Global Proteome Changes in Liver Tissue 6 Weeks after FOLFOX Treatment of Colorectal Cancer Liver Metastases

Abstract

(1) Oxaliplatin-based chemotherapy for colorectal cancer liver metastasis is associated with sinusoidal injury of liver parenchyma. The effects of oxaliplatin-induced liver injury on the protein level remain unknown. (2) Protein expression in liver tissue was analyzed—from eight patients treated with FOLFOX (combination of fluorouracil, leucovorin, and oxaliplatin) and seven controls—by label-free liquid chromatography mass spectrometry. Recursive feature elimination–support vector machine and Welch t-test were used to identify classifying and relevantly changed proteins, respectively. Resulting proteins were analyzed for associations with gene ontology categories and pathways. (3) A total of 5891 proteins were detected. A set of 184 (3.1%) proteins classified the groups with a 20% error rate, but relevant change was observed only in 55 (0.9%) proteins. The classifying proteins were associated with changes in DNA replication (p < 0.05) through upregulation of the minichromosome maintenance complex and with the innate immune response (p < 0.05). The importance of DNA replication changes was supported by the results of Welch t-test (p < 0.05). (4) Six weeks after FOLFOX treatment, less than 1% of identified proteins showed changes in expression associated with DNA replication, cell cycle entry, and innate immune response. We hypothesize that the changes remain after recovery from FOLFOX treatment injury.

VDAC1 oligomerization may enhance DDP‐induced hepatocyte apoptosis by exacerbating oxidative stress and mitochondrial DNA damage

“…Liver and kidney toxicities are the most common side effects and dose-limiting factor under DDP treatment and reduced therapeutic effect and life expectance of patients. However, the exact mechanism of how to protect against liver toxicity has not been clarified clearly [1]. Generally, the interactions with purine residues to form DNA cross-linking complexes are considered as the major biological mechanism of DDP [2].…”