Oxaliplatin-induced blood brain barrier loosening: a new point of view on chemotherapy-induced neurotoxicity.

Abstract

Oxaliplatin is a key drug in the treatment of advanced metastatic colorectal cancer. Despite its beneficial effects in tumor reduction, the most prevalent side-effect of oxaliplatin treatment is a chemotherapy-induced neuropathy that frequently forces to discontinue the therapy. Indeed, along with direct damage to peripheral nerves, the chemotherapy-related neurotoxicity involves also the central nervous system (CNS) as demonstrated by pain chronicity and cognitive impairment (also known as chemobrain), a newly described pharmacological side effect. The presence of the blood brain barrier (BBB) is instrumental in preventing the entry of the drug into the CNS; here we tested the hypothesis that oxaliplatin might enter the endothelial cells of the BBB vessels and trigger a signaling pathway that induce the disassembly of the tight junctions, the critical components of the BBB integrity. By using a rat brain endothelial cell line (RBE4) we investigated the signaling pathway that ensued the entry of oxaliplatin within the cell. We found that the administration of 10 μM oxaliplatin for 8 and 16 h induced alterations of the tight junction (TJs) proteins zonula occludens-1 (ZO-1) and of F-actin, thus highlighting BBB alteration. Furthermore, we reported that intracellular oxaliplatin rapidly induced increased levels of reactive oxygen species and endoplasmic reticulum stress, assessed by the evaluation of glucose-regulated protein GRP78 expression levels. These events were accompanied by activation of caspase-3 that led to extracellular ATP release. These findings suggested a possible novel mechanism of action for oxaliplatin toxicity that could explain, at least in part, the chemotherapy-related central effects.

• Authors: Jacopo Junio Valerio Branca, Mario Maresca, Gabriele Morucci, Matteo Becatti, Ferdinando Paternostro, Massimo Gulisano, Carla Ghelardini, Daniela Salvemini, Lorenzo Di Cesare Mannelli, Alessandra Pacini
• Journal: Oncotarget (Oncotarget) Vol. 9 Issue 34 Pg. 23426-23438 (05 04 2018) ISSN: 1949-2553 [Electronic] United States
• PMID: 29805744 (Publication Type: Journal Article)