Summary
Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are the major cause of in-stent restenosis (ISR). Intervention proliferation and migration of VSMCs is an important strategy for antirestenotic therapy. Roscovitine, a second-generation cyclin-dependent kinase inhibitor, can inhibit cell cycle of multiple cell types. We studied the effects of roscovitine on cell cycle distribution, proliferation and migration of VSMCs in vitro by flow cytometry, BrdU incorporation and wound healing assay, respectively. Our results showed that roscovitine increased the proportion of G0/G1 phase cells after 12 h (69.57±3.65 vs. 92.50±1.68, P=0.000), 24 h (80.87±2.24 vs. 90.25±0.79, P=0.000) and 48 h (88.08±3.86 vs. 88.87±2.43, P=0.427) as compared with control group. Roscovitine inhibited proliferation and migration of VSMCs in a concentration-dependent way. With the increase of concentration, roscovitine showed increased capacity for growth and migration inhibition. Roscovitine (30 μmol/L) led to an almost complete VSMCs growth and migration arrest. Combined with its low toxicity and selective inhibition to ISR-VSMCs, roscovitine may be a potential drug in the treatment of vascular stenosis diseases and particularly useful in the prevention and treatment of ISR.
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Dorros G, Cowley MJ, Simpson J, et al. Percutaneous transluminal coronary angioplasty: report of complications from the National Heart, Lung, and Blood Institute PTCA Registry. Circulation, 1983, 67(4):723–730
Grech ED. ABC of interventional cardiology: percutaneous coronary intervention. I: history and development. BMJ, 2003, 326(7398):1080–1082
Fischman DL, Leon MB, Baim DS, et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators. N Engl J Med, 1994, 331(8):496–501
Gershlick AH. Role of stenting in coronary revascularisation. Heart, 2001, 86(1):104–112
Komatsu R, Ueda M, Naruko T, et al. Neointimal tissue response at sites of coronary stenting in humans: macroscopic, histological, and immunohistochemical analyses. Circulation, 1998, 98(3):224–233
Bennett MR, O’sullivan M. Mechanisms of angioplasty and stent restenosis: implications for design of rational therapy. Pharmacol Ther, 2001, 91(2):149–166
Colombo A, Drzewiecki J, Banning A, et al. Randomized study to assess the effectiveness of slow- and moderate-release polymer-based paclitaxel-eluting stents for coronary artery lesions. Circulation, 2003, 108(7):788–794
Dawkins KD, Grube E, Guagliumi G, et al. Clinical efficacy of polymer-based paclitaxel-eluting stents in the treatment of complex, long coronary artery lesions from a multicenter, randomized trial: support for the use of drug-eluting stents in contemporary clinical practice. Circulation, 2005, 112(21):3306–3313
Grube E, Silber S, Hauptmann KE, et al. TAXUS I: six- and twelve-month results from a randomized, double-blind trial on a slow-release paclitaxel-eluting stent for de novo coronary lesions. Circulation, 2003, 107(1):38–42
Morice MC, Colombo A, Meier B, et al. Sirolimus- vs paclitaxel-eluting stents in de novo coronary artery lesions: the REALITY trial: a randomized controlled trial. JAMA, 2006, 295(8):895–904
Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med, 2002, 346(23):1773–1780
Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med, 2003, 349(14): 1315–1323
Schampaert E, Cohen EA, Schluter M, et al. The Canadian study of the sirolimus-eluting stent in the treatment of patients with long de novo lesions in small native coronary arteries (C-SIRIUS). J Am Coll Cardiol, 2004, 43(6):1110–1115
Stone GW, Ellis SG, Cannon L, et al. Comparison of a polymer-based paclitaxel-eluting stent with a bare metal stent in patients with complex coronary artery disease: a randomized controlled trial. JAMA, 2005, 294(10):1215–1223
Stone GW, Ellis SG, Cox DA, et al. One-year clinical results with the slow-release, polymer-based, paclitaxel-eluting TAXUS stent: the TAXUS-IV trial. Circulation, 2004, 109(16):1942–1947
Stone GW, Ellis SG, Cox DA, et al. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med, 2004, 350(3):221–231
Weisz G, Leon MB, Holmes DR Jr., et al. Two-year outcomes after sirolimus-eluting stent implantation: results from the Sirolimus-Eluting Stent in de Novo Native Coronary Lesions (SIRIUS) trial. J Am Coll Cardiol, 2006, 47(7):1350–1355
Windecker S, Juni P. Safety of drug-eluting stents. Nat Clin Pract Cardiovasc Med, 2008, 5(6):316–328
Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA, 2005, 293(17): 2126–2130
Imanishi T, Kobayashi K, Kuki S, et al. Sirolimus accelerates senescence of endothelial progenitor cells through telomerase inactivation. Atherosclerosis, 2006, 189(2):288–296
Joner M, Finn AV, Farb A, et al. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. J Am Coll Cardiol, 2006, 48(1):193–202
Ong AT, Mcfadden EP, Regar E, et al. Late angiographic stent thrombosis (LAST) events with drug-eluting stents. J Am Coll Cardiol, 2005, 45(12):2088–2092
Goodyear S, Sharma MC. Roscovitine regulates invasive breast cancer cell (MDA-MB231) proliferation and survival through cell cycle regulatory protein cdk5. Exp Mol Pathol, 2007, 82(1):25–32
Mcclue SJ, Blake D, Clarke R, et al. In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R-roscovitine). Int J Cancer, 2002, 102(5):463–468
Meijer L, Borgne A, Mulner O, et al. Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. Eur J Biochem, 1997, 243(1–2):527–536
Raynaud FI, Whittaker SR, Fischer PM, et al. In vitro and in vivo pharmacokinetic-pharmacodynamic relationships for the trisubstituted aminopurine cyclin-dependent kinase inhibitors olomoucine, bohemine and CYC202. Clin Cancer Res, 2005, 11(13):4875–4887
Wesierska-Gadek J, Gueorguieva M, Wojciechowski J, et al. Cell cycle arrest induced in human breast cancer cells by cyclin-dependent kinase inhibitors: a comparison of the effects exerted by roscovitine and olomoucine. Pol J Pharmacol, 2004, 56(5):635–641
Benson C, White J, De Bono J, et al. A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days. Br J Cancer, 2007, 96(1):29–37
Le Tourneau C, Faivre S, Laurence V, et al. Phase I evaluation of seliciclib (R-roscovitine), a novel oral cyclin-dependent kinase inhibitor, in patients with advanced malignancies. Eur J Cancer, 2010, 46(18):3243–3250
O’sullivan M, Scott SD, Mccarthy N, et al. Differential cyclin E expression in human in-stent stenosis smooth muscle cells identifies targets for selective anti-restenosis therapy. Cardiovasc Res, 2003, 60(3):673–683
Qiao M, Shapiro P, Fosbrink M, et al. Cell cycle-dependent phosphorylation of the RUNX2 transcription factor by cdc2 regulates endothelial cell proliferation. J Biol Chem, 2006, 281(11):7118–7128
Thompson CC, Ashcroft FJ, Patel S, et al. Pancreatic cancer cells overexpress gelsolin family-capping proteins, which contribute to their cell motility. Gut, 2007, 56(1):95–106
Milovanceva-Popovska M, Kunter U, Ostendorf T, et al. R-roscovitine (CYC202) alleviates renal cell proliferation in nephritis without aggravating podocyte injury. Kidney Int, 2005, 67(4):1362–1370
Wu PC, Tai MH, Hu DN, et al. Cyclin-dependent kinase inhibitor roscovitine induces cell cycle arrest and apoptosis in rabbit retinal pigment epithelial cells. J Ocul Pharmacol Ther, 2008, 24(1):25–33
Ljungman M, Paulsen MT. The cyclin-dependent kinase inhibitor roscovitine inhibits RNA synthesis and triggers nuclear accumulation of p53 that is unmodified at Ser15 and Lys382. Mol Pharmacol, 2001, 60(4):785–789
Sroka IM, Heiss EH, Havlicek L, et al. A novel roscovitine derivative potently induces G1-phase arrest in platelet-deried growth factor-BB-activated vascular smooth muscle cells. Mol Pharmacol, 2010, 77(2):255–261
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This project was supported by grants from the National Natural Science Foundation of China (Nos. 30870641 and 81030021), and the National Basic Research of China “973” Program (No. 2011CB504403).
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Zhang, Ss., Wang, W., Zhao, Cq. et al. Inhibitory effects of roscovitine on proliferation and migration of vascular smooth muscle cells in vitro . J. Huazhong Univ. Sci. Technol. [Med. Sci.] 34, 791–795 (2014). https://doi.org/10.1007/s11596-014-1354-5
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DOI: https://doi.org/10.1007/s11596-014-1354-5