Elsevier

NeuroToxicology

Volume 30, Issue 2, March 2009, Pages 312-319
NeuroToxicology

Role of MAPKs in platinum-induced neuronal apoptosis

https://doi.org/10.1016/j.neuro.2009.01.003Get rights and content

Abstract

An unsolved question is how platinum derivatives used for solid cancer therapy cause peripheral neuropathy in patients and apoptosis in “in vitro” models of chemotherapy-induced peripheral neuropathy. DRG neurons from E15 rat embryos were treated with toxic doses of oxaliplatin or cisplatin. Here, the role of MAPKs in neuronal apoptosis was studied. Both oxaliplatin and cisplatin induced a dose-dependent neuronal apoptosis, modulated by the proteins of Bcl-2 family. Regarding MAPKs, platinum derivatives activated p38 while they reduced the active form and the total amount of JNK/Sapk. Both oxaliplatin and cisplatin activated ERKs at early stages, although they behaved differently at later stages. By using specific inhibitors of the various MAPKs it was demonstrated that the platinum-induced neuronal apoptosis is mediated by early p38 and ERK1/2 activation, while JNK/Sapk has a neuroprotective role. These results suggest a role for the different MAPKs in peripheral neuropathies characterized by apoptosis of DRG neurons.

Introduction

The type and severity of Chemotherapy-Induced Peripheral Neuropathy (CIPN) is generally related to the drug used, the duration of the administration and the cumulative dose. Even if the peripheral nervous system has a great capacity for regeneration after injury, CIPN is only partly reversible and, in the worst cases, damage is irreversible (Cavaletti et al., 2001). Platinum derivatives are cytotoxic on tumoral cells by forming platinum-DNA adducts, thus leading the tumor cells to programmed cell death. A similar mechanism has been suggested for the toxicity of cisplatin on Dorsal Root Ganglia (DRG) neurons, the main target of cisplatin-induced peripheral neurotoxicity (Cavaletti et al., 2001). In vitro and in vivo studies have suggested that cisplatin-induced apoptosis in DRG neurons is related to changes in the expression of cell cycle proteins (Gill and Windebank, 1998, Fisher et al., 2001, McDonald et al., 2005). These changes have been interpreted as an abortive attempt to re-enter the cell cycle by post-mitotic cells, which the neurons are (Gill and Windebank, 1998). At present, little is known about the many other possible molecular mechanisms that may be relevant to the onset of platinum derivative apoptosis in DRG neurons.

Recently, some studies have reported the involvement of members of the Mitogen-Activated Protein Kinases (MAPK) family in different models of peripheral nerve damage (Purves et al., 2001, Colucci-D’Amato et al., 2003, Gozdz et al., 2003, Myers et al., 2003, Price et al., 2004) making this family of serine-threonine kinases, which includes extracellular signaling-regulated kinase (ERK1/2, also termed p44/42), NH2-terminal c-Jun Kinase/Stress Activated Protein Kinase (JNK/Sapk), and p38, a good candidate for a role in DRG neuron apoptosis after exposure to platinum derivatives (Cavaletti et al., 2007).

MAPKs control a wide variety of cellular functions such as the proliferation, differentiation and regulation of apoptosis (Lewis et al., 1998). ERKs1/2 are generally activated by proliferation or differentiation stimuli, while JNK/Sapk and p38 mediate the cellular response to stress signals, even if the role of MAPK members is not so narrowly defined. ERKs are highly expressed in mature neurons and their activation has been observed in many forms of synaptic plasticity, in learning and memory (Thomas and Huganir, 2004) and in neurite outgrowth (Williams et al., 2000), but also in neurodegeneration (Colucci-D’Amato et al., 2003), apoptosis (Choi et al., 2004, Stoica et al., 2005, Oh et al., 2006) and in oxidative stress that has resulted in neuronal damage (Purves et al., 2001). ERK activation has been observed after cisplatin treatment in cortical neurons and has been interpreted as a protective response by neurons to injury (Gozdz et al., 2003). Therefore, ERK activation alone is not predictive of the cellular response, since they may be involved either in neuronal survival and differentiation or even in cell death.

There are also controversial observations regarding JNK/Sapk which is usually activated by stress signals and which mediates apoptosis (Nicolini et al., 2003, Donzelli et al., 2004, Oh et al., 2006). Recently, however, this protein has been related to neuronal differentiation and neurite outgrowth (Giasson et al., 1999, Coffey et al., 2000). JNK/Sapk mediates also DNA repair and cellular viability after chemotherapy treatment (Potapova et al., 1997). In some neuropathies such as in experimental diabetes, JNK/Sapk is activated, although there is no evidence of cellular death. Based on these results, some authors have hypothesized a protective role for this protein (Middlemas et al., 2003).

On the contrary, almost all reports agree in indicating p38 as a protein that mediates stress signals in cells (Raingeaud et al., 1995, Ozaki et al., 1999, Nakahara et al., 1999, Hao et al., 2006). In diabetic neuropathy, p38 activation is closely related to a reduction in nerve conduction velocity (Price et al., 2004) and mediates oxidative stress damage (Purves et al., 2001). However, it has been reported that PC12 differentiation occurs in a p38 activity-dependent manner (Takeda and Ichijo, 2002).

In the present study, we focused our attention on the MAPK role in sensory neuron damage induced by cisplatin (CDDP) and oxaliplatin (OHP), two antineoplastic agents widely used in the therapy of several solid tumors (Misset, 1998).

Section snippets

Materials and methods

All the procedures on animals were carried out under anesthesia in accordance with the European Communities Council Directive 86/609/EEC.

Results

In order to determine the drug concentrations to use in the present study we tested different OHP and CDDP doses at different time points (2  24 h). On the basis of these results, for our experiments, we chose the 100 μM OHP and 30 μM CDDP doses, both of which cause a neuronal death of about 60–70%. The drug concentrations we used in the present study are representative of the plasmatic concentrations of OHP and CDDP in patients (Grolleau et al., 2001, Quasthoff and Hartung, 2002). For both drugs

Discussion

In the present study, we have demonstrated that the two anticancer platinum derivates, CDDP and OHP, induce apoptosis in DRG neurons, by modulating the proteins of the Bcl-2 family which regulate the survival or death of the cells (Davies, 1995). Moreover, our work try to shed light on the molecular pathway, still poorly understood, exploited by anticancer drugs to induce neuronal neurotoxicity. We have demonstrated that MAPKs are involved in apoptosis induced by OHP and CDDP in DRG sensory

Acknowledgement

We are grateful to Dr. E. Genton for language assistance.

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