Oxaliplatin-induced blood brain barrier loosening: a new point of view on chemotherapy-induced neurotoxicity
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Jacopo Junio Valerio Branca1, Mario Maresca2, Gabriele Morucci1, Matteo Becatti3, Ferdinando Paternostro1, Massimo Gulisano1, Carla Ghelardini2, Daniela Salvemini4, Lorenzo Di Cesare Mannelli2,* and Alessandra Pacini1,*
1Department of Experimental and Clinical Medicine, Anatomy and Histology Section, University of Florence, Florence, Italy
2Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Pharmacology and Toxicology Section, University of Florence, Florence, Italy
3Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
4Department of Pharmacology and Physiology Saint Louis University, Saint Louis, Missouri, United States
*These authors contributed equally to this work
Jacopo Junio Valerio Branca, email: [email protected]
Alessandra Pacini, email: [email protected]
Keywords: blood brain barrier; RBE4 cell line; Oxaliplatin; tight junctions; neuropathic pain
Received: February 28, 2018 Accepted: April 02, 2018 Published: May 04, 2018
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.
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