Cell Cycle Regulation of Smooth Muscle Cells—Searching for Inhibitors of Neointima Formation: Is Combretastatin A4 an Alternative to Sirolimus and Paclitaxel?

• Published in: Journal of vascular and interventional radiology Vol. 26; no. 9; pp. 1388 - 1395
• Main Authors: Spira, Daniel, MD, Grözinger, Gerd, MD, Domschke, Nicole, MD, Bantleon, Rüdiger, PhD, Schmehl, Jörg, MD, Wiskirchen, Jakub, MD, Wiesinger, Benjamin, MD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2015
• Subjects: Cell Cycle - drug effects; Cell Proliferation - drug effects; Cells, Cultured; Humans; Myocytes, Smooth Muscle - cytology; Myocytes, Smooth Muscle - drug effects; Neointima - pathology; Neointima - prevention & control; Paclitaxel - administration & dosage; Radiology; Sirolimus - administration & dosage; Stilbenes - administration & dosage; Treatment Outcome; Tubulin Modulators - administration & dosage; mammalian target of rapamycin; smooth muscle cell; CI; CA4; mTOR; SMC; confidence interval; CDK; cyclin-dependent kinase; peroxisome proliferator activated receptor γ; PPARγ; combretastatin A4
• ISSN: 1051-0443; 1535-7732
• DOI: 10.1016/j.jvir.2015.05.025

Abstract Purpose To compare the effects of sirolimus, paclitaxel, and combretastatin A4 (CA4) on regulatory proteins of the cell cycle in proliferating smooth muscle cells (SMCs). Materials and Methods Human aortic SMCs were treated with sirolimus, paclitaxel, and CA4 at 5 × 10−9 mol/L. After 1 day, half of the cells were harvested (DAY1 group). The treatment medium of the other half was replaced with culture medium on day 4, and those cells were harvested on day 5 (DAY5 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. Results In the DAY1 group, treatment with sirolimus resulted in decreased intracellular levels of cyclins D2 and A ( P < .05). Increased D cyclins and reduced levels of cyclins E and A ( P < .05) in the DAY5 group indicated a permanent G1 /S block by sirolimus. Paclitaxel led to only slight alterations of cyclin and CDK inhibitor expression ( P > .05). In the DAY1 group, CA4 decreased intracellular levels of cyclins D2 , E, and A ( P < .05). Despite recovery effects in the DAY5 group (increase of cyclins D1 , D2 , and A compared with DAY1 group; P < .05), the upregulation of the CDK inhibitor p21, increased D cyclins, and decreased cyclins E and A ( P < .05) are compatible with a G1 arrest. Conclusions CA4 is a stronger inhibitor of the SMC cycle than sirolimus or paclitaxel and may represent an alternative for drug-eluting stents in atherosclerotic luminal stenosis. The effect of CA4 on neointima formation should be evaluated further.