An investigation into the prevention of cisplatin-induced nephrotoxicity by dichloroacetate

Abstract

Cisplatin is a highly effective anticancer drug used to treat a range of cancers. However, cisplatin use often leads to nephrotoxicity, which limits its clinical effectiveness. Dichloroacetate (DCA), which has been used to treat lactic acidosis, has emerged over the past decade as a novel anticancer medication. This is primarily due to its ability to reverse the glycolytic phenotype of cancer cells (the Warburg effect). A number of clinical trials assessing its anticancer properties are in progress. It is therefore highly likely that DCA will be used in combination with other well-established anti-cancer drugs. Hence, in this study the effects of DCA on the antineoplastic and nephrotoxic effects of cisplatin were studied in a mouse model of cisplatin-induced acute kidney injury (AKI). It was demonstrated that DCA did not attenuate the antineoplastic activity of cisplatin while it significantly attenuated the cisplatin-induced nephrotoxicity; as detected by an attenuation of cisplatin-induced increase in serum markers of kidney injury (serum creatinine and blood urea nitrogen), renal tubular apoptosis, renal oxidative stress and cisplatin-induced changes in kidney histology, leading to increased survival of mice. Additionally, pretreatment with DCA accelerated renal tubular epithelial cell (RTEC) regeneration after cisplatin-induced renal damage. However, we also found that DCA co-treatment with cisplatin surprisingly increased the urinary markers of tubular injury. This response to DCA was attributed to faster RTEC regeneration and dead cell debris clearance from the renal tubular lumen. Further examination of the mechanism by which DCA attenuates cisplatin nephrotoxicity revealed that DCA did not reduce kidney platinum accumulation, reduce the formation of a highly reactive thiol toxin in the kidney or reduce serum TNF-alpha levels. Whole kidney transcriptome sequencing revealed a key nephroprotective mechanism; DCA co-treatment prevented mitochondrial dysfunction and preserved the energy-generating capacity of the kidneys by preventing the cisplatin-induced downregulation of genes involved in fatty acid and glucose oxidation, and of genes involved in the Krebs cycle and oxidative phosphorylation. Thus the mechanism by which DCA ameliorates nephrotoxicity appears to be two fold. Firstly DCA prevents cisplatin-induced mitochondrial dysfunction and thereby renal ATP depletion, renal oxidative stress and RTEC apoptosis. Secondly, as a result of the maintenance of ATP levels and the absence of oxidative stress there is an increased capacity for RTEC regeneration. The findings of this study raise the possibility of combining DCA with cisplatin therapy to reduce nephrotoxicity. This could allow escalation of cisplatin doses for greater therapeutic effectiveness in cancer chemotherapy. Furthermore, work presented in this thesis opens a new research direction exploring DCA as potentially the first medication for the treatment of drug induced AKI, which may increase the therapeutic usage of nephrotoxic drugs and reduce the mortality and morbidity associated with toxic AKI. Show more