title: Systems biology of cisplatin resistance: past, present and future.
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.
authors.affiliation: 1] Gustave Roussy, Villejuif, France [2] Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France [3] Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Galluzzi
authors.affiliation: 1] Regina Elena National Cancer Institute, Rome, Italy [2] National Institute of Health, Rome, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Vitale
authors.affiliation: 1] Gustave Roussy, Villejuif, France [2] Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France [3] INSERM, U848, Villejuif, France.
authors.forename: J
authors.initials: J
authors.lastname: Michels
authors.affiliation: 1] INSERM, UMRS 769; LabEx LERMIT, Châtenay Malabry, France [2] Faculté de Pharmacie, Université de Paris Sud/Paris XI, Châtenay Malabry, France.
authors.forename: C
authors.initials: C
authors.lastname: Brenner
authors.affiliation: 1] Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London, London, UK [2] Department of Biomedical Sciences, Università Degli Studi di Padova, Padova, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Szabadkai
authors.affiliation: 1] Laboratoire Epigenetique et Cancer, Université de Paris Sud/Paris XI, Gif-Sur-Yvette, France [2] CNRS, FRE3377, Gif-Sur-Yvette, France [3] Commissariat à l'Energie Atomique (CEA), Saclay, France.
authors.forename: A
authors.initials: A
authors.lastname: Harel-Bellan
authors.affiliation: 1] Gustave Roussy, Villejuif, France [2] Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France [3] INSERM, U848, Villejuif, France.
authors.forename: M
authors.initials: M
authors.lastname: Castedo
authors.affiliation: 1] Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France [2] Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France [3] INSERM, U848, Villejuif, France [4] Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France [5] Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, France.
authors.forename: G
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002945:Cisplatin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D049490:Systems Biology / Q000379:methods / Q000639:trends
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin