Publication: The cyclin-dependent kinase inhibitor abemaciclib-induced hepatotoxicity: Insight on the molecular mechanisms in HepG2/THP-1 co-culture model
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Date
2024-01-01
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BORAN T.
ZENGİN Ö. S.
Seker Z.
GÜNAYDIN AKYILDIZ A.
ÖZTAŞ E.
ÖZHAN G.
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Abstract
Drug-induced liver injury (DILI) is one of the widespread causes of liver injury and immune system plays important role. Abemaciclib (ABE) is a cyclin-dependent kinase inhibitor used as monotherapy or combination therapy in the treatment of breast cancer. Like other kinase inhibitors, the underlying mechanisms of ABE-induced hepatotoxicity are not completely known yet. In the current study, hepatotoxicity of ABE was evaluated with HepG2/THP-1 co-culture model which has been developed in recent years for the evaluation of DILI potential. Following ABE treatment, oxidative stress, mitochondrial damage, cytokine secretion levels, apoptotic/necrotic cell death were determined. According to our results, ROS production along with GSH depletion was observed in HepG2 cells after ABE treatment. ABE promoted secretion of pro-inflammatory mediators (TNF-α and MCP-1) and declined anti-inflammatory cytokine IL-10 release. Besides, NFKβ and JNK1 protein expression levels increased following ABE treatment. ABE enhanced intracellular calcium levels, induced early apoptotic and necrotic cell deaths in HepG2 cells. Furthermore, the changes in some mitochondrial parameters including a reducement in intracellular ATP levels and complex V activity; hyperpolarized mitochondrial membrane potential and enhanced mitochondrial ROS levels were observed, whereas mitochondrial mass did not show any differences after ABE treatments. Therefore, ABE-induced hepatotoxic effects is probably via oxidative stress, inflammatory response and necrotic cell death rather than direct mitochondrial toxicity. In conclusion; the study makes a significant contribution to strengthening the infrastructure we have on in vitro toxicity mechanism evaluations, which are the basis of preclinical toxicity studies.
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Keywords
Eczacılık, Meslek Bilimleri, Farmasötik Toksikoloji, Yaşam Bilimleri, Sağlık Bilimleri, Temel Bilimler, Pharmacology and Therapeutics, Professional Sciences, Pharmaceutical Toxicology, Life Sciences, Health Sciences, Natural Sciences, Yaşam Bilimleri (LIFE), Farmakoloji ve Toksikoloji, TOKSİKOLOJİ, Life Sciences (LIFE), PHARMACOLOGY & TOXICOLOGY, TOXICOLOGY, Toksikoloji, Toxicology, Abemaciclib, Drug-induced liver injury, Hepatotoxicity, HepG2/THP-1 co-culture model, Immune-mediated hepatotoxicity
Citation
BORAN T., ZENGİN Ö. S., Seker Z., GÜNAYDIN AKYILDIZ A., ÖZTAŞ E., ÖZHAN G., "The cyclin-dependent kinase inhibitor abemaciclib-induced hepatotoxicity: Insight on the molecular mechanisms in HepG2/THP-1 co-culture model", Toxicology Letters, cilt.391, ss.1-12, 2024