Atorvastatin attenuates intestinal mucositis induced by 5-fluorouracil in mice by modulating the epithelial barrier and inflammatory response

Abstract

Chemotherapy-induced intestinal mucositis is a major side effect of cancer treatment. Statins are 3-hydroxy-3-methyl glutaryl coenzyme reductase inhibitors used to treat hypercholesterolemia and atherosclerotic diseases. Recent studies have demonstrated that atorvastatin (ATV) has antioxidant, anti-inflammatory, and resulting from the regulation of different molecular pathways. In the present study, we investigated the effects of ATV on intestinal homeostasis in 5-fluorouracil (5-FU)-induced mucositis. Our results showed that ATV protected the intestinal mucosa from epithelial damage caused by 5-FU mainly due to inflammatory infiltrate and intestinal permeability reduction, downregulation of inflammatory markers, such as Tlr4, MyD88, NF-κB, Tnf-a, Il1β, and Il6 dose-dependent. ATV also improved epithelial barrier function by upregulating the mRNA transcript levels of mucin 2 (MUC2), and ZO-1 and occludin tight junction proteins. The results suggest that the ATV anti-inflammatory and protective effects on 5-FU-induced mice mucositis involve the inhibition of the TLR4/MYD88/NPRL3/NF-κB, iNos, and caspase 3.

Keywords:

• Mucositis gastrointestinal
• intestinal permeability
• atorvastatin
• drug repositioning
• inflammatory molecular pathway
• mevalonate pathway

Disclosure statement

No potential conflict of interest was reported by the author(s).

Ethics approval

The study was conducted according to the guidelines of the Brazilian College of Animal Experimentation (COBEA) and approved by the Local Animal Experimental Ethics Committee (CEUA-UFMG) (Protocol n ° 266/2019).

Data availability statement

The current study’s data are available from the corresponding author upon reasonable request.

Author contributions

Conceptualization: Kátia Duarte Vital, Flaviano Santos Martins; Valbert Nascimento Cardoso; Simone Odília Antunes Fernandes; Methodology: Luiz Octavio Pires, Bruno Gallotti; Janayne Luihan Silva; Luís Cláudio Lima de Jesus; Ênio Ferreira; Formal analysis and investigation: Kátia Duarte Vital, Luís Cláudio Lima de Jesus, Bruno Gallotti; Janayne Luihan Silva; Jacqueline Alvarez-Leite Writing-original draft preparation: Kátia Duarte Vital; Writing-review and editing: Simone Odília Antunes Fernandes, Valbert Nascimento Cardoso, Enio Ferreira, Flaviano Santos Martins, Jacqueline Alvarez-Leite and Vasco Azevedo; Supervision: Simone Odília Antunes Fernandes; Funding acquisition: Simone Odília Antunes Fernandes, Valbert Nascimento Cardoso, Flaviano Santos Martins, and Vasco Azevedo.

All authors read and approved the final manuscript.

Consent for publication

All authors consent to the publication of this article.

Additional information

Funding

The authors would like to acknowledge the Pró-Reitoria de Pesquisa - Universidade Federal de Minas Gerais, Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq); Simone Odília Antunes Fernandes is supported by a grant from Fundação de Amparo à Pesquisa do Estado de Minas Gerais - FAPEMIG (Minas Gerais Network for Translational Research in Immunobiologicals and Biopharmaceuticals in Cancer - REMITRIBIC, RED-00031-21, APQ-00056-18, and APQ-00593-14). Kátia Duarte Vital is grateful to Coordenação de Aperfeiçoamento de Pessoal do Nível Superior (CAPES) for a Ph.D. fellowship.