Cisplatin and Taxane side-effects: Kidney and Neuronal systeMS

Abstract

Cisplatin and taxanes are anticancer drugs commonly used to treat solid tumour type of cancers. The mechanisms of action of these drugs on the cells are vastly different, with cisplatin being a DNA intercalating agent and taxanes being microtubule polymerization inhibitors. However, clinical observations show similar debilitating side effects, which involve changes in sensory perception such as numbness, cold hypersensitivity, pain perception, and even renal toxicity in case of cisplatin. These side-effects could be explained by the changes in nociceptive and mechanosensory ion channels, which mediate these functions. Firstly we investigated the effect of these anticancer drugs on the mRNA levels of these channels and found significant modifications in cultured dorsal root ganglion and kidney cells. Using computational tools, we identified common transcription factors involved in these disregulations. Secondly, using electrophysiological techniques, we measured sodium and calcium currents to determined whether the changes in mRNAs were correlated with modification of functional expression. We also identified a possible mechanism involving oxidative stress in regulating the ion channels. Strikingly we had also observed the upregulation of CFTR mRNA and found it correlated with an increased in CFTR currents, suggesting a possible role in MDR.