{"title":"Low Dose of 5-Aminolevulinic Acid Hydrochloride Alleviates the Damage in Cardiomyocytes Induced by Lenvatinib via PI3K/AKT Signaling Pathway.","authors":"Yun Shi, Fengying Hu, Hao Fu, Shaojie Li, Chengzhi Lu, Chunxiu Hu","doi":"10.24976/Discov.Med.202335177.49","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Lenvatinib is an oral tyrosine kinase inhibitor (TKI), and has been applied in the clinical trials for the treatment of hepatocellular carcinoma (HCC). The function of 5-aminolevulinic acid hydrochloride (ALA) treatment in protecting cardiomyocytes under lenvatinib stimulation was investigated.</p><p><strong>Methods: </strong>H9c2 cells were treated with 2 mg/mL lenvatinib for 48 h and 1 mM ALA in the lenvatinib with low dose 5-aminolevulinic acid treatment group (LL) group, 10 mM ALA in the lenvatinib with high-dose 5-aminolevulinic acid treatment group (LH) group and cells without treatment were used as an internal control. C57/BL mice were treated with 10 mg/kg lenvatinib and 200 mg/kg ALA in the LL group and 400 mg/kg ALA in the LH group by gavage once per day for 4 weeks. The proliferation ability of cells was detected using the methyl thiazolyl tetrazolium (MTT) assay. Target gene expression was calculated through real-time quantitative PCR (qPCR), and target protein expression was calculated through Western blotting analysis. The concentrations of cardiovascular protective factors were detected using enzyme linked immunosorbent assay (ELISA).</p><p><strong>Results: </strong>In these experiments, 10 mM ALA significantly increased the viability rate of cardiomyocytes (105.4 ± 8.0%) compared with the single lenvatinib treatment group (73.2 ± 6.5%). We also noticed that activation of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathways were activated after low-dose ALA treatment. 5-ALA treatment led to the downregulation of intercellular cell adhesion molecule-1 (ICAM-1) (0.81- and 0.71-fold), vascular cell adhesion molecule (VCAM) (0.63- and 0.66-fold), angiotensin I (ANGI) (0.88- and 0.66-fold), ANGII (0.66- and 0.48-fold) and upregulation of endothelial nitric oxide synthases (eNOS) (1.25- and 1.89-fold) compared with non 5-ALA treatment group.</p><p><strong>Conclusions: </strong>With more experiments on animal models, low-dose of ALA treatment might be a therapeutic strategy to alleviate the damage to cardiomyocytes induced by lenvatinib.</p>","PeriodicalId":11379,"journal":{"name":"Discovery medicine","volume":null,"pages":null},"PeriodicalIF":2.0000,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Discovery medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.24976/Discov.Med.202335177.49","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Lenvatinib is an oral tyrosine kinase inhibitor (TKI), and has been applied in the clinical trials for the treatment of hepatocellular carcinoma (HCC). The function of 5-aminolevulinic acid hydrochloride (ALA) treatment in protecting cardiomyocytes under lenvatinib stimulation was investigated.
Methods: H9c2 cells were treated with 2 mg/mL lenvatinib for 48 h and 1 mM ALA in the lenvatinib with low dose 5-aminolevulinic acid treatment group (LL) group, 10 mM ALA in the lenvatinib with high-dose 5-aminolevulinic acid treatment group (LH) group and cells without treatment were used as an internal control. C57/BL mice were treated with 10 mg/kg lenvatinib and 200 mg/kg ALA in the LL group and 400 mg/kg ALA in the LH group by gavage once per day for 4 weeks. The proliferation ability of cells was detected using the methyl thiazolyl tetrazolium (MTT) assay. Target gene expression was calculated through real-time quantitative PCR (qPCR), and target protein expression was calculated through Western blotting analysis. The concentrations of cardiovascular protective factors were detected using enzyme linked immunosorbent assay (ELISA).
Results: In these experiments, 10 mM ALA significantly increased the viability rate of cardiomyocytes (105.4 ± 8.0%) compared with the single lenvatinib treatment group (73.2 ± 6.5%). We also noticed that activation of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathways were activated after low-dose ALA treatment. 5-ALA treatment led to the downregulation of intercellular cell adhesion molecule-1 (ICAM-1) (0.81- and 0.71-fold), vascular cell adhesion molecule (VCAM) (0.63- and 0.66-fold), angiotensin I (ANGI) (0.88- and 0.66-fold), ANGII (0.66- and 0.48-fold) and upregulation of endothelial nitric oxide synthases (eNOS) (1.25- and 1.89-fold) compared with non 5-ALA treatment group.
Conclusions: With more experiments on animal models, low-dose of ALA treatment might be a therapeutic strategy to alleviate the damage to cardiomyocytes induced by lenvatinib.
期刊介绍:
Discovery Medicine publishes novel, provocative ideas and research findings that challenge conventional notions about disease mechanisms, diagnosis, treatment, or any of the life sciences subjects. It publishes cutting-edge, reliable, and authoritative information in all branches of life sciences but primarily in the following areas: Novel therapies and diagnostics (approved or experimental); innovative ideas, research technologies, and translational research that will give rise to the next generation of new drugs and therapies; breakthrough understanding of mechanism of disease, biology, and physiology; and commercialization of biomedical discoveries pertaining to the development of new drugs, therapies, medical devices, and research technology.