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Investigation of potential sex-based differences in trastuzumab-induced chronic cardiotoxicity in a rat model.
Front. Pharmacol. 17, DOI: 10.3389/fphar.2026.1809964 (2026)
Background: Although
trastuzumab (TZB) significantly increases survival in patients with
human epidermal growth factor receptor 2 (HER2/ErbB2)-positive breast
and gastrointestinal cancers, its use may be limited by chronic
cardiotoxicity. Several tryptophan (Trp) metabolites are associated with
oxidative stress, inflammation, and metabolic disturbances in heart
failure (HF). Here, we aimed to characterize changes in left ventricular
(LV) concentrations of selected Trp metabolites in a rat model of
TZB-induced chronic cardiotoxicity.Methods: Male
and female Wistar-Hannover rats (300–400 g) were divided into 2-2
groups: i) physiological saline-treated (6 × 1 mL/kg, i.p.) control, and
ii) TZB-treated (2 mg/kg, then 5 × 1 mg/kg, i.p.) groups. At weeks 12
and 19, echocardiography was performed. At week 20, blood and LV samples
were collected. Then, histology, RT-qPCR, and UHPLC-MS/MS analyses of
genes and metabolites related to nitro-oxidative stress, inflammation,
glucose and fatty acid metabolism, and Trp metabolism were performed.Results: Diastolic
dysfunction began in both TZB-treated groups by week 12. At the
endpoint, both TZB-treated groups showed echocardiographic, histologic,
and molecular signs of chronic cardiotoxicity, accompanied by LV
overexpression of genes associated with inflammation and nitro-oxidative
stress, repression of glucose transporter 4, glycerol-3-phosphate
dehydrogenase, and carnitine palmitoyltransferase. However, only female
TZB-treated rats showed increased LV levels of Trp, 3-hydroxykynurenine,
quinolinic acid, and nicotinamide adenine dinucleotide (NAD+). In contrast, TZB-treated males presented lower LV levels of kynurenine and xanthurenic acid.Conclusion: Comparable
TZB-induced chronic cardiotoxicity developed in both sexes. However, LV
Trp metabolite concentrations showed sex-divergent alterations, the
significance of which should be clarified in further mechanistic
studies.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Kynurenine ; Cardiotoxicity ; Metabolite ; Carnitine ; Quinolinic Acid ; Heart Failure ; Inflammation ; Kynurenine Pathway
ISSN (print) / ISBN
1663-9812
e-ISSN
1663-9812
Journal
Frontiers in Pharmacology
Quellenangaben
Volume: 17
Publisher
Frontiers
Publishing Place
Lausanne
Reviewing status
Peer reviewed
Institute(s)
Institute of AI for Health (AIH)