Chemotherapy-induced neuropathy in monomethyl Auristatin E treatment: prevention by lithium.

Abstract

BACKGROUND: The increasing number of cancer survivors, thanks to improved cancer treatments, has escalated the prevalence of adverse effects, especially chemotherapy-induced peripheral neuropathy (CIPN) and chemotherapy-induced cognitive impairment (CICI). New drug classes, including antibody-drug conjugates (ADCs), are being developed to target cancer cells and avoid noxious effects. Despite the efforts, ADCs present a high prevalence of neuropathy. A drug often employed in approved ADCs is Monomethyl Auristatin E (MMAE), a microtubule-based agent. The aim of this study was to investigate the sensory and cognitive effects of MMAE in a mouse model and test the potential use of lithium to alleviate MMAE-induced neuropathy. METHODS: We developed a model of MMAE-induced CIPN and CICI and used behavior and sensory tests to analyze these conditions. We also evaluated calcium signaling and protein levels in neuropathic tissues and tumor progression upon treatments with lithium and MMAE. RESULTS: MMAE administration leads to loss of peripheral sensitivity and cognitive impairment and lithium prevents both central and peripheral neuropathies induced by chemotherapy, without affecting the antitumor activity of MMAE. CONCLUSION: This study shows that strategies including lithium pretreatment can prevent both central and peripheral neuropathies induced by chemotherapy to improve quality of life of cancer survivors.