Cisplatin‐ and dietary ascorbic acid‐mediated changes in the mitochondria of Dalton’s lymphoma‐bearing mice

Abstract

Cisplatin treatment caused a significant increase in the life span of ascites Dalton's lymphoma (DL) Tumor-bearing (TB) mice. However, as compared to cisplatin (CP) alone, combination treatment with ascorbic acid plus CP resulted in better therapeutic efficacy against murine DL. Cisplatin treatment of TB mice resulted in the appearance of thickened and irregular arrangement of mitochondrial cristae in the liver, kidney and DL tumor cells. Combination treatment of the hosts with ascorbic acid and CP lessened deformities in the mitochondria of liver and kidney, while in tumor cells, this increased the formation of vacuoles and disruption in mitochondrial cristae. Cisplatin treatment decreased the succinate dehydrogenase (SDH) activity in the mitochondria of kidney and DL cells and combination treatment caused further decrease in SDH activity in kidney and DL cells during 24-48 h of treatment. After CP treatment, the protein content in the mitochondria of these tissues decreased, and during combination treatment, it showed significant improvement. Mitochondrial lipid peroxidation (LPO) increased in these tissues after CP treatment. However, combination treatment significantly decreased mitochondrial LPO in liver and kidney but increased in DL cells. This increase in mitochondrial LPO in DL cells and decrease in liver and kidney could play an important role in the antitumor activity of combination treatment and at the same time reduce CP-induced toxicity in the host. However, further study may be desirable to explore some aspects of the mechanism(s) involved in these changes in mitochondria.

Biochemical changes associated with ascorbic acid–cisplatin combination therapeutic efficacy and protective effect on cisplatin-induced toxicity in tumor-bearing mice

“…Thus, based on earlier studies [36] the dose of cisplatin (10 mg/kg body weight) was used in present studies. Similarly, the dose of AA was selected to be 1% in drinking water which has already been standardized as an effective dose [12] , [37] . Tumor transplanted mice were randomly divided into four groups consisting of 10 mice in each group.…”

Involvement of DNA Damage Response Pathways in Hepatocellular Carcinoma

“…Excision repair cross complementation group 1 (ECCR1) belong to the nucleotide excision repair (NER) pathway and are essential to the repair of cisplatin DNA adducts [234]. Ueda et al indicated that high nuclear staining of ECCR1 was found in 33% of paraffin-embedded HCC tissue ( n = 43), which is positively associated with succinic dehydrogenase, a major target aimed by cisplatin in mitochondria [235] and resistance to treatment of cisplatin [236]. A previous study has shown that overexpression of two NER genes, ERCC1 and XPC, is associated with liver fibrogenesis and cancer and could be related to the well-recognized resistance of HCC to chemotherapeutics [135].…”

Effects of cisplatin on testicular enzymes and Sertoli cell function in rats

“…The activity of malate dehydrogenase (MDH), an important enzyme in the mitochondrial tricarboxylic acid cycle, decreased after CP (7.5 mg/kg) intraperitoneal injection as a result of cellular mitochondrial dysfunction in the kidneys of rats (Ozaki et al, 2013). Additionally, the activity of succinate dehydrogenase (SDH), a pivotal mitochondrial enzyme in oxidative phosphorylation, also decreased after CP treatment, and this response combined with an increased level of lipid peroxidation in kidney mitochondria could play an important role in CP-induced nephrotoxicity in mice (Martha et al, 2013).…”