Vascular endothelial growth factor and HDAC 6: a neuroprotective signalling pathway against cancer therapy-induced neuropathy

Abstract

In the context of treatments for cancer, the use of chemotherapeutic agents focuses on arresting cell division, anti-angiogenesis and targeting mechanisms responsible for metastasis. For that purpose, treatments are designed to manipulate molecules that impair each of these processes by inhibition of signalling pathways and growth factor receptors, as well as changing the dynamics of cytoskeletal proteins involved in cell division and migration. However, chemotherapeutic drugs affect not only tumour cells but also the physiology of other host tissues, including neurons: specifically, anti-cancer drugs exert direct and indirect effects on sensory nerves. Peripheral neuropathies result from dysregulation of mechanisms controlling neuronal physiology and myelination. Toxic neuropathies caused by chemotherapeutic agents are prominent amongst the many genetic and non-genetic causes of neuropathy (von Hehn et al. , 2012). The mechanisms involved in neuropathy associated with the use of paclitaxel include terminal arbour degeneration, mitochondrial changes, inflammation, activation of calpain and caspases and changes in the expression and function of calcium, sodium and potassium voltage-gated ionic channels (Jaggi and Singh, 2012). These changes may predispose to profound loss of motor and sensory function with pain. Paclitaxel binds to beta-tubulin and stabilizes its polymerization, disrupting the dynamics of microtubules, arresting cell division and activating apoptotic pathways. Paclitaxel also increases tubulin acetylation, which has several consequences on physiological and pathological processes (Polomano et al. , 2001). Tubulin acetylation impacts on subcellular organelles, and vesicular traffic and signalling that control the localization and movement of plasma membrane proteins (Janke …