Polo-like kinase 4 inhibitor CFI-400945 inhibits carotid arterial neointima formation but increases atherosclerosis

by Selleckchem | Jan 31 2024

Neointima lesion and atherosclerosis are proliferative vascular diseases associated with deregulated proliferation of vascular smooth muscle cells (SMCs). CFI-400945 is a novel, highly effective anticancer drug that inhibits polo-like kinase 4 (PLK4) and targets mitosis. In this study, we aim to investigate how CFI-400945 affects the development of proliferative vascular diseases. In C57BL/6 mice, neointima formation was generated by complete carotid ligation. In apolipoprotein E knockout (ApoE-/-) mice fed a high-fat diet, atherosclerosis was induced by partial carotid ligation. CFI-400945 was directly applied to carotid arteries via a perivascular collar. Our results showed that CFI-400945 drastically inhibited neointima formation but significantly accelerated atherosclerosis. In vitro studies showed that CFI-400945 treatment induced SMC polyploidization and arrested cells in the G2/M phase. CFI-400945 treatment upregulated p53 and p27 expression but decreased p21 and cyclin B1 expression. CFI-400945 also induced SMC apoptosis, which was inhibited by hydroxyurea, a DNA synthesis inhibitor that inhibits polyploidization. Furthermore, CFI-400945 caused supernumerary centrosomes, leading to mitotic failure, resulting in polyploidization. In conclusion, CFI-400945 prevents carotid arterial neointima formation in C57BL/6 mice but accelerates atherosclerosis in ApoE-/- mice, likely through mitotic arrest and subsequent induction of polyploidization and apoptosis.

Comments:

The study you're discussing seems to explore the effects of CFI-400945, a drug known for its anticancer properties due to its inhibition of polo-like kinase 4 (PLK4), on vascular diseases like neointima formation and atherosclerosis.

Here's a summary of your findings:

### **In Vivo Experiments:**
1. **Neointima Formation:** In C57BL/6 mice with induced neointima formation via complete carotid ligation, CFI-400945 notably inhibited the development of neointima lesions.

2. **Atherosclerosis:** In Apolipoprotein E knockout (ApoE-/-) mice fed a high-fat diet and subjected to partial carotid ligation to induce atherosclerosis, CFI-400945 actually accelerated the progression of atherosclerosis.

### **In Vitro Studies:**
1. **Effects on Smooth Muscle Cells (SMCs):**
   - **Polyploidization & Cell Cycle Arrest:** CFI-400945 treatment induced polyploidization of SMCs and arrested them in the G2/M phase of the cell cycle.

   - **Gene Expression Changes:** It upregulated the expression of p53 and p27 but decreased the expression of p21 and cyclin B1 in SMCs.

   - **Apoptosis Induction:** CFI-400945 treatment also led to SMC apoptosis, which could be inhibited by hydroxyurea, suggesting a link to DNA synthesis inhibition and polyploidization.

2. **Mechanism of Action:**
- **Centrosome Abnormalities:** CFI-400945 caused an increase in supernumerary centrosomes, leading to mitotic failure and subsequent polyploidization.

### **Conclusion:**
CFI-400945 seems to have dual effects on vascular diseases:
- **Neointima Formation Inhibition:** It prevents the formation of neointima in C57BL/6 mice.
- **Atherosclerosis Acceleration:** However, it accelerates the progression of atherosclerosis in ApoE-/- mice, likely through its induction of mitotic arrest, polyploidization, and subsequent apoptosis in SMCs.

This study sheds light on the complex effects of CFI-400945 on different vascular pathologies, possibly indicating the need for caution when considering its therapeutic use in conditions like atherosclerosis where it might exacerbate the disease.

Do you need more details or further clarification on any specific aspect?