Natural compound library screening identifies Sanguinarine chloride for the treatment of SCLC by upregulating CDKN1A

Zhong, Mingtian; Li, Xun; Zhao, Fengyun; Huang, Yanni; Long, Yihao; Chen, Kaizhao; Tian, Xuemei; Liu, Ming; Ma, Xiaodong

doi:10.1016/j.tranon.2022.101345

Cited by 3 publications

(2 citation statements)

References 28 publications

(27 reference statements)

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“…4A ; fig. S6, A to C; and table S3), we identified five compounds that reduced the nuclear enrichment of polyQ-expanded AR by 20 to 30%: three of them, namely, 6-chloro-7-(2-morpholin-4-ylethylamino)quinoline-5,8-dione (also known as NSC-663284) ( 22 ), 2,3-bis-(2-hydroxyethylsulfanyl)-1,4-naphthoquinone (also known as NSC-95397) ( 23 ), and shikonin ( 24 ), which inhibit the phosphatase cell division cycle 25 (CDC25); sanguinarine chloride, which inhibits not only phosphatases, such as protein posphatase 2C (PP2C), but also CDK2 through up-regulation of p21 CIP1 ( 25 , 26 ); and 9,10-phenanthrenequinone, which inhibits CD45 tyrosine phosphatase. The latter compound does not target serine phosphorylation, so it was not investigated further in this work.…”

Section: Resultsmentioning

confidence: 99%

Antagonistic effect of cyclin-dependent kinases and a calcium-dependent phosphatase on polyglutamine-expanded androgen receptor toxic gain of function

et al. 2023

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Spinal and bulbar muscular atrophy is caused by polyglutamine (polyQ) expansions in androgen receptor (AR), generating gain-of-function toxicity that may involve phosphorylation. Using cellular and animal models, we investigated what kinases and phosphatases target polyQ-expanded AR, whether polyQ expansions modify AR phosphorylation, and how this contributes to neurodegeneration. Mass spectrometry showed that polyQ expansions preserve native phosphorylation and increase phosphorylation at conserved sites controlling AR stability and transactivation. In small-molecule screening, we identified that CDC25/CDK2 signaling could enhance AR phosphorylation, and the calcium-sensitive phosphatase calcineurin had opposite effects. Pharmacologic and genetic manipulation of these kinases and phosphatases modified polyQ-expanded AR function and toxicity in cells, flies, and mice. Ablation of CDK2 reduced AR phosphorylation in the brainstem and restored expression of Myc and other genes involved in DNA damage, senescence, and apoptosis, indicating that the cell cycle–regulated kinase plays more than a bystander role in SBMA-vulnerable postmitotic cells.

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Section: Resultsmentioning

confidence: 99%

Antagonistic effect of cyclin-dependent kinases and a calcium-dependent phosphatase on polyglutamine-expanded androgen receptor toxic gain of function

et al. 2023

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“…It induces the activation of reactive oxygen species (ROS), disrupts mitochondrial membrane potential and ultimately triggers the mitochondrial apoptosis pathway (Zhang & Huang, 2019). Furthermore, SNG modulates cell cycle regulation by influencing the expression of cyclins (Zhong et al, 2022). In addition, SNG has been found to induce autophagy by impeding lysosome formation and inhibiting autophagosome degradation, thereby impeding the progression of various cancers (Su et al, 2020; J. Wang, Su, et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Sanguinarine induces apoptosis in osteosarcoma by attenuating the binding of STAT3 to the single‐stranded DNA‐binding protein 1 (SSBP1) promoter region

Wang,

Zhu,

Qin

et al. 2023

British J Pharmacology

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Background and PurposeOsteosarcoma, a primary malignant bone tumor prevalent among adolescents and young adults, remains a considerable challenge despite protracted progress made in enhancing patient survival rates over the last forty years. Consequently, the development of novel therapeutic approaches for osteosarcoma is imperative. Sanguinarine (SNG), a compound with demonstrated potent anticancer properties against various malignancies, presents a promising avenue for exploration. Nevertheless, the intricate molecular mechanisms underpinning SNG’s actions in osteosarcoma remain elusive, necessitating further elucidation.Experimental ApproachSingle stranded DNA binding protein 1 (SSBP1) was screened out by differential proteomic analysis. The apoptosis, cell cycle, reactive oxygen species (ROS) and mitochondrial changes were assessed via flow cytometry. Western blotting and qRT‐PCR were used to determine relevant protein and gene levels. The anti‐tumor mechanism of SNG was explored at molecular level using chromatin immunoprecipitation (ChIP) and dual luciferase reporter plasmids.Key ResultsOur investigation revealed that SNG exerted an upregulated effect on SSBP1, disrupting mitochondrial function and inducing apoptosis. In‐depth analysis uncovered a specific mechanism whereby SNG hindered the JAK/STAT3 signaling pathway, relieved the inhibitory effect of STAT3 on SSBP1 transcription and inhibited the downstream PI3K/Akt/mTOR signaling axis, ultimately activating the apoptosis.Conclusion and ImplicationsThe study delved further into elucidating the anti‐cancer mechanism of SNG in the context of osteosarcoma. Notably, we unraveled the previously undisclosed apoptotic potential of SSBP1 in osteosarcoma cells. This finding holds substantial promise in advancing the development of novel anti‐cancer drugs and the identification of therapeutic targets.

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Bioactivity and mechanism of action of sanguinarine and its derivatives in the past 10 years

Huang,

Lan,

Wang

et al. 2024

Biomedicine & Pharmacotherapy

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Natural compound library screening identifies Sanguinarine chloride for the treatment of SCLC by upregulating CDKN1A

Cited by 3 publications

References 28 publications

Antagonistic effect of cyclin-dependent kinases and a calcium-dependent phosphatase on polyglutamine-expanded androgen receptor toxic gain of function

Antagonistic effect of cyclin-dependent kinases and a calcium-dependent phosphatase on polyglutamine-expanded androgen receptor toxic gain of function

Sanguinarine induces apoptosis in osteosarcoma by attenuating the binding of STAT3 to the single‐stranded DNA‐binding protein 1 (SSBP1) promoter region

Bioactivity and mechanism of action of sanguinarine and its derivatives in the past 10 years

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