Role for Drug Transporters in Chemotherapy‐Induced Peripheral Neuropathy

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and dose-limiting toxicity to widely used chemotherapeutics. Although the exact molecular mechanism of chemotherapy-induced peripheral neuropathy remains elusive, there is consensus that it is caused by damage to the peripheral nervous system leading to sensory symptoms. Recently developed methodologies have provided evidence of expression of drug transporters in the peripheral nervous system. In this literature review, we explore the role for drug transporters in CIPN. First, we assessed the transport of chemotherapeutics that cause CIPN (taxanes, platins, vincristine, bortezomib, epothilones, and thalidomide). Second, we cross-referenced the transporters implicated in genetic or functional studies with CIPN with their expression in the peripheral nervous system. Several drug transporters are involved in the transport of chemotherapeutics that cause peripheral neuropathy and particularly efflux transporters, such as ABCB1 and ABCC1, are expressed in the peripheral nervous system. Previous literature has linked genetic variants in efflux transporters to higher risk of peripheral neuropathy with the taxanes paclitaxel and docetaxel and the vinca alkaloid vincristine. We propose that this might be due to accumulation of the chemotherapeutics in the peripheral nervous system due to reduced neuronal efflux capacity. Thus, concomitant administration of efflux transporter inhibitors may lead to higher risk of adverse events of drugs that cause CIPN. This might prove valuable in drug development where screening new drugs for neurotoxicity might also require drug transporter consideration. There are ongoing efforts targeting drug transporters in the peripheral nervous system to reduce intraneuronal concentrations of chemotherapeutics that cause CIPN, which might ultimately protect against this dose-limiting adverse event.

Pathological Mechanisms of Bortezomib-Induced Peripheral Neuropathy

“…Over the last 5−10 years, preclinical data have identified the transporters responsible for the development of CIPN, such as oxaliplatin and paclitaxel [ 84 , 85 , 86 , 87 ]. However, it remains unclear which transporter is responsible for bortezomib accumulation in the DRG [ 88 ]. Additionally, it is also unknown which cell type (sensory neurons, macrophages, satellite glial cells, or others) uptakes bortezomib, leading to the development of BIPN.…”

Pharmacologic Management of Persistent Pain in Cancer Survivors

“…Thus, compounds that prevent OATP1B2- [ 72 ] and OCT2-dependent [ 73 , 74 ] uptake of paclitaxel and oxaliplatin, respectively, may have the potential to protect against CIPN. The ability of dasatinib inhibition of OCT2 to prevent oxaliplatin-induced peripheral neuropathy in patients with colorectal cancer [ 74 , 75 ] is currently being evaluated in a clinical trial (ClinicalTrial.gov identifier: NCT04164069; open to recruitment at the time of writing).…”

Emerging Pharmacological and Non-Pharmacological Therapeutics for Prevention and Treatment of Chemotherapy-Induced Peripheral Neuropathy

“…For many small-molecule anticancer drugs, this process is mediated by uptake transporters located in DRG neurons, and ongoing efforts attempt to block these transporters, reduce intra-neuronal concentrations of the neurotoxic agents, and ultimately protect against a dose-limiting injury. The role of drug transporters in CIPN was recently extensively reviewed [ 13 ], and this field of research will be illustrated here for oxaliplatin and paclitaxel, two agents for which defined transporters have been identified that can be targeted pharmacologically.…”

“…Preceding investigations have found that facilitated transport mechanisms are responsible for the neuronal uptake of platinum-based chemotherapeutic drugs associated with CIPN such as oxaliplatin [ 14 ]. Although recent have suggested emerging importance of multiple solute carriers in oxaliplatin neurotoxicity, including the organic cation transporters novel 1 (OCTN1) and multidrug and toxin extrusion 1 (MATE1), the actual in vivo contribution of these proteins to CIPN has remained inconclusive [ 13 ]. Using transporter-deficient mouse models, it was recently suggested that the direct contribution of OCTN1 and MATE1 to oxaliplatin neurotoxicity is negligible and that the neuronal uptake of oxaliplatin and the subsequent neurotoxicity is predominantly mediated by the related transporter organic cation transporter 2 (OCT2) [ 15 ].…”