Oxaliplatin-induced neurotoxicity is dependent on the organic cation transporter OCT2

Abstract

Oxaliplatin is an integral component of colorectal cancer therapy, but its clinical use is associated with a dose-limiting peripheral neurotoxicity. We found that the organic cation transporter 2 (OCT2) is expressed on dorsal root ganglia cells within the nervous system where oxaliplatin is known to accumulate. Cellular uptake of oxaliplatin was increased by 16-to 35-fold in cells overexpressing mouse Oct2 or human OCT2, and this process was associated with increased DNA platination and oxaliplatin-induced cytotoxicity. Furthermore, genetic or pharmacologic knockout of Oct2 protected mice from hypersensitivity to cold or mechanical-induced allodynia, which are established tests to assess acute oxaliplatin-induced neurotoxicity. These findings provide a rationale for the development of targeted approaches to mitigate this debilitating toxicity.neuropathy | chemotherapy | solute carriers

OATP1B2 deficiency protects against paclitaxel-induced neurotoxicity

“…Gene transcripts were quantified using TaqMan Universal PCR Master Mix (Thermo Fisher Scientific) and primers obtained from Origene that were specific for OATP1B1 (HP209396) and OATP1B3 (HP213461). Reactions were carried out in triplicate as previously reported (41). Transcripts of each sample were normalized to the housekeeping gene, GAPDH.…”

“…Protein expression analyses on isolated liver and DRG samples from wild-type and OAT-P1B2 -/-mice were performed as described previously (41 …”

Uptake Carriers and Oncology Drug Safety

“…This observation has since been replicated using an independent cohort of patients (Iwata et al, 2012). The implications of these findings have since generated promising clinical applications, given that expression of OCT2 appears to be absent in most tumors (Franke et al, 2010b;Sprowl et al, 2013a). Collectively, it therefore appears possible to decrease cisplatin-induced nephrotoxicity via pharmacological inhibition of OCT2 function without sacrificing the antitumor efficacy of cisplatin.…”

“…However, like cisplatin, oxaliplatin accumulates at relatively high levels within dorsal root ganglia of the peripheral nervous system, which is the initial trigger leading to peripheral neuropathy (Holmes et al, 1998;Screnci et al, 2000;McDonald et al, 2005). Oxaliplatin is a substrate for OCT2, and this SLC was recently found to be expressed at high levels in both murine and human dorsal root ganglia (Yonezawa et al, 2006;Burger et al, 2010;Sprowl et al, 2013a). In fact, genetic or pharmacological inhibition of Oct2 function protects mice from acute oxaliplatin-induced neuropathy and, like cisplatin, decreases urinary elimination without altering systemic concentrations (Sprowl et al, 2013a).…”

“…Oxaliplatin is a substrate for OCT2, and this SLC was recently found to be expressed at high levels in both murine and human dorsal root ganglia (Yonezawa et al, 2006;Burger et al, 2010;Sprowl et al, 2013a). In fact, genetic or pharmacological inhibition of Oct2 function protects mice from acute oxaliplatin-induced neuropathy and, like cisplatin, decreases urinary elimination without altering systemic concentrations (Sprowl et al, 2013a). Further studies are currently underway to assess whether inhibition of OCT2 function will ameliorate chronic forms of cisplatinand oxaliplatin-induced neuropathy, as well as to assess the clinical applications of this strategy.…”