.1159/000012192 pmid: 11096347
[51] Ramakrishnan R, Assudani D, Nagaraj S, et al. Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice. J Clin Invest, 2010; 120(4): 1111-1124.
doi: 10.1172/JCI40269 pmid: 2846048
[52] Bergmann-Leitner ES, Abrams SI. Treatment of human colon carcinoma cell lines with anti-neoplastic agents enhances their lytic sensitivity to antigen-specific CD8+ cytotoxic T lymphocytes. Cancer Immunol Immunother, 2001; 50(9): 445-455.
doi: 10.1007/s002620100229 pmid: 11761438
[53] Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med, 2018; 378(22): 2078-2092.
[54] Villanueva MT. Signal transduction: The old dog’s new tricks. Nat Rev Clin Oncol, 2011; 8(10): 569.
doi: 10.1038/nrclinonc.2011.131 pmid: 21862979
[55] Hu J, Kinn J, Zirakzadeh AA, Sherif A, Norstedt G , Wikström AC ,et al. The effects of chemotherapeutic drugs on human monocyte-derived dendritic cell differentiation and antigen presentation. Clin Exp Immunol, 2013; 172(3): 490-499.
doi: 10.1111/cei.12060 pmid: 23600838
[56] Wong DY, Yeo CH, Ang WH. Immuno-chemotherapeutic platinum(IV) prodrugs of cisplatin as multimodal anticancer agents. Angew Chem Int Ed Engl, 2014; 53(26): 6752-6756.
doi: 10.1002/ange.201402879 pmid: 24844571
[57] Bever KM, Le DT. DNA repair defects and implications for immunother-apy. J Clin Invest, 2018; 128(10): 4236-4242.
doi: 10.1172/JCI122010
[58] Lee H, Nho D, Chung HS, Lee H, Shin MK, Kim SH, et al. CD4+CD25+ regulatory T cells attenuate cisplatin-induced nephrotoxi-city in mice. Kidney Int, 2010; 78(11): 1100-1109.
doi: 10.1038/ki.2010.139 pmid: 20463654
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