The CDK inhibitor AT7519 inhibits human glioblastoma cell growth by inducing apoptosis, pyroptosis and cell cycle arrest

Zhao, Wenpeng; Zhang, Liang; Zhang, Yaya; Jiang, Zhengye; Lu, Hanwen; Xie, Yuanyuan; Han, Wanhong; Zhao, Wentao; He, Jiawei; Shi, Zhenxiang; Yang, Hui Ying; Chen, Junjie; Chen, Sifang; Li, Zhangyu; Mao, Jianyao; Zhou, Liwei; Gào, Xin; Li, Wenhua; Tan, Guowei; Zhang, Bingchang; Wang, Zhanxiang

doi:10.1038/s41419-022-05528-8

Cited by 39 publications

(17 citation statements)

References 40 publications

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“…Cell cycle control describes the regulatory process of cell growth that is dictated by coordinated interactions of various cyclins and their respective cyclin-dependent kinases (CDKs) [ 18 , 19 ]. Cyclins and CDKs together form various checkpoints that can either usher or inhibit progression of a cell through the cell cycle.…”

Section: Discussionmentioning

confidence: 99%

Tetrastigma hemsleyanum (Sanyeqing) root extracts evoke S phase arrest while inhibiting the migration and invasion of human pancreatic cancer PANC-1 cells

Sun,

Qin,

Zhang

et al. 2024

BMC Complement Med Ther

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Background Ethyl acetate extracts from Tetrastigma hemsleyanum (Sanyeqing) (EFT), a member of the Vitaceae plant family, have been shown to exhibit efficacy against a variety of cancers. In this light, our current study seeks to examine the mechanism of efficacy between EFT extracts and human pancreatic cancer PANC-1 cells. Methods The chemical components of EFT were analyzed by gas chromatography–mass spectrometry. The cytotoxicity of EFT on PANC-1 cells was measured using an MTT assay. In order to investigate EFT induction of cell cycle arrest, changes in cell-cycle distribution were monitored by flow cytometry. Wound healing and transwell assays were employed to investigate whether migration and invasion of PANC-1 cells were inhibited by EFT. Relative protein expression was detected using Western blot. Results GC-MS analysis of the chemical composition of EFT revealed that the majority of constituents were organic acids and their corresponding esters. EFT exhibits measurable cytotoxicity and inhibition of PANC-1 invasion. Growth inhibition was primarily attributed to downregulation of CDK2 which induces cell cycle arrest in the S-phase. Inhibition of metastasis is achieved through downregulation of mesenchymal-associated genes/activators, including ZEB1, N-cadherin, Vimentin, and Fibronectin. Meanwhile, the expression of E-cadherin was significantly increased by EFT treatment. Furthermore, downregulation of MMP-2 and MMP-9 were observed. Conclusion Treatment of PANC-1 with EFT demonstrated measurable cytotoxic effects. Furthermore, EFT evoked S phase arrest while inhibiting the migration and invasion of PANC-1 cells. Additionally, EFT inhibited the epithelial to mesenchymal transition and MMPs expression in PANC-1 cells. This study serves to confirm the strong therapeutic potential of EFT while identifying the mechanisms of action.

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Section: Discussionmentioning

confidence: 99%

Tetrastigma hemsleyanum (Sanyeqing) root extracts evoke S phase arrest while inhibiting the migration and invasion of human pancreatic cancer PANC-1 cells

Sun,

Qin,

Zhang

et al. 2024

BMC Complement Med Ther

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“…Cell cycle dysregulation is one of the key hallmarks of cancer cells. Numerous chemotherapeutic agents cause cell cycle arrest and promote apoptosis to stop the growth of human glioblastoma and other types of cancer cells ( 34 , 35 ). Furthermore, rapamycin has been shown to induce cell cycle arrest in the G 1 phase and promote apoptosis in several cancer types, including renal cancer cells and glioma cells ( 36 , 37 ).…”

Section: Discussionmentioning

confidence: 99%

Rapamycin inhibits B16 melanoma cell viability in vitro and in vivo by inducing autophagy and inhibiting the mTOR/p70‑S6k pathway

Wang,

Zhang,

Guo

et al. 2024

Oncol Lett

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Rapamycin is an immunosuppressant that has been shown to prevent tumor growth following organ transplantation. However, its exact mode of antitumor action remains unknown. The present study used the B16-F10 (B16) murine melanoma model to explore the antitumor mechanism of rapamycin, and it was revealed that rapamycin reduced B16 cell viability in vitro and in vivo . In addition, in vitro and in vivo , the results of western blotting showed that rapamycin reduced Bcl2 expression, and enhanced the protein expression levels of cleaved caspase 3 and Bax, indicating that it can induce the apoptosis of B16 melanoma cells. Furthermore, the results of cell cycle analysis and western blotting showed that rapamycin induced B16 cell cycle arrest in the G 1 phase, based on the reduction in the protein expression levels of CDK1, cyclin D1 and CDK4, as well as the increase in the percentage of cells in G 1 phase. Rapamycin also significantly increased the number of autophagosomes in B16 melanoma cells, as determined by transmission electron microscopy. Furthermore, the results of RT-qPCR and western blotting showed that rapamycin upregulated the protein expression levels of microtubule-associated protein light chain 3 (LC3) and Beclin-1, while downregulating the expression of p62 in vitro and in vivo , thus indicating that rapamycin could trigger cellular autophagy. The present study revealed that rapamycin in combination with chloroquine (CQ) further increased LC3 expression compared with that in the CQ group, suggesting that rapamycin induced an increase in autophagy in B16 cells. Furthermore, the results of western blotting showed that rapamycin blocked the phosphorylation of p70 ribosomal S6 kinase (p70-S6k) and mammalian target of rapamycin (mTOR) proteins in vitro and in vivo , thus suggesting that rapamycin may exert its antitumor effect by inhibiting the phosphorylation of the mTOR/p70-S6k pathway. In conclusion, rapamycin may inhibit tumor growth by inducing cellular G 1 phase arrest and apoptosis. In addition, rapamycin may exert its antitumor effects by inducing the autophagy of B16 melanoma cells in vitro and in vivo , and the mTOR/p70-S6k signaling pathway may be involved in this process.

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“…Furthermore, several studies have shown that certain drugs and small molecular inhibitors can induce pyroptosis in GBM. The GBM cell lines LN-229, U87-MG, and U251 after treatment with galangin [ 28 ], kaempferol [ 29 ], benzimidazoles [ 30 ], 4,5-Dimethoxycanthin-6-one [ 31 ] (new LSD1 inhibitor), and AT7519 [ 32 ] (multi-CDKs inhibitors) can induce obvious pyroptosis, and mouse cell-derived xenograft (CDX) model experiments have also illustrated their anti-tumor role. J.Y.…”

Section: Pyroptosis and Glioblastomamentioning

confidence: 99%

Pyroptosis, ferroptosis, and autophagy cross-talk in glioblastoma opens up new avenues for glioblastoma treatment

et al. 2023

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Glioma is a common primary tumor of the central nervous system (CNS), with glioblastoma multiforme (GBM) being the most malignant, aggressive, and drug resistant. Most drugs are designed to induce cancer cell death, either directly or indirectly, but malignant tumor cells can always evade death and continue to proliferate, resulting in a poor prognosis for patients. This reflects our limited understanding of the complex regulatory network that cancer cells utilize to avoid death. In addition to classical apoptosis, pyroptosis, ferroptosis, and autophagy are recognized as key cell death modalities that play significant roles in tumor progression. Various inducers or inhibitors have been discovered to target the related molecules in these pathways, and some of them have already been translated into clinical treatment. In this review, we summarized recent advances in the molecular mechanisms of inducing or inhibiting pyroptosis, ferroptosis, or autophagy in GBM, which are important for treatment or drug tolerance. We also discussed their links with apoptosis to better understand the mutual regulatory network among different cell death processes.

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The CDK inhibitor AT7519 inhibits human glioblastoma cell growth by inducing apoptosis, pyroptosis and cell cycle arrest

Cited by 39 publications

References 40 publications

Tetrastigma hemsleyanum (Sanyeqing) root extracts evoke S phase arrest while inhibiting the migration and invasion of human pancreatic cancer PANC-1 cells

Tetrastigma hemsleyanum (Sanyeqing) root extracts evoke S phase arrest while inhibiting the migration and invasion of human pancreatic cancer PANC-1 cells

Rapamycin inhibits B16 melanoma cell viability in vitro and in vivo by inducing autophagy and inhibiting the mTOR/p70‑S6k pathway

Pyroptosis, ferroptosis, and autophagy cross-talk in glioblastoma opens up new avenues for glioblastoma treatment

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