TW-01, a piperazinedione-derived compound, inhibits Ras-mediated cell proliferation and angioplasty-induced vascular restenosis

Journal Article · Mon Aug 15 04:00:00 EDT 2016 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2016.06.013· OSTI ID:22689239

Lin, Chao-Feng ^[1]; Huang, Han-Li ^[1]; Peng, Chieh-Yu ^[2]; Lee, Yu-Ching ^[3]; Wang, Hui-Po ^[4]; Teng, Che-Ming ^[4]; Pan, Shiow-Lin ^[1]

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1. The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan (China)
2. Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung 404, Taiwan (China)
3. The Center of Translational Medicine, Taipei Medical University, Taipei, Taiwan (China)
4. College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan (China)

Purpose: Vascular smooth muscle cell (VSMC) proliferation plays a critical role in the pathogenesis of atherosclerosis and restenosis. This study investigated piperazinedione derived compound TW-01-mediated inhibitory effects on VSMC proliferation and intimal hyperplasia. Methods: Cell proliferation was determined using [{sup 3}H]-thymidine incorporation and MTT assay; cell cycle distribution was measured using flow cytometry; proteins and mRNA expression were determined using western blotting and RT-PCR analyses; DNA binding activity of nuclear factor-κB (NF-κB), as measured using enzyme-linked immunosorbent assays (ELISA); in vivo effects of TW-01 were determined using balloon angioplasty in the rat. Results: TW-01 significantly inhibited cell proliferation. At the concentrations used, no cytotoxic effects were observed. Three predominant signaling pathways were inhibited by TW-01: (a) extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinase (MAPK) activation and its downstream effectors of c-fos, c-jun, and c-myc; (b) DNA binding activity of nuclear factor-κB (NF-κB); and, (c) Akt/protein kinase B (PKB) and cell cycle progression. Furthermore, TW-01 also inhibited Ras activation, a shared upstream event of each of these signaling cascades. In vascular injury studies, oral administration of TW-01 significantly suppressed intimal hyperplasia induced by balloon angioplasty. Conclusion: The present study suggests that TW-01 might be a potential candidate for atherosclerosis treatment. - Highlights: • TW-01significantly inhibits vascular smooth muscle cell proliferation. • TW-01 inhibits ERK, Akt and Ras pathway and DNA binding activity of NF-κB. • TW-01 significantly suppresses intimal hyperplasia induced by balloon angioplasty. • TW-01 might be a potential candidate for atherosclerosis treatment.

• OSTI ID: 22689239
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Vol. 305; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ARTERIOSCLEROSIS
CELL CYCLE
CELL PROLIFERATION
CONCENTRATION RATIO
DNA
ENZYME IMMUNOASSAY
MESSENGER-RNA
MUSCLES
ORAL ADMINISTRATION
PHOSPHOTRANSFERASES
POLYMERASE CHAIN REACTION
RATS
THYMIDINE
TRITIUM