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Cyclin-dependent kinase inhibitor abemaciclib-induced cutaneous responses mediated by inflammation
Tugce Boran1, Özce Pala Çamlı2, Mahmoud Abudayyak3
1Department of Pharmaceutical Toxicology, Faculty of Pharmacy, İstanbul University Cerrahpaşa, İstanbul, Türkiye.
Abstract:
Abemaciclib is a cyclin-dependent kinase (CDK) enzyme inhibitor approved by the FDA for advanced and metastatic breast cancer therapy. Abemaciclib has caused someadverse reactions, such as dermatitis and skin reactions; however, the underlying cellular mechanism is still not obvious. In the current study, human keratinocyte HaCaT cells were treated with 0-10 µM abemaciclib for 24 h. The cytotoxic, apoptosis/necrosis, oxidative stress, and inflammation-inducing potentials of abemaciclib were evaluated. Abemaciclib induced cytotoxicity and the half-maximal inhibitory concentration (IC50) was computed to be ≥ 24.18 µM. It significantly induced apoptosis and oxidative damage in the lowest treatment group (0.1 µM). The time-dependent effects show that the highest effects were seen after 24 h. The study on low concentrations indicated that the maximum effects were seen in the 0.1 µM treatment group. There was a notable rise in the secretion of MCP-1, IL-6, and IL-8 at 0.1 µM, while it decreased at 1-10 µM. Similarly, the levels of other mediators were increased solely at 0.1 µM; however, no changes in the higher concentrations. The increase in TNF-α was significant at 5 µM; however, the increase diminished at the highest treatment concentration. It could be concluded that abemaciclib-induced toxicity could be via oxidative inflammation leading to cell death in human keratinocytes. No effect was detected in the higher concentrations, while the effect was observed in the lowest treatment group. These findings underscore the need for further comprehensive studies of the spectrum of activity and risk profile of abemaciclib and encourage future research in this area.
Insights
Abemaciclib, a breast cancer drug, can cause skin reactions. This study found low doses induce cell death via oxidative inflammation in human skin cells, while higher doses show no effect. Further research is needed.
Area of Science:
- Pharmacology and Toxicology
- Dermatology
- Oncology
Background:
- Abemaciclib is an FDA-approved cyclin-dependent kinase (CDK) inhibitor for advanced and metastatic breast cancer.
- Adverse skin reactions like dermatitis are associated with abemaciclib, but the cellular mechanisms remain unclear.
- Understanding abemaciclib's cellular effects is crucial for managing its side effect profile.
Purpose of the Study:
- To investigate the cellular mechanisms underlying abemaciclib-induced skin reactions.
- To evaluate the cytotoxic, apoptotic, necrotic, oxidative stress, and inflammation-inducing potentials of abemaciclib in human keratinocytes.
Main Methods:
- Human keratinocyte (HaCaT) cells were treated with varying concentrations of abemaciclib (0-10 µM) for 24 hours.
- Assays were performed to assess cytotoxicity (IC50), apoptosis/necrosis, oxidative stress markers, and inflammatory mediator secretion (MCP-1, IL-6, IL-8, TNF-α).
Main Results:
- Abemaciclib induced cytotoxicity with an IC50 ≥ 24.18 µM.
- Low concentrations (0.1 µM) significantly induced apoptosis, oxidative damage, and increased secretion of inflammatory mediators (MCP-1, IL-6, IL-8, TNF-α).
- Higher concentrations (1-10 µM) showed diminished or no significant effects on these cellular parameters, with TNF-α increasing at 5 µM but decreasing at 10 µM.
Conclusions:
- Abemaciclib-induced toxicity in human keratinocytes may occur via oxidative inflammation, leading to cell death, particularly at low concentrations.
- The observed effects are concentration-dependent, with significant cellular impact noted at 0.1 µM and reduced effects at higher concentrations.
- These findings highlight the need for comprehensive studies on abemaciclib's risk profile and encourage further research into its cellular mechanisms.
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