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Cisplatin generates oxidative stress which is accompanied by rapid shifts in central carbon metabolism.

ABSTRACT: Cisplatin is commonly utilized in the treatment of solid tumors. Its mechanism of action is complex and multiple mechanisms of resistance have been described. We sought to determine the impact of cisplatin-generated oxidative stress on head and neck squamous cell carcinoma (HNSCC) proliferation, survival and metabolic activity in order to identify a potential metabolic signature associated with cisplatin response. DNA-bound cisplatin represents a small fraction of total intra-cellular cisplatin but generates a robust oxidative stress response. Neutralization of oxidative stress reverses cisplatin toxicity independent of the mechanism of cell death and TP53 mutational status. Cisplatin-induced oxidative stress triggers rapid shifts in carbon flux in 3 commonly utilized catabolic pathways: glycolysis, pentose phosphate pathway and citric acid cycle. Among these metabolic shifts, decreased flux from pyruvate into lactate is the only metabolic effect consistently observed across multiple HNSCC cell lines of varying genomic backgrounds and may reflect differential cisplatin sensitivity. Oxidative stress is a critical component of cisplatin cytotoxicity in HNSCC and is reflected in acute changes in carbon flux from pyruvate into lactate. This suggests that lactate may contribute to a metabolic signature of acute cisplatin toxicity, and could prove useful in optimizing cisplatin-based treatment regimens in HNSCC.

SUBMITTER: Yu W

PROVIDER: S-EPMC5844883 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Cisplatin generates oxidative stress which is accompanied by rapid shifts in central carbon metabolism.

Yu Wangie W Chen Yunyun Y Dubrulle Julien J Stossi Fabio F Putluri Vasanta V Sreekumar Arun A Putluri Nagireddy N Baluya Dodge D Lai Stephen Y SY Sandulache Vlad C VC

Scientific reports 20180309 1

Cisplatin is commonly utilized in the treatment of solid tumors. Its mechanism of action is complex and multiple mechanisms of resistance have been described. We sought to determine the impact of cisplatin-generated oxidative stress on head and neck squamous cell carcinoma (HNSCC) proliferation, survival and metabolic activity in order to identify a potential metabolic signature associated with cisplatin response. DNA-bound cisplatin represents a small fraction of total intra-cellular cisplatin ...[more]

PMID: 29523854

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Project description:BackgroundThe primary and secondary metabolites of fungi are critical for adaptation to environmental stresses, host pathogenicity, competition with other microbes, and reproductive fitness. Drought-derived reactive oxygen species (ROS) have been shown to stimulate aflatoxin production and regulate in Aspergillus flavus, and may function in signaling with host plants. Here, we have performed global, untargeted metabolomics to better understand the role of aflatoxin production in oxidative stress responses, and also explore isolate-specific oxidative stress responses over time.ResultsTwo field isolates of A. flavus, AF13 and NRRL3357, possessing high and moderate aflatoxin production, respectively, were cultured in medium with and without supplementation with 15 mM H2O2, and mycelia were collected following 4 and 7 days in culture for global metabolomics. Overall, 389 compounds were described in the analysis which encompassed 9 biological super-pathways and 47 sub-pathways. These metabolites were examined for differential accumulation. Significant differences were observed in both isolates in response to oxidative stress and when comparing sampling time points.ConclusionsThe moderately high aflatoxin-producing isolate, NRRL3357, showed extensive stimulation of antioxidant mechanisms and pathways including polyamines metabolism, glutathione metabolism, TCA cycle, and lipid metabolism while the highly aflatoxigenic isolate, AF13, showed a less vigorous response to stress. Carbohydrate pathway levels also imply that carbohydrate repression and starvation may influence metabolite accumulation at the later timepoint. Higher conidial oxidative stress tolerance and antioxidant capacity in AF13 compared to NRRL3357, inferred from their metabolomic profiles and growth curves over time, may be connected to aflatoxin production capability and aflatoxin-related antioxidant accumulation. The coincidence of several of the detected metabolites in H2O2-stressed A. flavus and drought-stressed hosts also suggests their potential role in the interaction between these organisms and their use as markers/targets to enhance host resistance through biomarker selection or genetic engineering.

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Cisplatin generates oxidative stress which is accompanied by rapid shifts in central carbon metabolism.

Publications

Cisplatin generates oxidative stress which is accompanied by rapid shifts in central carbon metabolism.

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