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The rediscovery of platinum-based cancer therapy

Nature Reviews Cancer volume 21, pages 37–50 (2021)Cite this article

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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.

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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.

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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.

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Authors and Affiliations

  1. Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland

    Sven Rottenberg & Carmen Disler

  2. Bern Center for Precision Medicine, University of Bern, Bern, Switzerland

    Sven Rottenberg

  3. Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    Paola Perego

Authors
  1. Sven Rottenberg
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  2. Carmen Disler
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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.

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Correspondence to Paola Perego.

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Dedication

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

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

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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.

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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

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