Could combretastatin A4 be an alternative to sirolimus and paclitaxel in the inhibition of the smooth muscle cell cycle?

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Preclinical research published online ahead of print in the Journal of Vascular and Interventional Radiology (JVIR) in July shows that combretastatin A4 is a stronger inhibitor of the smooth muscle cell cycle than sirolimus or paclitaxel. Thus, it may represent an alternative coating for drug-eluting stents and balloons in atherosclerotic luminal stenosis, the investigators write.

Sirolimus and paclitaxel are drugs that are loaded onto a wide variety of drug-eluting or drug-coated device platforms for use in the coronary arteries and periphery. For example, Ultimaster, is an example of a sirolimus-eluting bioabsorbable coronary stent (Terumo) and Zilver PTX (Cook Medical), a peripheral paclitaxel-eluting stent system that has shown beneficial long-term effects in combating femoropoliteal disease.

Researchers Daniel Spira and colleagues set out to compare the effects of sirolimus, paclitaxel, and combretastatin A4 on the regulatory proteins of the cell cycle in proliferating smooth muscle cells.

Spira and colleagues treated human aortic smooth muscle cells with sirolimus, paclitaxel, and combretastatin A4 at 5×10-9 mol/L. After one day, half of the cells were harvested (D1 group). The treatment medium of the other half was replaced with culture medium on day four, and those cells were harvested on day five (D5 group). Cyclins D1, D2, E, and A and cyclin-dependent kinase (CDK) inhibitors p16, p21, and p27 were detected by Western blot technique. Quantification was performed by scanning densitometry of the specific bands.

As reported in JVIR, the researchers found that in the D1 group, treatment with sirolimus resulted in decreased intracellular levels of cyclins D2 and A (p0.05). In the D1 group, combretastatin A4 decreased intracellular levels of cyclins D2, E, and A (p<0.05). Despite recovery effects in the D5 group (increase of cyclins D1, D2, and A compared with D1 group; p<0.05), the upregulation of the CDK inhibitor p21, increased D cyclins, and decreased cyclins E and A (p <0.05) are compatible with a G1 arrest.

“The effect of combretastatin A4 on neointima formation should be evaluated further,” the authors recommend.

 

Factfile

  • Combretastatin belongs to a class of natural phenols (and despite its name, is unrelated to statins). Several natural combretastatin molecules are found in the bark of South African Bush willow trees.
  • Paclitaxel (also called Taxol) is found in the bark of yew trees.
  • Sirolimus is the generic name for the natural product rapamycin and is produced by a strain of Streptomyces hygroscopicus.