Title

Exosomes from cerebral endothelial cells suppress chemotherapyinduced peripheral neuropathy and sensitize anti-tumour effects of platinum drugs

Document Type

Conference Proceeding

Publication Date

2019

Publication Title

J Extracell Vesicles

Abstract

Introduction: Platinum-based drugs are commonly used to treat cancers. However, peripheral neuropathy is a common adverse effect of platinum-based chemotherapy. Neurotoxicity often requires platinum drug dose reduction thereby, compromising therapeutic efficacy of platinum drugs to suppress tumour progression. Methods: Using differential ultracentrifugation, we isolated exosomes from cultured human primary cerebral endothelial cells (CEC-exos). Ovarian tumour was induced in mice by implantation of human ovarian cancer cells. Platinum-induced CIPN start from distal axons. Thus, we examined the direct effect of platinum drugs on distal axons of dorsal root ganglia (DRG) neurons using a microfluidic device that separates distal axons from their parent cell bodies. Results: We found that addition of oxaliplatin or carboplatin into the axonal compartment significantly suppressed axonal elongation, whereas application of CEC-exos into the axonal compartment completely abolished oxaliplatin-inhibited axonal growth. In vivo, treatment of tumour-bearing mice with platinum drugs (n = 7/group) induced CIPN characterized by tactile and cold allodynia, reduction of sensory nerve conduction velocity, and decreases of the number of epidermal nerve fibres compared to the control mice (n = 7/ group). However, tumour-bearing mice treated with platinum drugs along with CEC-exos (n = 7/group) exhibited a significant reduction of platinum-drug induced peripheral neuropathy. Moreover, CEC-exos in combination with platinum drugs significantly decreased tumour size by 80-91% compared to platinum drugs alone which reduced tumour growth only by 50-72%. In sciatic nerve tissues, CEC-exos in combination with platinum drugs significantly increased miR-15b, -26a, and -214, and substantially reduced axonal damage protein levels of PTEN, SARM1, and TRPV1. In tumour tissues, the combination treatment significantly increased miR-15b and -26a, and reduced their target chemoresistant protein levels of P-gp and ABCC1. Summary/Conclusion: Our data demonstrate that CEC-exos reduce CIPN by reversing the platinuminactivated neuroprotective network and that CECexos suppress a chemoresistant network of miRNAs/ protein-coding genes to enhance the anti-tumour effect of platinum drugs.

Volume

8

First Page

142

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