Introduction
Oxaliplatin (OXA), which belongs to the third generation of platinum
antitumour drugs, is used for the treatment of multiple solid tumours,
such as colorectal cancer and ovarian cancer (Staff & Grisold et al.,
2017). Compared to the first and second generation of platinum drugs,
such as cisplatin and carboplatin, it shows the mildest nephrotoxicity
and almost no ototoxicity clinically (Ruggiero & Trombatore et al.,
2013). However, OXA-induced severe and high-incidence neurotoxicity,
especially peripheral neurotoxicity, has greatly limited its clinical
application (Bano & Najam et al., 2016).
It is reported that approximately 90% patients suffer from varying
degrees of peripheral neurotoxicity, presented as muscle cramps,
paraesthesia, and dysphasia, after the first administration of OXA
(Argyriou & Cavaletti et al., 2013). When the cumulative dose of OXA
exceeds 1170 mg/m2, approximately 40-50% patients
suffer from chronic peripheral neurotoxicity, which lasts for several
months or even years after therapy (Argyriou & Zolota et al., 2010).
Therefore, OXA-induced peripheral neurotoxicity greatly limits its
clinical application and affects the quality of life of patients.
Because the mechanism underlying peripheral neurotoxicity is complex and
unclear, reduced glutathione, a calcium-magnesium mixture, and a sodium
ion channel blocker (Scuteri & Galimberti A et al., 2010; Descoeur &
Pereira et al., 2011; Nieto & Entrena et al., 2008) were recently
evaluated for the clinical alleviation of peripheral neurotoxicity;
however, these interventions did not show sufficient efficiency.
Considering the wide clinical use of OXA, it is critical to explore new
strategies for OXA-induced peripheral neurotoxicity.
OXA primarily damages the sensory neurons of the spinal dorsal root
ganglion (DRG) (Avan & Postma et al., 2015). Because DRG lacks the
protection provided by the blood–brain barrier, it is particularly
vulnerable to neurotoxic damage, explaining the occurrence of primarily
sensory symptoms in chemotherapy-induced peripheral neurotoxicity
(Carozzi & Canta et al., 2015). It was found that the concentration of
platinum in the DRG was much higher than that in the plasma, which
indicated that platinum can be accumulated in the DRG (Screnci &
McKeage et al., 2000). Due to the poor passive permeability of OXA (Hall
& Okabe et al., 2008), membrane transporters probably play crucial
roles in the transcellular transport of OXA (Johnson & Jun et al.,
2012). Therefore, the co-administration of a selective inhibitor of the
transporter-mediated influx of OXA into DRG cells is probably an
efficient strategy to attenuate OXA-induced peripheral neurotoxicity.
DRG cells express multiple ATP-binding transporters and solute carrier
transporters (SLC). It has been reported that organic cation transporter
2 (OCT2) (Sprowl & Ciarimboli et al., 2013; Cavaletti G, 2014; Burger
& Zoumaro et al., 2010), copper ion transporter 1 (CTR1) (Larson &
Blair et al., 2009), and carnitine/organic cation transporter 1 (OCTN1)
(Jong & Nakanishi et al., 2011) mediate OXA uptake in DRG cells, while
MRP2 plays a crucial role in the efflux of OXA from DRG cells (Myint &
Li et al., 2015). Because CTR1 is also expressed in
most tumours, such as human malignant
tissues of colon carcinomas (Holzer & Varki et al., 2006), and the
expression of OCT2 in most tumour cells is down-regulated or even lost
due to epigenetic modification (Ciarimboli G, 2014), therefore, the
inhibition of OCT2 and OCTN1 but not CTR1 and MRP2 may attenuate
OXA-induced peripheral neurotoxicity without influencing its antitumour
effect. Our previous research showed that L-THP could strongly inhibit
the activity of OCT2; the present study aims to explore whether L-THP
would selectively inhibit OCT2 and OCTNs and subsequently alleviate
OXA-induced peripheral neurotoxicity without impairing its antitumour
effect.