TAK-733 inhibits inflammatory neointimal formation by suppressing proliferation, migration, and inflammation in vitro and in vivo

• Published in: Experimental & molecular medicine Vol. 50; no. 4; pp. 1 - 12
• Main Authors: Park, Jun-Hee, Kim, Sang Woo, Cha, Min-Ji, Yoon, Nara, Lee, Chang Youn, Lee, Jiyun, Seo, Hyang-Hee, Shin, Sunhye, Choi, Jung-Won, Lee, Seahyoung, Lim, Soyeon, Hwang, Ki-Chul
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.04.2018; Springer Nature B.V; Nature Publishing Group; 생화학분자생물학회
• Subjects: 13; 13/106; 13/95; 631/80; 692/308; Allosteric properties; Angiotensin; Angiotensin II; Animals; Anti-inflammatory agents; Apoptosis; Balloon catheters; Biomedical and Life Sciences; Biomedicine; Cancer; Cardiovascular system; Cell cycle; Cell growth; Cell proliferation; Cell Proliferation - drug effects; Disease Models, Animal; Graft Occlusion, Vascular - metabolism; Graft Occlusion, Vascular - pathology; Graft Occlusion, Vascular - prevention & control; Humans; Hyperplasia; Inflammation; Inflammation - metabolism; Inflammation - pathology; Inflammation - prevention & control; Intercellular adhesion molecule 1; Leukocyte migration; Male; Medical Biochemistry; Mice; Molecular Medicine; Monocytes; Neointima - metabolism; Neointima - pathology; Neointima - prevention & control; Pyridones - pharmacology; Pyrimidinones - pharmacology; Rats; Rats, Sprague-Dawley; RAW 264.7 Cells; Restenosis; Smooth muscle; Stem Cells; Stents; Wound healing; 생화학
• ISSN: 1226-3613; 2092-6413
• DOI: 10.1038/s12276-018-0052-y

As a potent and selective allosteric inhibitor of MEK, TAK-733 has been shown to exert anti-cancer effects for a wide range of cancers both in vitro and in vivo. However, its effects on inhibiting growth have never been investigated in the cardiovascular system, where regulation of abnormal vascular smooth muscle cell growth in neointimal hyperplasia is an important area of focus. Angiotensin II was used to mimic inflammatory neointimal hyperplasia in an in vitro environment, and balloon catheter-induced injury with an infusion of angiotensin II was used to generate an in vivo rat restenosis model under inflammatory conditions. TAK-733 exerted anti-proliferative and anti-migratory effects on human vascular smooth muscle cells. These multiple effects of TAK-733 were evaluated using various assays, such as cell cycle analysis and wound healing. Interestingly, TAK-733 did not induce apoptosis in smooth muscle cells but only reduced the proliferation rate; additionally, it did not affect EC viability. TAK-733 also exhibited anti-inflammatory activity, as observed by attenuated monocyte adhesion to smooth muscle cells via inhibition of ICAM1 and VCAM1 overexpression. The in vivo study demonstrated that neointimal hyperplasia after balloon injury and angiotensin II stimulation was suppressed by TAK-733, and downregulation of the inflammatory signal and enhanced re-endothelialization were observed. TAK-733 may have therapeutic potential for treating neointimal hyperplasia by attenuating smooth muscle cell proliferation, migration, and inflammation. Thus, TAK-733 could be a promising drug candidate for treating patients with restenosis. Atherosclerosis: Potential therapy based on prospective cancer drug Drug undergoing trials as a cancer treatment shows promise in tackling the narrowing of blood vessels in other diseases. The thickening of arterial walls and consequent restriction of blood flow, typical of conditions like atherosclerosis, increases the risk of heart attacks and strokes. Soyeon Lim and Ki-Chul Hwang at the Catholic Kwandong University, South Korea, and co-workers have investigated the efficacy of a prospective cancer drug called TAK-733 against atherosclerosis both in cell culture and in trials on rat models of the disease. The team hypothesized that TAK-733’s anti-cancer effects could prove useful in treating other conditions. They demonstrated that TAK-733 successfully blocked the proliferation and migration of vascular smooth muscle cells, the overexpression of which is a dominant factor in the development of atherosclerosis.