Evodiamine causes mitotic catastrophe in PDGF-induced vascular smooth muscle cells

Proliferation of vascular smooth muscle cells (VSMC) is a key factor driving atherosclerosis and restenosis [1]. Evodiamine, an indoloquinazoline alkaloid found in fructus Evodiae [2], inhibits the proliferation of platelet derived growth factor (PDGF)-stimulated VSMC with an IC₅₀ of 0.67 µmol/L, as determined by a BrdU incorporation assay. Thus, it may serve as a therapeutic/preventive agent against atherosclerosis and restenosis. This study characterises evodiamine’s anti-proliferative activity and the underlying molecular mechanisms in PDGF-stimulated VSMC.

In addition to a G2/M arrest, flow cytometry revealed an increase in polyploidy upon 3 µmol/L evodiamine treatment. This indicates mitotic catastrophe (MC), which is a state of improper cell cycle entry and progression that precedes cell death or slippage of irregularly divided cells into a new cell cycle [3]. Immunofluorescence confocal microscopy revealed an increased occurrence of round-shaped cells with irregular nuclei and micronuclei in response to evodiamine treatment, further corroborating MC as a mode of action. Whereas a minor increase in apoptotic cells was observed by Annexin V/PI staining, LDH release was unaffected upon evodiamine treatment. Apoptosis (caspase-3 and PARP-1 cleavage) and DNA-damage (γ-H2A.X) indicators were unaffected in western blot, compared to respective controls, staurosporine and etoposide. Western blot further demonstrated no effect on the signalling cascades downstream of PDGF receptor (AMPK, p38, JNK, STAT3) by evodiamine.

These findings indicate that apoptosis is not the main driving force of the anti-proliferative activity of evodiamine in VSMC, but rather a consequence of MC caused by a mechanism yet to be elucidated.

 

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Conflict of Interest

The authors declare no conflict of interest.

• References

• 1 Basatemur GL, Jorgensen HF, Clarke MCH, Bennett MR, Mallat Z.. Vascular smooth muscle cells in atherosclerosis. Nat Rev Cardiol 2019; 16 (12) 727-744
• 2 Sun Q, Xie L, Song J, Li X.. Evodiamine: A review of its pharmacology, toxicity, pharmacokinetics and preparation researches. JEthnopharmacol 2020; 262: 113164
• 3 Vakifahmetoglu H, Olsson M, Zhivotovsky B.. Death through a tragedy: mitotic catastrophe. Cell Death Differ 2008; 15 (07) 1153-62

Publication History

Article published online:
16 November 2023