Hydroxychloroquine ameliorates dasatinib-induced liver injury via decrease in hepatic lymphocytes infiltration

Dasatinib is an effective treatment for chronic myeloid leukemia. However, cases of idiosyncratic hepatotoxicity were reported. This study was conducted to investigate the chemopreventive effects of hydroxychloroquine against dasatinib-induced hepatotoxicity. Balb/c mice were randomly assigned into...

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Published in:Human & experimental toxicology 2023-01, Vol.42, p.9603271231188492-9603271231188492
Main Authors: Alhazzani, Khalid, Alrewily, Salah Q, Aljerian, Khaldoon, Alhosaini, Khaled, Algahtani, Mohammad M., Almutery, Mohammed Fhad, Alhamed, Abdullah S, Nadeem, Ahmed, Alotaibi, Moureq R., Alanazi, Ahmed Z.
Format: Article
Language:English
Subjects:
Animals
Antioxidants
Biomarkers
CD20 antigen
CD3 antigen
CD4 antigen
CD8 antigen
Chemical and Drug Induced Liver Injury, Chronic
Chronic myeloid leukemia
Dasatinib - pharmacology
Dasatinib - therapeutic use
Enzymes
Fibrosis
Gene expression
Hepatotoxicity
Hydroxychloroquine
Hydroxychloroquine - therapeutic use
Immune response
Immune system
Immunohistochemistry
Infiltration
Injuries
Leukemia
Liver
Lymphocytes
Mice
MnSOD gene
Myeloid leukemia
Reduction
Superoxide Dismutase
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Summary:Dasatinib is an effective treatment for chronic myeloid leukemia. However, cases of idiosyncratic hepatotoxicity were reported. This study was conducted to investigate the chemopreventive effects of hydroxychloroquine against dasatinib-induced hepatotoxicity. Balb/c mice were randomly assigned into four groups; vehicle control (5% DMSO, i.p., n = 6), dasatinib (50 mg/kg; i.p., n = 6), hydroxychloroquine (10 mg/kg, i.p., n = 6), and hydroxychloroquine + dasatinib (10 mg/kg + 50 mg/kg; i.p., n = 6). Treatments were given once every 2 days for 14 days. Serum and histopathological assessments of liver architecture and fibrosis were performed using H&E, Masson’s trichrome, and reticulin staining. The infiltration of lymphocytes was assessed using immunohistochemistry. The gene expression of antioxidant enzymes (CAT, SOD-2, GPX-1) was assessed using real-time quantitative PCR. Dasatinib showed a significant increase in liver injury biomarkers (AST and ALT) with higher lymphocytes infiltration (as indicated by CD3+, CD4+, CD8+, and CD20+ immunohistochemistry). Hepatic tissue of Dasatinib group exhibited significant downregulation in the gene expression of antioxidant enzymes (CAT, SOD-2, and GPX-1) compared to the control group. However, the combination of hydroxychloroquine with dasatinib showed a slight increase in AST and ALT. Also, hydroxychloroquine + dasatinib treated mice showed a significant reduction in lymphocytes infiltration as compared to dasatinib. The results showed that dasatinib induces an immune response leading to an increase in lymphocytes infiltration which promotes hepatocyte destruction and persistent liver injury. The results also suggest that hydroxychloroquine ameliorates dasatinib-induced hepatotoxicity via reduction in hepatic infiltration of T and B immune cells.
ISSN:0960-3271
1477-0903
DOI:10.1177/09603271231188492