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.

Consensus guidelines for the detection of immunogenic cell death

“…[1][2][3][4][5][6][7] This said, how cell death has been investigated and conceived since its pristine descriptions (dating back to the mid-19 th century) 8 has obviously evolved along with the technological advances that have been made throughout the last one and a half centuries. 9,10 Thus, morphology-based classifications postulating the existence of 3 cell death subroutines (i.e., type I, type II and type III cell death) 2,[11][12][13][14] have been progressively abandoned in favor of definitions that rely on objectively quantifiable functional features. 3,[15][16][17][18][19] Alongside, the long-standing conception according to which distinct types of cell death like apoptosis and necrosis would constitute mutually exclusive and diametrically opposed entities has been refuted.…”

Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy

“…1,3,4 Importantly, some -but not all -cell death inducers are capable of eliciting ICD, 35 and this property cannot be anticipated by structural or functional considerations. 3,[36][37][38] Indeed, while cisplatin and oxaliplatin both exert cytostatic/cytotoxic effects as they induce inter-and intra-strand DNA adducts, [39][40][41][42] only the latter triggers bona fide ICD as it provokes a pre-mortem ER stress response. 43,44 Thus, although assays for the detection of surrogate ICD markers are available, 45 the gold standard approach for determining whether a cytotoxic intervention provokes bona fide ICD still relies on vaccination experiments involving murine cancer cells and syngeneic, immunocompetent mice.…”

Cisplatin resistance in cell models: evaluation of metallomic and biological predictive biomarkers to address early therapy failure

“…1 However, intrinsic and/or acquired cellular resistance is one important drawback preventing its wider therapeutic use. 2,3 The chemotherapeutic action of cisplatin is based on its capacity to damage DNA by covalently binding to N7-guanine residues, generating different types of adducts, such as monoadducts, a Dpt. of Functional Biology (Genetic Area) and Oncology University Institute and inter-and intra-strand crosslinks.…”