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  • Review Article
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Cellular processing of platinum anticancer drugs

Nature Reviews Drug Discovery volume 4, pages 307–320 (2005)Cite this article

Key Points

  • Cisplatin is a platinum-based drug that has been in widespread use for many years to treat several forms of cancer, including testicular, ovarian, cervical, head and neck, and non-small-cell lung cancer.

  • Treatment is limited, however, by side effects including nephrotoxicity, emetogenesis and neurotoxicity. In addition, both inherent and acquired resistance to the drug limits its applications.

  • A large body of knowledge on the cellular processing of cisplatin has now emerged. This information has afforded a much more detailed understanding of how cisplatin-induced DNA damage is recognized, how the damage signals are transduced, how the cell-cycle arrests, and how DNA repair and apoptosis are activated.

  • This knowledge provides us with a basis for developing improved therapeutic strategies exploiting platinum-based drugs and/or the rational design of new platinum-based compounds. Disruptions of certain pathways by inhibitors, activators or combinations of drugs that modulate cellular sensitivity to cisplatin are likely to lead to clinical benefit.

Abstract

Cisplatin, carboplatin and oxaliplatin are platinum-based drugs that are widely used in cancer chemotherapy. Platinum–DNA adducts, which are formed following uptake of the drug into the nucleus of cells, activate several cellular processes that mediate the cytotoxicity of these platinum drugs. This review focuses on recently discovered cellular pathways that are activated in response to cisplatin, including those involved in regulating drug uptake, the signalling of DNA damage, cell-cycle checkpoints and arrest, DNA repair and cell death. Such knowledge of the cellular processing of cisplatin adducts with DNA provides valuable clues for the rational design of more efficient platinum-based drugs as well as the development of new therapeutic strategies.

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Figure 1: Platinum-based anticancer drugs.
Figure 2: Mechanisms of cisplatin uptake and efflux.
Figure 3: Formation and effects of cisplatin adducts.
Figure 4: Recognition of platinum–DNA adducts: the roles of HMGB1.
Figure 5: Transduction of DNA-damage signals: p53 and cisplatin.
Figure 6: Transduction of DNA-damage signals: MAPK pathways and cisplatin.
Figure 7: Cisplatin and cell-death pathways.

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Acknowledgements

This work was supported by a National Cancer Institute grant to S.J.L. We thank K. R. Barnes for a critical reading of the manuscript.

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  1. Department of Chemistry, Massachusetts Institute of Technology, Room 18-498, 77 Massachusetts Avenue, Cambridge, 02139, Massachusetts, USA

    Dong Wang & Stephen J. Lippard

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  1. Dong Wang
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Correspondence to Stephen J. Lippard.

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DATABASES

Entrez Gene

ABCC2

APAF1

ATM

ATP7B

ATR

BRCA1

c-ABL

CASP3

CASP7

CASP8

CASP9

CDC25C

CHK1

CHK2

Cmb1

CSA

CSB

Ctr1

DDB2

ERCC1

FADD

GADD45

HMGB1

IXR1

MDM2

MEK1

MLH1

MSH2

MSK1

p38 MAPK

p53

p73

RAG1

RAG2

SPT16

SRC

SSRP1

TFIIH

XIAP

XPA

XPB

XPC

XPD

XPF

XPG

Glossary

V(D)J RECOMBINATION

Site-directed DNA recombination carried out by RAG1 and RAG2 to create an enormous diversity of immunoglobulins and T-cell receptors.

NUCLEOTIDE EXCISION REPAIR

A DNA-repair pathway that removes ultraviolet-light-induced DNA damage and chemical DNA adducts by excising the oligonucleotide that contains the damaged base(s). The single-stranded gap is filled in by using the intact strand as a template.

NUCLEOSOME

A packing unit for DNA within the cell nucleus, which gives the chromatin a 'beads-on-a-string' structure, in which the 'beads' consist of complexes of nuclear proteins (histones) and DNA, and the 'string' consists of DNA only. A histone octamer forms a core around which the double-stranded DNA helix is wound nearly twice.

UBIQUITYLATION

A type of protein modification involving the covalent addition of ubiquitin, a small protein, to lysine groups. Poly-ubiquitylation targets proteins for degradation.

CHECKPOINT

The cell cycle can be arrested before the G1–S or G2–M phase transitions at checkpoints where DNA damage is detected.

COCKAYNE SYNDROME

A rare inherited disorder in which people are sensitive to sunlight, have short stature, and have the appearance of premature aging. Two genes defective in Cockayne syndrome, CSA and CSB, have been identified so far, both of which code for proteins that interact with components of the transcriptional machinery and with DNA repair proteins.

MISMATCH REPAIR

A DNA-repair pathway that removes mismatched bases and corrects the insertion or deletion of short stretches of (repeated) DNA.

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Wang, D., Lippard, S. Cellular processing of platinum anticancer drugs. Nat Rev Drug Discov 4, 307–320 (2005). https://doi.org/10.1038/nrd1691

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