Developmental Toxicity of Ibrutinib: Insights from Stem Cell Dynamics and Neural Regeneration in Planarians

Area of Science:

• Toxicology
• Regenerative Biology
• Stem Cell Biology

Background:

• Ibrutinib (IB), a Bruton's tyrosine kinase (BTK) inhibitor, is a key treatment for B-cell malignancies.
• The adverse effects of IB on stem cell function and tissue homeostasis require further investigation.
• Freshwater planarians, with their neoblasts (pluripotent stem cells), serve as an excellent model for whole-organism toxicity studies.

Purpose of the Study:

• To assess the toxicity of Ibrutinib (IB) in the planarian model Dugesia constrictiva.
• To elucidate the mechanisms underlying IB toxicity, focusing on stem cell dynamics and regeneration.
• To investigate the role of Bruton's tyrosine kinase (BTK) in mediating IB's toxic effects.

Main Methods:

• Exposure of planarians to varying concentrations of Ibrutinib (IB).
• Assessment of morphological and regenerative capabilities post-exposure.
• Analysis of stem cell proliferation, differentiation, oxidative stress (ROS), and apoptosis.
• Gene silencing of Bruton's tyrosine kinase (BTK) using RNA interference (RNAi).

Main Results:

• IB exposure at 0.9 mg/L induced significant morphological and regenerative impairments, including neural regeneration defects.
• IB disrupted stem cell dynamics by suppressing proliferation and differentiation and increasing oxidative stress.
• IB exposure downregulated BTK expression, and BTK RNAi mimicked IB's toxic effects.

Conclusions:

• Ibrutinib (IB) exerts toxicity in planarians primarily through the inhibition of Bruton's tyrosine kinase (BTK).
• This study provides functional evidence linking BTK inhibition to stem cell dysfunction and regenerative defects.
• Findings offer insights for refining the clinical safety profile of Ibrutinib in cancer therapy.