Pharmacological properties of indirubin and its derivatives

Lin, Yang; Li, Xinyun; Huang, Wei; Rao, Xiangshu; Lai, Yu

doi:10.1016/j.biopha.2022.113112

Cited by 44 publications

(12 citation statements)

References 120 publications

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“…By the 1970s, IN gained attention for its therapeutic potential in treating various cancers, leading to the introduction of indirubin as a novel treatment for leukemia in China [ 21 ]. Several compounds, including indigo, indirubin, tryptanthrin, among others, are believed to contribute to the medicinal properties of IN [ 21 , 24 , 25 ]. Regarding the mechanism of action, indirubin and its derivatives target STAT5 and CDKs, leading to G1 or G2/M arrest [ 26 – 29 ].…”

Section: Discussionmentioning

confidence: 99%

Indigofera suffruticosa aerial parts extract induce G2/M arrest and ATR/CHK1 pathway in Jurkat cells

Tran,

Lai,

Chang

et al. 2024

BMC Complement Med Ther

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Background Indigofera suffruticosa Mill. is used as a folk medicine for treating patients with leukemia, however very little is known regarding the molecular mechanism of its anti-leukemic activity and the chemical profile of the active extract. The present study aimed to reveal the molecular effect of I. suffruticosa aerial parts extract (ISAE) on leukemia cells and its chemical constituents. Methods Cytotoxicity of ISAE were determined by resazurin viability assay, multitox – Glo multiplex cytotoxicity assay, and Annexin V staining assay. Cell cycle profiles were revealed by propidium iodide staining assay. The effects of ISAE on G2/M arrest signaling and DNA damage were evaluated by Western blot assay and phospho-H2A.X staining assay. The chemical profile of ISAE were determined by tandem mass spectroscopy and molecular networking approach. Results We showed that the acute lymphoblastic leukemia cell line Jurkat cell was more responsive to ISAE treatment than other leukemia cell lines. In contrast, ISAE did not induce cytotoxic effects in normal fibroblast cells. Cell cycle analysis revealed that ISAE triggered G2/M arrest in Jurkat cells in dose- and time-dependent manners. Elevation of annexin V-stained cells and caspase 3/7 activity suggested ISAE-induced apoptosis. Furthermore, ISAE alone could increase the phosphorylation of CDK1 at Y15 and activate the ATR/CHK1/Wee1/CDC25C signaling pathway. However, the addition of caffeine, a widely used ATR inhibitor to ISAE, reduced the phosphorylation of ATR, CHK1, and CDK1, as well as G2/M arrest in Jurkat cells. Moreover, increased phospho-H2A.X stained cells indicated the involvement of DNA damage in the anti-leukemic effect of ISAE. Finally, qualitative analysis using UPLC-tandem mass spectroscopy and molecular networking revealed that tryptanthrin was the most abundant organoheterocyclic metabolite in ISAE. At equivalent concentrations to ISAE, tryptanthrin induced G2/M arrest of Jurkat cells, which can be prevented by caffeine. Conclusions ISAE causes G2/M arrest via activating ATR/CHK1/CDK1 pathway and tryptanthrin is one of the active components of ISAE. Our findings provide subtle support to the traditional use of I. suffruitcosa in leukemia management in folk medicine.

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Section: Discussionmentioning

confidence: 99%

Indigofera suffruticosa aerial parts extract induce G2/M arrest and ATR/CHK1 pathway in Jurkat cells

Tran,

Lai,

Chang

et al. 2024

BMC Complement Med Ther

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“…Indirubin is also a component of the Chinese remedy Danggui Longhui Wan and the main active constituent of a prescription that is responsible for the treatment of chronic myelogenous leukemia (CML) . Indirubin and its derivatives also possess excellent antitumor, anti-inflammatory, and neuroprotective effects , and are effective and selective inhibitors of cyclin-dependent kinases (CDKs), a crucial family of serine–threonine kinases involved in the progression of various tumors . Recently, He’s group designed a new series of CDK–histone deacetylase (HDAC) dual inhibitors based on indirubin that display remarkable suppressive effects against CDK and HDAC …”

Section: Np-inspired Targeted Protein Degradersmentioning

confidence: 99%

Natural Product-Inspired Targeted Protein Degraders: Advances and Perspectives

Cai

et al. 2022

J. Med. Chem.

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Targeted protein degradation (TPD), a promising therapeutic strategy in drug discovery, has great potential to regulate the endogenous degradation of undruggable targets with small molecules. As vital resources that provide diverse structural templates for drug discovery, natural products (NPs) are a rising and robust arsenal for the development of therapeutic TPD. The first proof-of-concept study of proteolysis-targeting chimeras (PROTACs) was a natural polyketide ovalicin-derived degrader; since then, NPs have shown great potential to promote TPD technology. The use of NP-inspired targeted protein degraders has been confirmed to be a promising strategy to treat many human conditions, including cancer, inflammation, and nonalcoholic fatty liver disease. Nevertheless, the development of NP-inspired degraders is challenging, and the field is currently in its infancy. In this review, we summarize the bioactivities and mechanisms of NP-inspired degraders and discuss the associated challenges and future opportunities in this field.

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“…Furthermore, 6BIO has been investigated for its capacity to activate the Wnt/β-catenin signaling pathway, a crucial player in embryonic development and tissue regeneration [9]. The multifaceted pharmacological activities of 6BIO render it a subject of ongoing research, exploring its potential utility as a pharmacological tool and therapeutic agent across various medical contexts [10].…”

Section: Introductionmentioning

confidence: 99%

Metabolic imaging with FLIM/PLIM indirubin derivatives: an ultrafast window into cellular metabolism and oxygen consumption

N. S. dos Santos,

Naskar,

Reess

et al. 2024

Multiphoton Microscopy in the Biomedical Sciences XXIV

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Metabolic Fluorescence Lifetime Imaging Microscopy (FLIM) algorithms have emerged as powerful tools for unraveling the intricate dynamics of cellular and tissue metabolism. FLIM algorithms offer unique insights into cellular metabolic processes that transcend traditional imaging methods. By combining Metabolic FLIM with Phosphorescence Lifetime Imaging Microscopy (PLIM), it becomes possible to assess cellular metabolic states, such as oxygen consumption, redox states, pH levels, and energy production pathways.In our investigation, we employed a combination of 2-photon (2P) excited FLIM and PLIM techniques, along with timecorrelated single-photon counting (TCSPC) detection. Through this, we made a significant discovery of bromine indirubin derivatives that exhibit a PLIM/dFLIM signal in two living cell lines. Notably, indirubin is a natural dye, and though renowned for its anti-tumor properties, its mechanism of action remains to be fully investigated.Under normoxic conditions, the PLIM signal of indirubin exhibited a value of 62 ns living cells, while under hypoxic conditions, it increased significantly to 107ns. This observation demonstrates the potential of these indirubins as highly reliable oxygen consumption sensors. Moreover, our investigation revealed that bromine indirubin had a profound impact on cellular metabolism, prompting a shift from oxidative phosphorylation to glycolysis.Through our research, we aim to demonstrate that these techniques offer valuable insights into cellular metabolism, covering the way for deeper understanding and potential breakthroughs in various fields of biology and medicine.

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Pharmacological properties of indirubin and its derivatives

Cited by 44 publications

References 120 publications

Indigofera suffruticosa aerial parts extract induce G2/M arrest and ATR/CHK1 pathway in Jurkat cells

Indigofera suffruticosa aerial parts extract induce G2/M arrest and ATR/CHK1 pathway in Jurkat cells

Natural Product-Inspired Targeted Protein Degraders: Advances and Perspectives

Metabolic imaging with FLIM/PLIM indirubin derivatives: an ultrafast window into cellular metabolism and oxygen consumption

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