A novel indirubin derivative that increases somatic cell plasticity and inhibits tumorigenicity. Issue 13 (1st July 2019)

• Record Type: Journal Article
• Authors: Kim, Woong-Hee; Jeong, Pyeonghwa; Kim, Seon-Wook; Cho, Haaglim; Lee, Jeong-min; Seo, Shinae; Shen, Haihong; Ahn, Youngkeun; Jung, Da-Woon; Kim, Yong-Chul; Williams, Darren R.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 13(2019)
• Page Start: 2923
• Page End: 2934
• Publication Date: 2019-07-01
• Subjects: Metastasis -- Cell plasticity -- Cellularization -- Indirubin derivative -- Glycogen synthase kinase-3β -- Aurora A kinase; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.05.025
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Indirubin-based compounds affect diverse biological processes, such as inflammation and angiogenesis. In this study, we tested a novel indirubin derivative, LDD-1819 (2-((((2Z, 3E)-5-hydroxy-5′-nitro-2′-oxo-[2, 3′-biindolinylidene]-3-ylidene)amino)oxy)ethan-1-aminium chloride) for two major biological activities: cell plasticity and anti-cancer activity. Biological assays indicated that LDD-1819 induced somatic cell plasticity. LDD-1819 potentiated myoblast reprogramming into osteogenic cells and fibroblast reprogramming into adipogenic cells. Interestingly, in an assay of skeletal muscle dedifferentiation, LDD-1819 induced human muscle cellularization and blocked residual proliferative activity to produce a population of mononuclear refractory cells, which is also observed in the early stages of limb regeneration in urodele amphibians. In cancer cell lines, LDD-1819 treatment inhibited cell invasion and selectively induced apoptosis compared to normal cells. In an animal tumor xenograft model, LDD-1819 reduced human cancer cell metastasis in vivo at doses that did not produce toxicity. Biochemical assays showed that LDD-1819 possessed inhibitory activity against glycogen synthase kinase-3β, which is linked to cell plasticity, and aurora kinase, which regulates carcinogenesis. These results indicate that novel indirubin derivative LDD-1819 is a dual inhibitor of glycogen synthase kinase-3β and aurora A kinase, and has potential for development as an anti-cancer drug or as a reprogramming agent for cell-therapy based approaches to treat degenerative diseases.