Insights into platinum-induced peripheral neuropathy-current perspective

Abstract

Cancer is a global health problem that is often successfully addressed by therapy, with cancer survivors increasing in numbers and living longer world around. Although new cancer treatment options are continuously explored, platinum based chemotherapy agents remain in use due to their efficiency and availability. Unfortunately, all cancer therapies affect normal tissues as well as cancer, and more than 40 specific side effects of platinum based drugs documented so far decrease the quality of life of cancer survivors. Chemotherapy-induced peripheral neuropathy is a frequent side effects of platinum-based chemotherapy agents. This cluster of complications is often so debilitating that patients occasionally have to discontinue the therapy. Sensory neurons of dorsal root ganglia are at the core of chemotherapy-induced peripheral neuropathy symptoms. In these postmitotic cells, DNA damage caused by platinum chemotherapy interferes with normal functioning. Accumulation of DNA-platinum adducts correlates with neurotoxic severity and development of sensation of pain. While biochemistry of DNA-platinum adducts is the same in all cell types, molecular mechanisms affected by DNA-platinum adducts are different in cancer cells and non-dividing cells. This review aims to raise awareness about platinum associated chemotherapy-induced peripheral neuropathy as a medical problem that has remained unexplained for decades. We emphasize the complexity of this condition both from clinical and mechanistical point of view and focus on recent findings about chemotherapy-induced peripheral neuropathy in in vitro and in vivo model systems. Finally, we summarize current perspectives about clinical approaches for chemotherapy-induced peripheral neuropathy treatment.

Keywords: CIPN; DNA-Pt adducts; DRG; Pt; chemotherapy-induced peripheral neuropathy; dorsal root ganglia; model systems; molecular mechanisms; neurotoxic; platinum based chemotherapy; sensory neurons treatment; side effects.

Figure 1

Summary of biological mechanisms underlying peripheral neuropathy induced by Pt based chemotherapy drugs. Many different mechanisms of action were proposed for chemotherapy-induced peripheral neuropathy (CIPN). The mechanisms include: DNA injury, mitochondrial dysfunction; dysregulation of intracellular signaling pathways, dysfunction of voltage-gated ion channels, as well as the effects on inflammatory mediators such as cytokines and chemokines.