Transient Receptor Potential Channels in Chemotherapy-Induced Neuropathy

Abstract

Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a common dose-limiting side effect of many chemotherapeutic drugs, including platinum-based compounds (e.g., cisplatin and oxaliplatin), taxanes (e.g., paclitaxel), vinca alkaloids (e.g., vincristine), and the first-in-class proteasome inhibitor, bortezomib. Among the various sensory symptoms of CIPN, paresthesia, dysesthesia, spontaneous pain, and mechanical and thermal hypersensitivity are prominent. Inflammation, oxidative stress, loss of intraepidermal nerve fibers, modifications of mitochondria, and various ion channels alterations are part of the several mechanisms contributing to CIPN. Because attempts to mitigate chemotherapeutic-induced acute neuronal hyperexcitability and the subsequent peripheral neuropathy have yielded unsatisfactory results, a more in-depth understanding of the mechanism(s) responsible for the neurotoxic action of anticancer drugs is required.Some members of the transient receptor potential (TRP) family of channels, as the TRPV1 and TRPV4 (vanilloid), TRPA1 (ankyrin) and TRPM8 (melastatin) are expressed on the plasma membrane of primary sensory neurons (nociceptors), where they are activated by an unprecedented series of physical and chemical stimuli. There is evidence that TRPV1, TRPV4, TRPA1 and TRPM8 are prominent contributors of mechanical and thermal hypersensitivity in models of CIPN. In particular, in vitro and in vivo studies have pointed out the unique role of TRPA1 and oxidative stress in the mechanism responsible for cold and mechanical hyperalgesia in rodent models of CIPN.

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…CIPN represents a major dose-limiting side effect for many commonly used antineoplastic agents, both platinumbased (e.g., cisplatin and oxiplatin) and other (e.g., vincristine, paclitaxel and thalidomide) agents. CIPN can be especially severe in patients with coexisting independent risk factors for neuropathic pain such as diabetes and/or alcohol abuse (see Nassini et al, 2013).…”

“…Indeed, exposure to cold can trigger an acute, transient syndrome characterized by cramps, paresthesia, and dysesthesia in patients taking oxaliplatin, presumably by activating TRPA1 . Furthermore, oxaliplatin may cause chronic peripheral neuropathy resembling that linked to cisplatin (see Nassini et al, 2013).…”

“…Finally, significant changes in the expression of various genes, including those controlling mitochondrial dysfunction due to vincristine-and bortezomibassociated peripheral neuropathy, have been demonstrated in humans (Broyl et al, 2010). Given their role in both generating neuropathic pain and regulating mitochondrial calcium homeostasis, TRP channels are attractive targets to explore in CIPN (see Nassini et al, 2013).…”

“…Furthermore, neither TRPV4 nor TRPV1 can account for the cold hyperalgesia that patients with CIPN often display (see Nassini et al, 2013).…”

“…However, in CHO cells transfected with the mouse TRPA1 channel, oxaliplatin evokes intracellular Ca 2+ mobilization in a glutathione-sensitive manner that is absent in untransfected CHO cells. To explain these seemingly contradictory results, the authors have hypothesized that the Ca 2+ response to oxaliplatin challenge requires two conditions: 1) the presence of TRPA1, and 2) cells that generate sufficient levels of oxidative stress in response to oxaliplatin to activate TRPA1 (see Nassini et al, 2013). It is possible that DRG neurons do not produce oxidative stress products in amounts sufficient to activate TRPA1, whereas CHO cells possess the metabolic and enzymatic repertoire to produce high enough ROS levels (Nassini et al, 2011).…”