Pathophysiology of Chemotherapy-Induced Peripheral Neuropathy

Abstract

Chemotherapy-induced neuropathy is a common, dose-dependent adverse effect of several antineoplastics. It can lead to detrimental dose reductions and discontinuation of treatment, and severely affects the quality of life of cancer survivors. Clinically, chemotherapy-induced peripheral neuropathy presents as deficits in sensory, motor, and autonomic function which develop in a glove and stocking distribution due to preferential effects on longer axons. The pathophysiological processes are multi-factorial and involve oxidative stress, apoptotic mechanisms, altered calcium homeostasis, axon degeneration and membrane remodeling as well as immune processes and neuroinflammation. This review focusses on the commonly used antineoplastic substances oxaliplatin, cisplatin, vincristine, docetaxel, and paclitaxel which interfere with the cancer cell cycle-leading to cell death and tumor degradation-and cause severe acute and chronic peripheral neuropathies. We discuss drug mechanism of action and pharmacokinetic disposition relevant to the development of peripheral neuropathy, the epidemiology and clinical presentation of chemotherapy-induced neuropathy, emerging insight into genetic susceptibilities as well as current understanding of the pathophysiology and treatment approaches.

Keywords: cancer; chemotherapy; cisplatin; neuropathy; oxaliplatin; paclitaxel; pain; vincristine.

Figure 1

Mechanism of action of vincristine, paclitaxel, oxaliplatin and cisplatin. Anti-tumor mechanism of action of vincristine, paclitaxel, oxaliplatin and cisplatin leading to cell arrest and cell death. (A) Vincristine prevents microtubule aggregation, whereas paclitaxel prevents microtubule disaggregation, an effect leading to cancer cell division arrest and cell death. (B) Oxaliplatin and cisplatin bind to nuclear DNA (deoxyribonucleic acid) of cancer cells, causing disruption of DNA replication and RNA (ribonucleic acid) transcription and subsequent arrest of cancer cell division. The DNA adducts activate apoptotic pathways that induce cell death and tumor degradation. (C) All four anti-tumor agents alter the function of mitochondria, followed by disruption of respiratory chain function and increased production of reactive oxygen species (ROS). Additionally, oxaliplatin and cisplatin cause damage to cancer cell mitochondria by binding to mitochondrial DNA, altering mDNA replication and transcription. (D) All four agents cause activation of immune cells, an effect likely contributing to tumor cell degradation. Only a few representative immune cell-types are shown.

Figure 2

Putative mechanisms involved in the development of cisplatin- and oxaliplatin-induced peripheral neuropathy. Overview of possible effects of oxaliplatin and cisplatin on the immune system (Raghavendra et al., ; Callizot et al., ; Boyette-Davis and Dougherty, ; Wang et al., ; Di Cesare Mannelli et al., ; Janes et al., 2015), microglia (Di Cesare Mannelli et al., 2014) and peripheral neurons (Zwelling et al., ; Thompson et al., ; Faivre et al., ; Tomaszewski and Busselberg, ; Todd and Lippard, ; Tesniere et al., ; Alcindor and Beauger, ; Boyette-Davis and Dougherty, ; Deuis et al., ; Areti et al., ; Boehmerle et al., ; Dasari and Tchounwou, ; Canta et al., ; Leo et al., 2017) leading to neuronal inflammation (Janes et al., 2015) and altered neuronal excitability (Adelsberger et al., ; Krishnan et al., ; Kagiava et al., ; Gauchan et al., ; Ta et al., ; Descoeur et al., ; Nassini et al., ; Schulze et al., ; Sittl et al., ; Deuis et al., , ; Yamamoto et al., ; Mizoguchi et al., 2016). TNFα, Tumor necrosis factor alpha; DNA, deoxyribonucleic acid; ROS, Reactive oxygen species; Na_V, Voltage-gated sodium channel; K_V, Voltage-gated potassium channel; TRP, Transient receptor potential channel; Ca_V, Voltage-gated calcium channel.

Figure 3

Putative mechanisms involved in the development of vincristine-induced peripheral neuropathy. Overview of possible effects of vincristine on the immune system (Callizot et al., ; Kiguchi et al., ; Wang et al., ; Chatterjee et al., ; Old et al., ; Makker et al., 2017), peripheral tissues (Old et al., 2014) and sensory neurons (Kaba et al., ; Topp et al., ; Gan et al., ; Areti et al., ; Canta et al., ; Carozzi et al., ; Xu et al., 2017) leading to neuronal inflammation (Chatterjee et al., ; Xu et al., 2017) and altered excitability of peripheral neurons (Alessandri-Haber et al., ; Old et al., 2014) which may be considered as the main mechanisms contributing to the development of vincristine-induced CIPN. CXCL12, C-X-C Motif Chemokine Ligand 12; CX3CR, C-X-3-C motif chemokine receptor; TNF α, Tumor necrosis factor alpha; ILs, Interleukins; CXCR4, C-X-C motif chemokine receptor 4; ROS, Reactive oxygen species; Na_V, Voltage-gated sodium channel; K_V, Voltage-gated potassium channel; TRP, Transient receptor potential channel; Ca_V, Voltage-gated calcium channel.

Figure 4

Putative mechanisms involved in the development of paclitaxel-induced peripheral neuropathy. Overview of possible effects of paclitaxel on the immune system (Ledeboer et al., ; Loprinzi et al., , ; Callizot et al., ; Doyle et al., ; Wang et al., ; Zhang et al., , ; Pevida et al., ; Janes et al., ,; Liu et al., ; Li et al., ; Krukowski et al., ; Zhang et al., ; Makker et al., 2017), microglia (Burgos et al., ; Ruiz-Medina et al., ; Makker et al., 2017) and peripheral neurons (Sahenk et al., ; Cavaletti et al., , ; Dorr, ; Kidd et al., ; ten Tije et al., ; Mironov et al., ; Flatters and Bennett, ; Argyriou et al., ; Doyle et al., ; Areti et al., ; Boehmerle et al., ; Griffiths and Flatters, ; Duggett et al., ; Wozniak et al., 2016) leading to neuronal inflammation (Ledeboer et al., ; Loprinzi et al., , ; Callizot et al., ; Doyle et al., ; Wang et al., ; Zhang et al., , ; Pevida et al., ; Janes et al., ,; Liu et al., ; Li et al., ; Krukowski et al., ; Zhang et al., ; Makker et al., 2017) and altered excitability of peripheral neurons (Materazzi et al., ; Zhang and Dougherty, 2014). TLR4, Toll-Like Receptor 4; TNFα, Tumor necrosis factor alpha; ROS, Reactive oxygen species; Na_V, Voltage-gated sodium channel; K_V, Voltage-gated potassium channel; TRP, Transient receptor potential channel; Ca_V, Voltage-gated calcium channel.