Itaborahy Matheus F, Feng Isadora Z L F, Vieira-Machado Uri F, da Silveira Izabela B, Valverde Thalita M, Costa Guilherme M J, Guimarães Jennifer D S, Laet-Souza Daniela, Malamut Carlos, Martins M Alessandra F, Marques Júlia M, Rezende-Ribeiro Julia, Gorshkov Vladimir, Kjeldsen Frank, Favalessa Maria Eduarda S, Acipreste Izabella F, Verano-Braga Thiago, Carvalho Hernandes F, Oliveira André G, Dias Marlon Lemos, Goes Alfredo M, Ehrlich Barbara E, Leite M Fatima
Departamento de Fisiologia e Biofísica, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
Departmento de Morfologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
Br J Cancer. 2025 Jul 1. doi: 10.1038/s41416-025-03020-6.
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.
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.
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.
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.
由于癌症治疗的改善，癌症幸存者数量不断增加，不良反应的患病率也随之上升，尤其是化疗引起的周围神经病变（CIPN）和化疗引起的认知障碍（CICI）。包括抗体药物偶联物（ADC）在内的新型药物类别正在研发中，旨在靶向癌细胞并避免有害影响。尽管做出了这些努力，但ADC引起神经病变的患病率仍然很高。一种常用于已获批ADC的药物是单甲基奥瑞他汀E（MMAE），一种基于微管的药物。本研究的目的是在小鼠模型中研究MMAE的感觉和认知作用，并测试锂缓解MMAE诱导的神经病变的潜在用途。
我们建立了MMAE诱导的CIPN和CICI模型，并使用行为和感觉测试来分析这些情况。我们还评估了锂和MMAE治疗后神经病变组织中的钙信号和蛋白质水平以及肿瘤进展情况。
给予MMAE会导致外周敏感性丧失和认知障碍，而锂可预防化疗诱导的中枢和外周神经病变，且不影响MMAE的抗肿瘤活性。
本研究表明，包括锂预处理在内的策略可以预防化疗诱导的中枢和外周神经病变，从而提高癌症幸存者的生活质量。
