Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The rediscovery of platinum-based cancer therapy

Abstract

Platinum (Pt) compounds entered the clinic as anticancer agents when cisplatin was approved in 1978. More than 40 years later, even in the era of precision medicine and immunotherapy, Pt drugs remain among the most widely used anticancer drugs. As Pt drugs mainly target DNA, it is not surprising that recent insights into alterations of DNA repair mechanisms provide a useful explanation for their success. Many cancers have defective DNA repair, a feature that also sheds new light on the mechanisms of secondary drug resistance, such as the restoration of DNA repair pathways. In addition, genome-wide functional screening approaches have revealed interesting insights into Pt drug uptake. About half of cisplatin and carboplatin but not oxaliplatin may enter cells through the widely expressed volume-regulated anion channel (VRAC). The analysis of this heteromeric channel in tumour biopsies may therefore be a useful biomarker to stratify patients for initial Pt treatments. Moreover, Pt-based approaches may be improved in the future by the optimization of combinations with immunotherapy, management of side effects and use of nanodelivery devices. Hence, Pt drugs may still be part of the standard of care for several cancers in the coming years.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Timeline of major milestones in Pt drug research and clinical application.
Fig. 2: Pt drug accumulation mechanisms.
Fig. 3: Pt drug resistance.
Fig. 4: Interaction between the TME and Pt drugs.
Fig. 5: Pt drug compounds and formulations.

References

  1. 1.

    US Food and Drug Administration. Drugs@FDA: FDA-approved drugs. New drug application (NDA): 018057 (FDA, 2019).

  2. 2.

    Kelland, L. The resurgence of platinum-based cancer chemotherapy. Nat. Rev. Cancer 7, 573–584 (2007).

    CAS  PubMed  Google Scholar 

  3. 3.

    Kauffman, G. B., Pentimalli, R., Doldi, S. & Hall, M. D. Michele Peyrone (1813–1883), discoverer of cisplatin. Platin Met. Rev. 54, 250–256 (2010).

    CAS  Google Scholar 

  4. 4.

    Rosenberg, B., van Camp, L. & Krigas, T. Inhibition of cell division in Escherichia coli by electrolysis products from a platinum electrode. Nature 205, 698–699 (1965).

    CAS  PubMed  Google Scholar 

  5. 5.

    Wiltshaw, E. Cisplatin in the treatment of cancer. Platin Met. Rev. 23, 90–98 (1979).

    CAS  Google Scholar 

  6. 6.

    US Food and Drug Administration. Drugs@FDA: FDA-approved drugs. Abbreviated new drug application (ANDA): 077139 (FDA, 2012).

  7. 7.

    Perego, P. & Robert, J. Oxaliplatin in the era of personalized medicine: from mechanistic studies to clinical efficacy. Cancer Chemother. Pharmacol. 77, 5–18 (2016).

    CAS  PubMed  Google Scholar 

  8. 8.

    Dilruba, S. & Kalayda, G. V. Platinum-based drugs: past, present and future. Cancer Chemother. Pharmacol. 77, 1103–1124 (2016).

    CAS  PubMed  Google Scholar 

  9. 9.

    Lippard, S. J. New chemistry of an old molecule: cis-[Pt(NH3)2Cl2. Science 218, 1075–1082 (1982).

    CAS  PubMed  Google Scholar 

  10. 10.

    Wang, D. & Lippard, S. J. Cellular processing of platinum anticancer drugs. Nat. Rev. Drug Discov. 4, 307–320 (2005).

    CAS  PubMed  Google Scholar 

  11. 11.

    Burger, H. et al. Drug transporters of platinum-based anticancer agents and their clinical significance. Drug Resist. Updat. 14, 22–34 (2011).

    CAS  PubMed  Google Scholar 

  12. 12.

    Borst, P., Rottenberg, S. & Jonkers, J. How do real tumors become resistant to cisplatin? Cell Cycle 7, 1353–1359 (2008).

    CAS  PubMed  Google Scholar 

  13. 13.

    Sakai, W. et al. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature 451, 1116–1120 (2008). This study shows that secondary intragenic BRCA2 mutations restore the wild-type reading frame as a mechanism of resistance to cisplatin in cancer cell lines and clinical specimens.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Zhao, W., Wiese, C., Kwon, Y., Hromas, R. & Sung, P. The BRCA tumor suppressor network in chromosome damage repair by homologous recombination. Annu. Rev. Biochem. 88, 221–245 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Harris, A. L. DNA repair and resistance to chemotherapy. Cancer Surv. 4, 601–624 (1985).

    CAS  PubMed  Google Scholar 

  16. 16.

    Lord, C. J. & Ashworth, A. The DNA damage response and cancer therapy. Nature 481, 287–294 (2012).

    CAS  PubMed  Google Scholar 

  17. 17.

    Nickoloff, J. A., Jones, D., Lee, S. H., Williamson, E. A. & Hromas, R. Drugging the cancers addicted to DNA repair. J. Natl. Cancer Inst. 109, djx059 (2017).

    PubMed Central  Google Scholar 

  18. 18.

    Miki, Y. et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266, 66–71 (1994).

    CAS  PubMed  Google Scholar 

  19. 19.

    Wooster, R. et al. Identification of the breast cancer susceptibility gene BRCA2. Nature 378, 789–792 (1995).

    CAS  PubMed  Google Scholar 

  20. 20.

    Nik-Zainal, S. et al. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature 534, 47–54 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    von Minckwitz, G. et al. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol. 15, 747–756 (2014).

    Google Scholar 

  22. 22.

    Telli, M. L. et al. Homologous recombination deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer. Clin. Cancer Res. 22, 3764–3773 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Silver, D. P. et al. Efficacy of neoadjuvant cisplatin in triple-negative breast cancer. J. Clin. Oncol. 28, 1145–1153 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Vollebergh, M. A. et al. An aCGH classifier derived from BRCA1-mutated breast cancer and benefit of high-dose platinum-based chemotherapy in HER2-negative breast cancer patients. Ann. Oncol. 22, 1561–1570 (2011).

    CAS  PubMed  Google Scholar 

  25. 25.

    Vollebergh, M. A. et al. Genomic patterns resembling BRCA1- and BRCA2-mutated breast cancers predict benefit of intensified carboplatin-based chemotherapy. Breast Cancer Res. 16, R47 (2014).

    PubMed  PubMed Central  Google Scholar 

  26. 26.

    Bryant, H. E. et al. Specific killing of BRCA2-deficient tumors with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005).

    CAS  Google Scholar 

  27. 27.

    Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Ledermann, J. et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 15, 852–861 (2014).

    CAS  PubMed  Google Scholar 

  29. 29.

    Ledermann, J. A. & Pujade-Lauraine, E. Olaparib as maintenance treatment for patients with platinum-sensitive relapsed ovarian cancer. Ther. Adv. Med. Oncol. 11, 1758835919849753 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Welsh, C. et al. Reduced levels of XPA, ERCC1 and XPF DNA repair proteins in testis tumor cell lines. Int. J. Cancer 110, 352–361 (2004).

    CAS  PubMed  Google Scholar 

  31. 31.

    Fenske, A. E. et al. Cisplatin resistance induced in germ cell tumor cells is due to reduced susceptibility towards cell death but not to altered DNA damage induction or repair. Cancer Lett. 324, 171–178 (2012).

    CAS  PubMed  Google Scholar 

  32. 32.

    Bagrodia, A. et al. Genetic determinants of cisplatin resistance in patients with advanced germ cell tumors. J. Clin. Oncol. 34, 4000–4007 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Luvero, D. et al. Ovarian cancer relapse: from the latest scientific evidence to the best practice. Crit. Rev. Oncol. Hematol. 140, 28–38 (2019).

    PubMed  Google Scholar 

  34. 34.

    Lo Russo, G., Imbimbo, M. & Garassino, M. C. Is the chemotherapy era in advanced non-small cell lung cancer really over? Maybe not yet. Tumori 3, 223–225 (2016).

    Google Scholar 

  35. 35.

    Gately, D. P. & Howell, S. B. Cellular accumulation of the anticancer agent cisplatin: a review. Br. J. Cancer 67, 1171–1176 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Harrach, S. & Ciarimboli, G. Role of transporters in the distribution of platinum-based drugs. Front. Pharmacol. 6, 85 (2015).

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Pan, B. F., Sweet, D. H., Pritchard, J. B., Chen, R. & Nelson, J. A. A transfected cell model for the renal toxin transporter, rOCT2. Toxicol. Sci. 47, 181–186 (1999).

    CAS  PubMed  Google Scholar 

  38. 38.

    Jong, N. N., Nakanishi, T., Liu, J. J., Tamai, I. & McKeage, M. J. Oxaliplatin transport mediated by organic cation/carnitine transporters OCTN1 and OCTN2 in overexpressing human embryonic kidney 293 cells and rat dorsal root ganglion neurons. J. Pharmacol. Exp. Ther. 338, 537–547 (2011).

    CAS  PubMed  Google Scholar 

  39. 39.

    Ishida, S., Lee, J., Thiele, D. J. & Herskowitz, I. Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals. Proc. Natl Acad. Sci. USA 99, 14298–14302 (2002).

    CAS  PubMed  Google Scholar 

  40. 40.

    Wen, X. et al. Transgenic expression of the human MRP2 transporter reduces cisplatin accumulation and nephrotoxicity in Mrp2-null mice. Am. J. Pathol. 184, 1299–1308 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Myint, K., Li, Y., Paxton, J. & McKeage, M. Multidrug resistance-associated protein 2 (MRP2) mediated transport of oxaliplatin-derived platinum in membrane vesicles. PLoS ONE 10, e0130727 (2015).

    PubMed  PubMed Central  Google Scholar 

  42. 42.

    Myint, K. et al. Identification of MRP2 as a targetable factor limiting oxaliplatin accumulation and response in gastrointestinal cancer. Sci. Rep. 9, 2245 (2019).

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Hall, M. D., Okabe, M., Shen, D. W., Liang, X. J. & Gottesman, M. M. The role of cellular accumulation in determining sensitivity to platinum-based chemotherapy. Annu. Rev. Pharmacol. Toxicol. 48, 495–535 (2008).

    CAS  PubMed  Google Scholar 

  44. 44.

    De Luca, A. et al. A structure-based mechanism of cisplatin resistance mediated by glutathione transferase P1-1. Proc. Natl Acad. Sci. USA 116, 13943–13951 (2019).

    PubMed  Google Scholar 

  45. 45.

    Planells-Cases, R. et al. Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt-based anti-cancer drugs. EMBO J. 34, 2993–3008 (2015). This study demonstrates that around 50% of cisplatin uptake is dependent on the LRRC8A and LRRC8D VRAC subunits.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    He, Y. J. et al. DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells. Nature 563, 522–526 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Sorensen, B. H., Dam, C. S., Sturup, S. & Lambert, I. H. Dual role of LRRC8A-containing transporters on cisplatin resistance in human ovarian cancer cells. J. Inorg. Biochem. 160, 287–295 (2016).

    PubMed  Google Scholar 

  48. 48.

    Perez, R. P. Cellular and molecular determinants of cisplatin resistance. Eur. J. Cancer 34, 1535–1542 (1998).

    CAS  PubMed  Google Scholar 

  49. 49.

    Cossa, G., Gatti, L., Zunino, F. & Perego, P. Strategies to improve the efficacy of platinum compounds. Curr. Med. Chem. 16, 2355–2365 (2009).

    CAS  PubMed  Google Scholar 

  50. 50.

    Perego, P. et al. Association between cisplatin resistance and mutation of p53 gene and reduced bax expression in ovarian carcinoma cell systems. Cancer Res. 56, 556–562 (1996).

    CAS  PubMed  Google Scholar 

  51. 51.

    Wu, A. Y. et al. Fn14 overcomes cisplatin resistance of high-grade serous ovarian cancer by promoting Mdm2-mediated p53-R248Q ubiquitination and degradation. J. Exp. Clin. Cancer Res. 38, 176 (2019).

    PubMed  PubMed Central  Google Scholar 

  52. 52.

    Hanna, N. H. & Einhorn, L. H. Testicular cancer — discoveries and updates. N. Engl. J. Med. 371, 2005–2016 (2014).

    PubMed  Google Scholar 

  53. 53.

    Swisher, E. M. et al. Secondary BRCA1 mutations in BRCA1-mutated ovarian carcinomas with platinum resistance. Cancer Res. 68, 2581–2586 (2008). This study describes secondary BRCA1 mutations as a mechanism of resistance to cisplatin in ovarian carcinoma clinical specimens.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Rottenberg, S. et al. Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancer. Proc. Natl Acad. Sci. USA 104, 12117–12122 (2007).

    CAS  PubMed  Google Scholar 

  55. 55.

    Pajic, M. et al. Selected alkylating agents can overcome drug tolerance of G0-like tumor cells and eradicate BRCA1-deficient mammary tumors in mice. Clin. Cancer Res. 23, 7020–7033 (2017).

    CAS  PubMed  Google Scholar 

  56. 56.

    Jaspers, J. E. et al. Loss of 53BP1 causes PARP inhibitor resistance in Brca1-mutated mouse mammary tumors. Cancer Discov. 3, 68–81 (2013).

    CAS  PubMed  Google Scholar 

  57. 57.

    Cavallo, F. et al. Reduced proficiency in homologous recombination underlies the high sensitivity of embryonal carcinoma testicular germ cell tumors to cisplatin and poly(ADP-ribose) polymerase inhibition. PLoS ONE 7, e51563 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Chaudhuri, A. R. et al. Replication fork stability confers chemoresistance in BRCA-deficient cells. Nature 535, 382–387 (2016). This paper demonstrates the relevance of replication fork stability as a determinant of resistance to cisplatin.

    CAS  PubMed Central  Google Scholar 

  59. 59.

    Becker, J. R. et al. The ASCIZ–DYNLL1 axis promotes 53BP1-dependent non-homologous end joining and PARP inhibitor sensitivity. Nat. Commun. 9, 5406 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Elaimy, A. L. et al. The VEGF receptor neuropilin 2 promotes homologous recombination by stimulating YAP/TAZ-mediated Rad51 expression. Proc. Natl Acad. Sci. USA 116, 14174–14180 (2019).

    CAS  PubMed  Google Scholar 

  61. 61.

    Liptay, M., Barbosa, J. S. & Rottenberg, S. Replication fork remodeling and therapy escape in DNA damage response-deficient cancers. Front. Oncol. 10, 670 (2020).

    PubMed  PubMed Central  Google Scholar 

  62. 62.

    Schlacher, K. et al. Double-strand break repair-independent role for BRCA2 in blocking stalled replication fork degradation by MRE11. Cell 145, 529–542 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Li, Q. et al. ERCC2 helicase domain mutations confer nucleotide excision repair deficiency and drive cisplatin sensitivity in muscle-invasive bladder cancer. Clin. Cancer Res. 25, 977–988 (2019).

    CAS  PubMed  Google Scholar 

  64. 64.

    Wojtaszek, J. L. et al. A small molecule targeting mutagenic translesion synthesis improves chemotherapy. Cell 178, 152–159.e11 (2019). This study identifies the first compound that sensitizes cells to cisplatin while inhibiting REV1-dependent mutagenic TLS.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Kuczynski, E. A., Sargent, D. J., Grothey, A. & Kerbel, R. S. Drug rechallenge and treatment beyond progression — implications for drug resistance. Nat. Rev. Clin. Oncol. 10, 571–587 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Glasspool, R. M., Teodoridis, J. M. & Brown, R. Epigenetics as a mechanism driving polygenic clinical drug resistance. Br. J. Cancer 94, 1087–1092 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Sharma, S. V. et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141, 69–80 (2010). This paper demonstrates the occurrence of unstable and non-hereditable drug resistance upon cisplatin treatment.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Borst, P. Cancer drug pan-resistance: pumps, cancer stem cells, quiescence, epithelial to mesenchymal transition, blocked cell death pathways, persisters or what? Open Biol. 2, 120066 (2012).

    PubMed  PubMed Central  Google Scholar 

  69. 69.

    Clevers, H. The cancer stem cell: premises, promises and challenges. Nat. Med. 17, 313–319 (2011).

    CAS  PubMed  Google Scholar 

  70. 70.

    Sharma, A. et al. Longitudinal single-cell RNA sequencing of patient-derived primary cells reveals drug-induced infidelity in stem cell hierarchy. Nat. Commun. 9, 4931 (2018).

    PubMed  PubMed Central  Google Scholar 

  71. 71.

    Hou, M. F. et al. The NuRD complex-mediated p21 suppression facilitates chemoresistance in BRCA-proficient breast cancer. Exp. Cell Res. 359, 458–465 (2017).

    CAS  PubMed  Google Scholar 

  72. 72.

    Guillemette, S. et al. Resistance to therapy in BRCA2 mutant cells due to loss of the nucleosome remodeling factor CHD4. Genes Dev. 29, 489–494 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Almeida, L. O. et al. NFκB mediates cisplatin resistance through histone modifications in head and neck squamous cell carcinoma (HNSCC). FEBS Open Bio 4, 96–104 (2013).

    PubMed  PubMed Central  Google Scholar 

  74. 74.

    Hu, S. et al. Overexpression of EZH2 contributes to acquired cisplatin resistance in ovarian cancer cells in vitro and in vivo. Cancer Biol. Ther. 10, 788–795 (2010).

    CAS  PubMed  Google Scholar 

  75. 75.

    Brown, R., Curry, E., Magnani, L., Wilhelm-Benartzi, C. S. & Borley, J. Poised epigenetic states and acquired drug resistance in cancer. Nat. Rev. Cancer 14, 747–753 (2014).

    CAS  PubMed  Google Scholar 

  76. 76.

    Rottenberg, S. et al. Impact of intertumoral heterogeneity on predicting chemotherapy response of BRCA1-deficient mammary tumors. Cancer Res. 72, 2350–2361 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Schouten, P. C. et al. High XIST and low 53BP1 expression predict poor outcome after high-dose alkylating chemotherapy in patients with a BRCA1-like breast cancer. Mol. Cancer Ther. 15, 190–198 (2016).

    CAS  PubMed  Google Scholar 

  78. 78.

    Sun, W., Zu, Y., Fu, X. & Deng, Y. Knockdown of lncRNA-XIST enhances the chemosensitivity of NSCLC cells via suppression of autophagy. Oncol. Rep. 38, 3347–3354 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Cassinelli, G. et al. Targeting the Akt kinase to modulate survival, invasiveness and drug resistance of cancer cells. Curr. Med. Chem. 20, 1923–1945 (2013).

    CAS  PubMed  Google Scholar 

  80. 80.

    Cossa, G. et al. Modulation of sensitivity to antitumor agents by targeting the MAPK survival pathway. Curr. Pharm. Des. 19, 883–894 (2013).

    CAS  PubMed  Google Scholar 

  81. 81.

    Jin, L. et al. MAST1 drives cisplatin resistance in human cancers by rewiring cRaf-independent MEK activation. Cancer Cell 34, 315–330.e7 (2018). This study strengthens the relevance of pathways inhibiting cisplatin-induced apoptosis in drug resistance, providing new options for treating resistant cancers with activation of survival pathways.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Cossa, G. et al. Differential outcome of MEK1/2 inhibitor–platinum combinations in platinum-sensitive and -resistant ovarian carcinoma cells. Cancer Lett. 347, 212–224 (2014).

    CAS  PubMed  Google Scholar 

  83. 83.

    Ishibashi, M. et al. Tyrosine kinase receptor TIE-1 mediates platinum resistance by promoting nucleotide excision repair in ovarian cancer. Sci. Rep. 8, 13207 (2018).

    PubMed  PubMed Central  Google Scholar 

  84. 84.

    Olive, K. P. et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324, 1457–1461 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Coffelt, S. B. & de Visser, K. E. Immune-mediated mechanisms influencing the efficacy of anticancer therapies. Trends Immunol. 36, 198–216 (2015).

    CAS  PubMed  Google Scholar 

  86. 86.

    Wu, T. & Dai, Y. Tumor microenvironment and therapeutic response. Cancer Lett. 387, 61–68 (2017).

    CAS  PubMed  Google Scholar 

  87. 87.

    Wang, W. et al. Effector T cells abrogate stroma-mediated chemoresistance in ovarian cancer. Cell 165, 1092–1105 (2016). This study shows that cisplatin resistance can occur by a non-genetic mechanism in the TME in which CAFs regulate thiol metabolism, thereby impairing cisplatin accumulation in ovarian cancer cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Diaz-Maroto, N. G. et al. Noncanonical TGFβ pathway relieves the blockade of IL1β/TGFβ-mediated crosstalk between tumor and stroma: TGFBR1 and TAK1 inhibition in colorectal cancer. Clin. Cancer Res. 25, 4466–4479 (2019).

    CAS  Google Scholar 

  89. 89.

    Dijkgraaf, E. M. et al. Chemotherapy alters monocyte differentiation to favor generation of cancer-supporting M2 macrophages in the tumor microenvironment. Cancer Res. 73, 2480–2492 (2013).

    CAS  PubMed  Google Scholar 

  90. 90.

    Sommariva, M. et al. TLR9 agonists oppositely modulate DNA repair genes in tumor versus immune cells and enhance chemotherapy effects. Cancer Res. 71, 6382–6390 (2011).

    CAS  PubMed  Google Scholar 

  91. 91.

    Iida, N. et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 342, 967–970 (2013). This study shows in mouse models of cancer that an intact microbiota is required for optimal activity of oxaliplatin, which is associated with induction of ROS contributed by tumour-infiltrating myeloid cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Bienvenu, P., Caron, L., Gasparutto, D. & Kergonou, J. F. Assessing and counteracting the prooxidant effects of anticancer drugs. EXS 62, 257–265 (1992).

    CAS  PubMed  Google Scholar 

  93. 93.

    Socinski, M. A. et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N. Engl. J. Med. 378, 2288–2301 (2018).

    CAS  PubMed  Google Scholar 

  94. 94.

    West, H. et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 20, 924–937 (2019).

    CAS  Google Scholar 

  95. 95.

    Gandhi, L. et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N. Engl. J. Med. 378, 2078–2092 (2018).

    CAS  PubMed  Google Scholar 

  96. 96.

    Schmid, P. et al. Pembrolizumab for early triple-negative breast cancer. N. Engl. J. Med. 382, 810–821 (2020).

    CAS  PubMed  Google Scholar 

  97. 97.

    Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Paz-Ares, L. et al. Durvalumab plus platinum–etoposide versus platinum–etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet 394, 1929–1939 (2019).

    CAS  PubMed  Google Scholar 

  99. 99.

    Kroon, P. et al. Radiotherapy and cisplatin increase immunotherapy efficacy by enabling local and systemic intratumoral T-cell activity. Cancer Immunol. Res. 7, 670–682 (2019).

    CAS  PubMed  Google Scholar 

  100. 100.

    Ramakrishnan, R. et al. Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice. J. Clin. Invest. 120, 1111–1124 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Galluzzi, L., Buque, A., Kepp, O., Zitvogel, L. & Kroemer, G. Immunogenic cell death in cancer and infectious disease. Nat. Rev. Immunol. 17, 97–111 (2017).

    CAS  PubMed  Google Scholar 

  102. 102.

    Ghiringhelli, F. et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β-dependent adaptive immunity against tumors. Nat. Med. 15, 1170–1178 (2009).

    CAS  PubMed  Google Scholar 

  103. 103.

    Obeid, M. et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat. Med. 13, 54–61 (2007).

    CAS  PubMed  Google Scholar 

  104. 104.

    Tesniere, A. et al. Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene 29, 482–491 (2010).

    CAS  PubMed  Google Scholar 

  105. 105.

    Munn, D. H. & Bronte, V. Immune suppressive mechanisms in the tumor microenvironment. Curr. Opin. Immunol. 39, 1–6 (2016).

    CAS  PubMed  Google Scholar 

  106. 106.

    de Biasi, A. R., Villena-Vargas, J. & Adusumilli, P. S. Cisplatin-induced antitumor immunomodulation: a review of preclinical and clinical evidence. Clin. Cancer Res. 20, 5384–5391 (2014).

    PubMed  PubMed Central  Google Scholar 

  107. 107.

    Galluzzi, L., Buque, A., Kepp, O., Zitvogel, L. & Kroemer, G. Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell 28, 690–714 (2015).

    CAS  PubMed  Google Scholar 

  108. 108.

    Lesterhuis, W. J. et al. Platinum-based drugs disrupt STAT6-mediated suppression of immune responses against cancer in humans and mice. J. Clin. Invest. 121, 3100–3108 (2011). This study highlights the capability of Pt compounds to down-modulate immunosuppressive molecules, particularly PDL2.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Blatter, S. et al. Chemotherapy induces an immunosuppressive gene expression signature in residual BRCA1/p53-deficient mouse mammary tumors. J. Mol. Clin. Med. 1, 7–17 (2018).

    Google Scholar 

  110. 110.

    Grabosch, S. et al. Cisplatin-induced immune modulation in ovarian cancer mouse models with distinct inflammation profiles. Oncogene 38, 2380–2393 (2019).

    CAS  PubMed  Google Scholar 

  111. 111.

    Khoo, L. T. & Chen, L. Y. Role of the cGAS–STING pathway in cancer development and oncotherapeutic approaches. EMBO Rep. 19, e46935 (2018).

    PubMed  PubMed Central  Google Scholar 

  112. 112.

    Della Corte, C. M. et al. STING pathway expression identifies NSCLC with an immune-responsive phenotype. J. Thorac. Oncol. 15, 777–791 (2020).

    PubMed  Google Scholar 

  113. 113.

    Harabuchi, S. et al. Intratumoral STING activations overcome negative impact of cisplatin on antitumor immunity by inflaming tumor microenvironment in squamous cell carcinoma. Biochem. Biophys. Res. Commun. 522, 408–414 (2020).

    CAS  PubMed  Google Scholar 

  114. 114.

    Fu, D. et al. T cell recruitment triggered by optimal dose platinum compounds contributes to the therapeutic efficacy of sequential PD-1 blockade in a mouse model of colon cancer. Am. J. Cancer Res. 10, 473–490 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Lips, E. H. et al. BRCAness digitalMLPA profiling predicts benefit of intensified platinum-based chemotherapy in triple-negative and luminal-type breast cancer. Breast Cancer Res. 22, 79 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Sarkar, A. Novel platinum compounds and nanoparticles as anticancer agents. Pharm. Pat. Anal. 7, 33–46 (2018).

    CAS  PubMed  Google Scholar 

  117. 117.

    Johnstone, T. C., Suntharalingam, K. & Lippard, S. J. The next generation of platinum drugs: targeted Pt(II) agents, nanoparticle delivery, and Pt(IV) prodrugs. Chem. Rev. 116, 3436–3486 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Komeda, S. et al. The phosphate clamp: a small and independent motif for nucleic acid backbone recognition. Nucleic Acids Res. 39, 325–336 (2011).

    CAS  PubMed  Google Scholar 

  119. 119.

    Rosa, N. M. P., Ferreira, F. H. D. C., Farrell, N. P. & Costa, L. A. S. TriplatinNC and biomolecules: building models based on non-covalent interactions. Front. Chem. 7, 307 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Gatti, L. et al. Novel bis-platinum complexes endowed with an improved pharmacological profile. Mol. Pharm. 7, 207–216 (2010).

    CAS  PubMed  Google Scholar 

  121. 121.

    Almaqwashi, A. A. et al. DNA intercalation facilitates efficient DNA-targeted covalent binding of phenanthriplatin. J. Am. Chem. Soc. 141, 1537–1545 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Zheng, Y. R. et al. Pt(IV) prodrugs designed to bind non-covalently to human serum albumin for drug delivery. J. Am. Chem. Soc. 136, 8790–8798 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123.

    Arosio, D., Manzoni, L., Corno, C. & Perego, P. Integrin-targeted peptide- and peptidomimetic-drug conjugates for the treatment of tumors. Recent Pat. Anticancer Drug Discov. 12, 148–168 (2017).

    CAS  PubMed  Google Scholar 

  124. 124.

    Stathopoulos, G. P. et al. Comparison of liposomal cisplatin versus cisplatin in non-squamous cell non-small-cell lung cancer. Cancer Chemother. Pharmacol. 68, 945–950 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Ghaferi, M., Asadollahzadeh, M. J., Akbarzadeh, A., Ebrahimi Shahmabadi, H. & Alavi, S. E. Enhanced efficacy of PEGylated liposomal cisplatin: in vitro and in vivo evaluation. Int. J. Mol. Sci. 21, 559 (2020).

    CAS  PubMed Central  Google Scholar 

  126. 126.

    Baumann, P. et al. CD24 expression causes the acquisition of multiple cellular properties associated with tumor growth and metastasis. Cancer Res. 65, 10783–10793 (2005).

    CAS  PubMed  Google Scholar 

  127. 127.

    Ashihara, K. et al. Pharmacokinetic evaluation and antitumor potency of liposomal nanoparticle encapsulated cisplatin targeted to CD24-positive cells in ovarian cancer. Oncol. Lett. 19, 1872–1880 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128.

    Wolff, J. E., Berrak, S., Koontz Webb, S. E. & Zhang, M. Nitrosourea efficacy in high-grade glioma: a survival gain analysis summarizing 504 cohorts with 24193 patients. J. Neurooncol. 88, 57–63 (2008).

    PubMed  Google Scholar 

  129. 129.

    Brock, P. R. et al. Sodium thiosulfate for protection from cisplatin-induced hearing loss. N. Engl. J. Med. 378, 2376–2385 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Berndtsson, M. et al. Acute apoptosis by cisplatin requires induction of reactive oxygen species but is not associated with damage to nuclear DNA. Int. J. Cancer 120, 175–180 (2007).

    CAS  PubMed  Google Scholar 

  131. 131.

    Alberti, E., Zampakou, M. & Donghi, D. Covalent and non-covalent binding of metal complexes to RNA. J. Inorg. Biochem. 163, 278–291 (2016).

    CAS  PubMed  Google Scholar 

  132. 132.

    Russo Krauss, I., Ferraro, G. & Merlino, A. Cisplatin–protein interactions: unexpected drug binding to N-terminal amine and lysine side chains. Inorg. Chem. 55, 7814–7816 (2016).

    CAS  PubMed  Google Scholar 

  133. 133.

    Takasato, M. et al. Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. Nature 526, 564–568 (2015).

    CAS  PubMed  Google Scholar 

  134. 134.

    Freyer, D. R. et al. Effects of sodium thiosulfate versus observation on development of cisplatin-induced hearing loss in children with cancer (ACCL0431): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 18, 63–74 (2017).

    CAS  PubMed  Google Scholar 

  135. 135.

    Oun, R., Moussa, Y. E. & Wheate, N. J. The side effects of platinum-based chemotherapy drugs: a review for chemists. Dalton Trans. 47, 6645–6653 (2018).

    CAS  PubMed  Google Scholar 

  136. 136.

    Lv, F., Ma, Y., Zhang, Y. & Li, Z. Relationship between GSTP1 rs1695 gene polymorphism and myelosuppression induced by platinum-based drugs: a meta-analysis. Int. J. Biol. Markers 33, 364–371 (2018).

    CAS  PubMed  Google Scholar 

  137. 137.

    Crona, D. J. et al. A systematic review of strategies to prevent cisplatin-induced nephrotoxicity. Oncologist 22, 609–619 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138.

    Kanat, O., Ertas, H. & Caner, B. Platinum-induced neurotoxicity: a review of possible mechanisms. World J. Clin. Oncol. 8, 329–335 (2017).

    PubMed  PubMed Central  Google Scholar 

  139. 139.

    Avan, A. et al. Platinum-induced neurotoxicity and preventive strategies: past, present, and future. Oncologist 20, 411–432 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Yan, F., Liu, J. J., Ip, V., Jamieson, S. M. & McKeage, M. J. Role of platinum DNA damage-induced transcriptional inhibition in chemotherapy-induced neuronal atrophy and peripheral neurotoxicity. J. Neurochem. 135, 1099–1112 (2015).

    CAS  PubMed  Google Scholar 

  141. 141.

    Karasawa, T. & Steyger, P. S. An integrated view of cisplatin-induced nephrotoxicity and ototoxicity. Toxicol. Lett. 237, 219–227 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142.

    More, S. S. et al. Role of the copper transporter, CTR1, in platinum-induced ototoxicity. J. Neurosci. 30, 9500–9509 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Ciarimboli, G. et al. Organic cation transporter 2 mediates cisplatin-induced oto- and nephrotoxicity and is a target for protective interventions. Am. J. Pathol. 176, 1169–1180 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144.

    Breglio, A. M. et al. Cisplatin is retained in the cochlea indefinitely following chemotherapy. Nat. Commun. 8, 1654 (2017).

    PubMed  PubMed Central  Google Scholar 

  145. 145.

    Sooriyaarachchi, M., Gailer, J., Dolgova, N. V., Pickering, I. J. & George, G. N. Chemical basis for the detoxification of cisplatin-derived hydrolysis products by sodium thiosulfate. J. Inorg. Biochem. 162, 96–101 (2016).

    CAS  PubMed  Google Scholar 

  146. 146.

    Elferink, F., van der Vijgh, W. J., Klein, I. & Pinedo, H. M. Interaction of cisplatin and carboplatin with sodium thiosulfate: reaction rates and protein binding. Clin. Chem. 32, 641–645 (1986).

    CAS  PubMed  Google Scholar 

  147. 147.

    Allan, S. G., Smyth, J. F., Hay, F. G., Leonard, R. C. & Wolf, C. R. Protective effect of sodium-2-mercaptoethanesulfonate on the gastrointestinal toxicity and lethality of cis-diamminedichloroplatinum. Cancer Res. 46, 3569–3573 (1986).

    CAS  PubMed  Google Scholar 

  148. 148.

    Perales-Puchalt, A. et al. Frontline science: microbiota reconstitution restores intestinal integrity after cisplatin therapy. J. Leukoc. Biol. 103, 799–805 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank P. Borst (The Netherlands Cancer Institute, Amsterdam), P. Francica (University of Bern, Switzerland), M. Mutlu (University of Bern, Switzerland), D. Colombo (University of Milan, Italy), M. Rodolfo (Istituto Nazionale dei Tumori, Milan, Italy) and G. Cossa (University of Würzbug, Germany) for critical reading of the manuscript. The authors’ research projects are supported by the Swiss National Science Foundation (310030_179360 to S.R.), the Swiss Cancer League (KLS-4282-08-2017 to S.R.), the European Union (ERC CoG-681572 to S.R.), the Wilhelm Sander Foundation (no. 2019.069.1 to S.R.) and the Italian Ministry of Health, Fondazione AIRC per la Ricerca sul Cancro and Fondazione Cariplo-Regione Lombardia (grant 2016-1019) to the P.P. laboratory.

Author information

Affiliations

Authors

Contributions

C.D. and P.P. researched data for the article, S.R. and P.P. made substantial contribution to the discussion of content and all authors wrote, reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Paola Perego.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Dedication

The authors dedicate this article to the memory of Lloyd Kelland, who greatly contributed to the field of the pharmacology of platinum agents.

Peer review information

Nature Reviews Cancer thanks W. Lesterhuis, M. McKeage and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Monoadducts

Platinum–DNA entities in which the platinum drug has only one of the two leaving groups (that is, the chlorides for cisplatin) displaced when bound to the target DNA.

DNA crosslinks

Crosslinks (either intrastrand or interstrand) that block DNA replication and/or DNA transcription and occur when various exogenous or endogenous agents react with two different positions in the DNA to form covalent adducts with DNA bases.

Alkylating agents

Agents that add alkyl groups to the bases of DNA, which can lead to DNA breaks and crosslinks and interference with DNA replication and transcription, all resulting in cell death.

Nucleophilic residues

Parts of molecules, for instance biological macromolecules, with an electron pair available to generate a covalent bond; electrophilic agents such as platinum drugs tend to react with nucleophilic residues.

Homologous recombination

(HR). High-fidelity repair of DNA lesions, including double-strand breaks, in the S and G2 phases of the cell cycle, using a sister chromatid as a template.

Triple-negative breast cancers

(TNBCs). A highly aggressive subtype of breast cancer defined by the absence of oestrogen receptor, progesterone receptor and ERBB2 gene amplification.

Nucleotide excision repair

(NER). A process that removes large DNA adducts or base modifications that distort the double helix and uses the opposite strand as a template for repair.

Cisplatin–glutathione conjugate

A non-toxic conjugate in which glutathione binds cisplatin to become a substrate for transporters of the ATP binding cassette superfamily, such as multidrug resistance-associated protein 2 (MRP2), and therefore can be extruded from cells.

RAD51 foci

The local accumulation of RAD51 protein at the sites of DNA double-strand breaks visualized through microscopic imaging.

Hippo pathway

An evolutionary conserved signalling pathway involved in vertebrate development, with a key role in angiogenesis; the pathway negatively regulates the activity of the transcriptional co-activators Yes associated protein (YAP) and Transcriptional co-activator with PDZ-binding motif (TAZ).

Translesion synthesis

(TLS). A DNA repair process introducing a nucleotide opposite to the lesion, followed by the elongation of the 3′ DNA terminus through DNA polymerases specialized to bypass the DNA lesion.

Drug-tolerant cells

(DTCs). Populations of tumour cells that survive acute treatment and rapidly adapt to therapy.

γ-Glutamyl transpeptidase family

Enzymes that act to promote extracellular glutathione degradation, allowing the platinum drug — no longer sequestered by glutathione — to reach the target DNA.

‘Warm’ tumours

Tumours with poor infiltration by T cells.

‘Hot’ tumours

Tumours with a T cell inflamed phenotype, that is, exhibiting T cell infiltration and tumour cell expression of type I interferons, as well as the presence of interferon-γ (IFNγ) in the tumour microenvironment.

Polynuclear Pt agents

Agents that contain more than one reactive platinum (Pt) centre available to form crosslinks in the DNA.

Trans-geometry Pt(II) complexes

Complexes characterized by leaving groups (that is, chlorides for cisplatin) in a trans configuration, resembling trans-platin, the inactive stereoisomer of cisplatin.

Monofunctional coordinating agents

Analogues of cisplatin containing only one leaving group (for example, chloride).

Pt(IV) prodrugs

Compounds with a +4 oxidation state undergoing intracellular reduction to generate active Pt(II) species; they contain four ligands of a Pt(II) precursor of known anticancer activity with two additional ligands.

Conventional Pt agents

Platinum (Pt) agents, such as cisplatin, carboplatin or oxaliplatin, in which Pt has a +2 oxidation state.

Ligand substitution

A reaction that occurs by the displacement of leaving groups (for example, cisplatin chlorides) by a nucleophile (for example, water, guanine-N7) that is pivotal for the interaction with the DNA target and is slow for compounds that are less prone to substitution.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Rottenberg, S., Disler, C. & Perego, P. The rediscovery of platinum-based cancer therapy. Nat Rev Cancer 21, 37–50 (2021). https://doi.org/10.1038/s41568-020-00308-y

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing