Cisplatin (cDDP) resistance is a matter of concern
in triple-negative breast cancer therapeutics. We measured the
metabolic response of cDDP-sensitive (S) and -resistant (R) MDAMB-231 cells to Pd2Sper Show more
Cisplatin (cDDP) resistance is a matter of concern
in triple-negative breast cancer therapeutics. We measured the
metabolic response of cDDP-sensitive (S) and -resistant (R) MDAMB-231 cells to Pd2Spermine(Spm) (a possible alternative to
cDDP) compared to cDDP to investigate (i) intrinsic response/
resistance mechanisms and (ii) the potential cytotoxic role of
Pd2Spm. Cell extracts were analyzed by untargeted nuclear
magnetic resonance metabolomics, and cell media were analyzed
for particular metabolites. CDDP-exposed S cells experienced
enhanced antioxidant protection and small deviations in the
tricarboxylic acid cycle (TCA), pyrimidine metabolism, and lipid
oxidation (proposed cytotoxicity signature). R cells responded
more strongly to cDDP, suggesting a resistance signature of
activated TCA cycle, altered AMP/ADP/ATP and adenine/uracil fingerprints, and phospholipid biosynthesis (without significant
antioxidant protection). Pd2Spm impacted more markedly on R/S cell metabolisms, inducing similarities to cDDP/S cells (probably
reflecting high cytotoxicity) and strong additional effects indicative of amino acid depletion, membrane degradation, energy/
nucleotide adaptations, and a possible beneficial intracellular γ-aminobutyrate/glutathione-mediated antioxidant mechanism.
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2020 · · American Society for Biochemistry and Molecular Biology · added 2026-04-20
Platinum-based chemotherapies, including oxaliplatin, are a mainstay in the management of solid tumors and induce cell death by forming intrastrand dinucleotide DNA adducts. Despite their common use, Show more
Platinum-based chemotherapies, including oxaliplatin, are a mainstay in the management of solid tumors and induce cell death by forming intrastrand dinucleotide DNA adducts. Despite their common use, they are highly toxic, and approximately half of cancer patients have tumors that are either intrinsically resistant or develop resistance. Previous studies suggest that this resistance is mediated by variations in DNA repair levels or net drug influx. Here, we aimed to better define the roles of nucleotide excision repair and DNA damage in platinum chemotherapy resistance by profiling DNA damage and repair efficiency in seven oxaliplatin-sensitive and three oxaliplatin-resistant colorectal cancer cell lines. We assayed DNA repair indirectly as toxicity and directly measured bulky adduct formation and removal from the genome by slot blot and repair capacity in an excision assay, and used excision repair sequencing (XR-seq) to map repair events genome-wide at single-nucleotide resolution. Using this combinatorial approach and proxies for oxaliplatin-DNA damage, we observed no significant differences in repair efficiency that could explain the relative sensitivities and chemotherapy resistances of these cell lines. In contrast, the levels of oxaliplatin-induced DNA damage were significantly lower in the resistant cells, indicating that decreased damage formation, rather than increased damage repair, is a major determinant of oxaliplatin resistance in these cell lines. XR-seq-based analysis of gene expression revealed up-regulation of membrane transport pathways in the resistant cells, and these pathways may contribute to resistance. In conclusion, additional research is needed to characterize the factors mitigating cellular DNA damage formation by platinum compounds. Show less
Oxaliplatin (Eloxatine) is a third-generation platinum compound which has shown a wide antitumour effect both in vitro and in vivo, a better safety profile than cisplatin and a lack of cross-resistanc Show more
Oxaliplatin (Eloxatine) is a third-generation platinum compound which has shown a wide antitumour effect both in vitro and in vivo, a better safety profile than cisplatin and a lack of cross-resistance with cisplatin and carboplatin. In this scenario, oxaliplatin may represent an innovative and challenging drug extending the antitumour activity in diseases such as gastrointestinal cancer that are not usually sensitive to these coordination complexes. Oxaliplatin has a non-hydrolysable diaminocyclohexane (DACH) carrier ligand which is maintained in the final cytotoxic metabolites of the drug. Like cisplatin, oxaliplatin targets DNA producing mainly 1,2-GG intrastrand cross-links. The cellular and molecular aspects of the mechanism of action of oxaliplatin have not yet been fully elucidated. However, the intrinsic chemical and steric characteristics of the DACH-platinum adducts appear to contribute to the lack of cross-resistance with cisplatin. To date, mismatch repair and replicative bypass appear to be the processes most likely involved in differentiating the molecular responses to these agents. Show less