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.

In vivo metabolic and SHG imaging for monitoring of tumor response to chemotherapy

“…A study by Yu et al suggests that glycolysis, more specifically the conversion of pyruvate into lactate, which requires NADH, is the predominant metabolic pathway to be affected by cisplatin as a result of oxidative stress. In addition to biochemical assays in cultured cells, the authors showed that the exposure of tumor xenografts to a single dose of cisplatin resulted in a rapid decrease in tumor lactate levels, and that this correlated with effects on the delay of tumor growth (20). By measuring glucose uptake, lactate production and the expression of glycolysis-related proteins, Wang et al found that the glycolysis levels of breast and cervical cancer cells were reduced after cisplatin treatment, resulting in the inhibition of cell growth and proliferation (21).…”

Norepinephrine-Induced DNA Damage in Ovarian Cancer Cells

“…A recent study by Yu et al showed that only a small fraction of cisplatin (<10%) bound to the DNA will generate a significant increase in γ-H2AX foci formation [61]. This group also found that the main mechanism for these effects is the induction of oxidative stress, as observed by the ability of the free radical scavenger N-acetyl cysteine (a precursor of glutathione) to reverse cisplatin toxicity and γ-H2AX foci formation [61].…”

“…A recent study by Yu et al showed that only a small fraction of cisplatin (<10%) bound to the DNA will generate a significant increase in γ-H2AX foci formation [61]. This group also found that the main mechanism for these effects is the induction of oxidative stress, as observed by the ability of the free radical scavenger N-acetyl cysteine (a precursor of glutathione) to reverse cisplatin toxicity and γ-H2AX foci formation [61]. In addition, a recent study performed on non-tumorigenic, immortalized ovarian surface epithelial cells reported that 10 µM NE reduced the levels of DNA damage in the presence of ROS-generating molecules (i.e., bleomycin) [51].…”

Laser‐driven radiation: Biomarkers for molecular imaging of high dose‐rate effects

“…However, they are more flexible in terms of setup and can be used to image therapy effects noninvasively as often as clinically necessary after initial and subsequent radiotherapy sessions . Chemotherapy, photodynamic therapy, or other treatments can be equally followed . Molecular monitoring of radiation effects by MR allows for translation of laboratory research to the clinic, as parallel in‐cell , ex vivo (on biological samples stemming from patients) and in vivo imaging of the effects of radiation can be conducted with the same approach.…”

“…19 Chemotherapy, photodynamic therapy, or other treatments can be equally followed. 11,[20][21][22] Molecular monitoring of radiation effects by MR allows for translation of laboratory research to the clinic, as parallel in-cell, ex vivo (on biological samples stemming from patients) and in vivo imaging of the effects of radiation can be conducted with the same approach.…”