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

Abstract

Cisplatin, one of the most extensively used metallodrugs in cancer treatment, presents the important drawback of patient resistance. This resistance is the consequence of different processes including those preventing the formation of DNA adducts and/or their quick removal. Thus, a tool for the accurate detection and quantitation of cisplatin-induced adducts might be valuable for predicting patient resistance. To prove the validity of such an assumption, highly sensitive plasma mass spectrometry (ICP-MS) strategies were applied to determine DNA adduct levels and intracellular Pt concentrations. These two metal-relative parameters were combined with an evaluation of biological responses in terms of genomic stability (with the Comet assay) and cell cycle progression (by flow cytometry) in four human cell lines of different origins and cisplatin sensitivities (A549, GM04312, A2780 and A2780cis), treated with low cisplatin doses (5, 10 and 20 mM for 3 hours). Cell viability and apoptosis were determined as resistance indicators. Univariate linear regression analyses indicated that quantitation of cisplatin-induced G-G intra-strand adducts, measured 1 h after treatment, was the best predictor for viability and apoptosis in all of the cell lines. Multivariate linear regression analyses revealed that the prediction improved when the intracellular Pt content or the Comet data were included in the analysis, for all sensitive cell lines and for the A2780 and A2780cis cell lines, respectively. Thus, a reliable cisplatin resistance predictive model, which combines the quantitation of adducts by HPLC-ICP-MS, and their repair, with the intracellular Pt content and induced genomic instability, might be essential to identify early therapy failure. Significance to metallomicsKnowledge about cisplatin as a chemotherapy drug is extensive, including information about the several processes that contribute to its resistance, the main problem of using this chemical. However, this knowledge and information does not yet allow the early identification of resistant tumors/patients, one of the most desired aims of clinicians. In this work we have developed a model that might allow the early detection of chemical resistance and, more importantly, might do so mostly regardless of the resistance mechanism involved, because it determines the dynamics of adduct induction/repair, considering chemical influx/efflux and induced genomic instability.

Platinum Complexes Can Bind to Telomeres by Coordination

“…These results suggest that either the adducts are more efficiently repaired than those generated by cisplatin and/or their covalent binding to DNA is less efficient [ 62 ]. Interestingly, in contrast to cisplatin, the amount of Pt-ttpy and Pt-tpy uptake was the same in both cell lines, but the amount of complexes bound to DNA was reduced in A2780cis cells, suggesting a more efficient repair mechanism in A2780cis cell lines as already reported [ 63 ].…”

An optical study of drug resistance detection in endometrial cancer cells by dynamic and quantitative phase imaging

“…Cisplatin is one of the most commonly used chemotherapies in gynecologic oncology. Unfortunately, many cancers initially respond well to platinum treatment but often develop resistance when tumors recur . Until now, studies have shown that increased DNA repair, altered cellular accumulation, and increased drug inactivation are the main reasons for cells to acquire drug resistance .…”

Molecular and Metabolic Subtypes in Sporadic and Inherited Clear Cell Renal Cell Carcinoma

“…The analysis can include essential trace metals and metalloids that contribute to different physiological processes and toxic metals that interfere with them. ICP-MS metallomics in cancer research has been used for the evaluation of the pharmacokinetics and toxicity of approved and proposed metallo-drugs (platinum, ruthenium, and nanoparticle-based drugs) [94][95][96]. Noninvasive techniques like positron emission tomography (PET) scans have been also used to identify global or localized flux of metals like Cu and Fe, relevant in altered cancer metabolism [97,98].…”