Systems biology of cisplatin resistance: Past, present and future

L. Galluzzi, I. Vitale, J. Michels, C. Brenner, G. Szabadkai, A. Harel-Bellan, M. Castedo, G. Kroemer

Research output: Contribution to journalArticle

311 Citations (Scopus)

Abstract

The platinum derivative cis-diamminedichloroplatinum(II), best known as cisplatin, is currently employed for the clinical management of patients affected by testicular, ovarian, head and neck, colorectal, bladder and lung cancers. For a long time, the antineoplastic effects of cisplatin have been fully ascribed to its ability to generate unrepairable DNA lesions, hence inducing either a permanent proliferative arrest known as cellular senescence or the mitochondrial pathway of apoptosis. Accumulating evidence now suggests that the cytostatic and cytotoxic activity of cisplatin involves both a nuclear and a cytoplasmic component. Despite the unresolved issues regarding its mechanism of action, the administration of cisplatin is generally associated with high rates of clinical responses. However, in the vast majority of cases, malignant cells exposed to cisplatin activate a multipronged adaptive response that renders them less susceptible to the antiproliferative and cytotoxic effects of the drug, and eventually resume proliferation. Thus, a large fraction of cisplatin-treated patients is destined to experience therapeutic failure and tumor recurrence. Throughout the last four decades great efforts have been devoted to the characterization of the molecular mechanisms whereby neoplastic cells progressively lose their sensitivity to cisplatin. The advent of high-content and high-throughput screening technologies has accelerated the discovery of cell-intrinsic and cell-extrinsic pathways that may be targeted to prevent or reverse cisplatin resistance in cancer patients. Still, the multifactorial and redundant nature of this phenomenon poses a significant barrier against the identification of effective chemosensitization strategies. Here, we discuss recent systems biology studies aimed at deconvoluting the complex circuitries that underpin cisplatin resistance, and how their findings might drive the development of rational approaches to tackle this clinically relevant problem.

Original languageEnglish
Article numbere1257
JournalCell Death and Disease
Volume5
DOIs
Publication statusPublished - May 29 2014

Fingerprint

Systems Biology
Cisplatin
Cell Aging
Cytostatic Agents
Head and Neck Neoplasms
Platinum
Urinary Bladder Neoplasms
Antineoplastic Agents
Colorectal Neoplasms
Lung Neoplasms
Neoplasms
Apoptosis
Technology
Recurrence

Keywords

  • BCL-2
  • carboplatin
  • CTR1
  • DNA damage response
  • oxaliplatin
  • p53

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience
  • Medicine(all)

Cite this

Galluzzi, L., Vitale, I., Michels, J., Brenner, C., Szabadkai, G., Harel-Bellan, A., ... Kroemer, G. (2014). Systems biology of cisplatin resistance: Past, present and future. Cell Death and Disease, 5, [e1257]. https://doi.org/10.1038/cddis.2013.428

Systems biology of cisplatin resistance : Past, present and future. / Galluzzi, L.; Vitale, I.; Michels, J.; Brenner, C.; Szabadkai, G.; Harel-Bellan, A.; Castedo, M.; Kroemer, G.

In: Cell Death and Disease, Vol. 5, e1257, 29.05.2014.

Research output: Contribution to journalArticle

Galluzzi, L, Vitale, I, Michels, J, Brenner, C, Szabadkai, G, Harel-Bellan, A, Castedo, M & Kroemer, G 2014, 'Systems biology of cisplatin resistance: Past, present and future', Cell Death and Disease, vol. 5, e1257. https://doi.org/10.1038/cddis.2013.428
Galluzzi L, Vitale I, Michels J, Brenner C, Szabadkai G, Harel-Bellan A et al. Systems biology of cisplatin resistance: Past, present and future. Cell Death and Disease. 2014 May 29;5. e1257. https://doi.org/10.1038/cddis.2013.428
Galluzzi, L. ; Vitale, I. ; Michels, J. ; Brenner, C. ; Szabadkai, G. ; Harel-Bellan, A. ; Castedo, M. ; Kroemer, G. / Systems biology of cisplatin resistance : Past, present and future. In: Cell Death and Disease. 2014 ; Vol. 5.
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