Mechanism of Cisplatin-Induced Cytotoxicity Is Correlated to Impaired Metabolism Due to Mitochondrial ROS Generation

DOI: http://dx.doi.org/10.1371/journal.pone.0135083

Yong-Min Choi, Han-Kyul Kim, Wooyoung Shim, Muhammad Ayaz Anwar, Ji-Woong Kwon, Hyuk-Kwon Kwon, Hyung Joong Kim, Hyobin Jeong, Hwan Myung Kim, Daehee Hwang, Hyung Sik Kim, Sangdun Choi

Received: 16 March 2015; Accepted: 16 July 2015; Published: 6 August 2015.

Abstract
The chemotherapeutic use of cisplatin is limited by its severe side effects. In this study, by conducting different omics data analyses, we demonstrated that cisplatin induces cell death in a proximal tubular cell line by suppressing glycolysis- and tricarboxylic acid (TCA)/mitochondria-related genes. Furthermore, analysis of the urine from cisplatin-treated rats revealed the lower expression levels of enzymes involved in glycolysis, TCA cycle, and genes related to mitochondrial stability and confirmed the cisplatin-related metabolic abnormalities. Additionally, an increase in the level of p53, which directly inhibits glycolysis, has been observed. Inhibition of p53 restored glycolysis and significantly reduced the rate of cell death at 24 h and 48 h due to p53 inhibition. The foremost reason of cisplatin-related cytotoxicity has been correlated to the generation of mitochondrial reactive oxygen species (ROS) that influence multiple pathways. Abnormalities in these pathways resulted in the collapse of mitochondrial energy production, which in turn sensitized the cells to death. The quenching of ROS led to the amelioration of the affected pathways. Considering these observations, it can be concluded that there is a significant correlation between cisplatin and metabolic dysfunctions involving mROS as the major player.

Link: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0135083