Dichloroacetate Prevents Cisplatin-Induced Nephrotoxicity without Compromising Cisplatin Anticancer Properties

Abstract

Cisplatin is an effective anticancer drug; however, cisplatin use often leads to nephrotoxicity, which limits its clinical effectiveness. In this study, we determined the effect of dichloroacetate, a novel anticancer agent, in a mouse model of cisplatin-induced AKI. Pretreatment with dichloroacetate significantly attenuated the cisplatin-induced increase in BUN and serum creatinine levels, renal tubular apoptosis, and oxidative stress. Additionally, pretreatment with dichloroacetate accelerated tubular regeneration after cisplatin-induced renal damage. Whole transcriptome sequencing revealed that dichloroacetate prevented mitochondrial dysfunction and preserved the energy-generating capacity of the kidneys by preventing the cisplatin-induced downregulation of fatty acid and glucose oxidation, and of genes involved in the Krebs cycle and oxidative phosphorylation. Notably, dichloroacetate did not interfere with the anticancer activity of cisplatin in vivo. These data provide strong evidence that dichloroacetate preserves renal function when used in conjunction with cisplatin.

Dual‐Targeting Dual‐Action Platinum(IV) Platform for Enhanced Anticancer Activity and Reduced Nephrotoxicity

“…Lipo‐3cis and 3cis , however, demonstrated significant attenuation of NOX4 and TNF‐α levels over that of the CDP‐treated group. Previously, it was reported that DCA was able to preserve the renal functions when used in conjunction with CDP, thereby supporting our observations …”

Fluoro‐Photoacoustic Polymeric Renal Reporter for Real‐Time Dual Imaging of Acute Kidney Injury

“…The mice were challenged with cisplatin (an antineoplastic drug) at a reported nephrotoxic dosage (intraperitoneal injection, 20 mg kg –1 bw). [ 35 ] The control mice were treated with saline or protected with N ‐acetyl‐l‐cysteine (NAC, i.v. injection, 400 mg kg –1 bw) 0.5 h prior to cisplatin challenge, and real‐time imaging was conducted at t dpt = 48 h. [ 36 ] NAC was reported to be able to attenuate kidney damage by reducing oxidative stress and alleviating kidney inflammation in mouse model.…”

“…Thereafter, similar to real‐time imaging, FPRR‐based urinalysis noninvasively detected AKI at 24 h post‐cisplatin treatment, which was 48 h earlier than reported detection time points for elevated serum creatinine and kidney tissue injury ( t dpt = 72 h). [ 35 ]…”

Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways

“…The combination of CQ with biguanide metformin entered a clinical trial for patients with solid tumors bearing mutations in the IDH1 and IDH2 genes. 261 Their effectiveness in pH regulation of the tumor microenvironment will still need to be empirically determined. These gliomas had shown a decreased capacity to generate an acidic extracellular microenvironment, an effect, however, that cannot be generalized.…”

“…260 One potential solution to decrease tissue acidity is the use of inhibitors of glycolytic flux such as dichloroacetate, which might inhibit acidosis without compromising cancer treatment. 261 Their effectiveness in pH regulation of the tumor microenvironment will still need to be empirically determined.…”