HM-3-HSA exhibits potent anti-angiogenesis and antitumor activity in hepatocellular carcinoma

Li, Ting; Ge, Guangfei; Zhang, Hanzi; Wang, Ruyue; Liu, Yiyao; Zhang, Qian; Yue, Zhaorong; Ma, Wuli; Li, Wenbo; Zhang, Jingjing; Yang, Hui; Wang, Peiya; Zhao, Jian-Fu; Fang, Yanhao; Xie, Qinjian; Wang, Meizhu; Li, Yang; Zhu, Hongmei; Li, Hongyu

doi:10.1016/j.ejps.2021.106017

Cited by 7 publications

(4 citation statements)

References 37 publications

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“…Time‐course analysis would be performed to monitor angiogenesis in control and BAY1143269‐treated tumors. Compared to studies that investigate inhibitors of tumor angiogenesis using endothelial cells (ECs) isolated from normal tissues, 20 , 21 microvascular endothelial cells used in our study are GMECs that are isolated and further purified from glioblastoma tissues from various patients, which are specific to glioblastoma angiogenesis and represent tumor angiogenesis. BAY1143269 is also active against glioblastoma cells by suppressing proliferation and inducing apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Preclinical anti‐angiogenic and anti‐cancer activities of BAY1143269 in glioblastoma via targeting oncogenic protein expression

Wan

Zhang²,

Huang

et al. 2022

Pharmacology Res & Perspec

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Glioblastoma angiogenesis is critical for tumor growth, making it an appealing target for treatment development. BAY1143269 is a novel inhibitor of mitogen‐activated protein kinase interacting serine/threonine‐protein kinase 1 (MKN1) and has potent anti‐cancer activity. We identified BAY1143269 as an angiogenesis inhibitor, by in vitro and in vivo glioblastoma angiogenesis models. BAY1143269 inhibited the capillary network formation of glioblastoma microvascular endothelial cells (GMECs), particularly the early stage of tubular structure formation. It also inhibited migration and proliferation, and induced apoptosis of GMECs isolated from glioblastoma patients. We found that BAY1143269 acted on GMECs by suppressing the eukaryotic translation initiation factor 4E (eIF4E) and eIF4E‐mediated expression of oncogenic proteins, including those involved in cell cycle, epithelial‐mesenchymal transition (EMT), and pro‐survival. In addition, BAY1143269 suppressed eIF4E phosphorylation, inhibited proliferation, and induced apoptosis of glioblastoma cells. Interestingly, it reduced vascular endothelial growth factor (VEGF) level in tumor cells and culturing medium, demonstrating the inhibitory effect of BAY1143269 on tumor proangiogenic microenvironment. We finally challenged BAY1143269 on the glioblastoma xenograft mice model and observed a significant tumor growth reduction without toxicity in mice receiving oral BAY1143269. Immunoblotting analysis demonstrated significantly less phosphorylated‐eIF4E (p‐eIF4E), cluster of differentiation 31 (CD31) (microvascular endothelial cell marker), and VEGF in tumors from drug‐treated mice. In summary, the inhibition of glioblastoma angiogenesis with BAY1143269 may provide an alternative approach for anti‐glioblastoma therapy.

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Section: Discussionmentioning

confidence: 99%

Preclinical anti‐angiogenic and anti‐cancer activities of BAY1143269 in glioblastoma via targeting oncogenic protein expression

Wan

Zhang²,

Huang

et al. 2022

Pharmacology Res & Perspec

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“…We review below the evidence supporting the multiple functions of integrins in HCC pathogenesis. EDIL3-integrin aVb3/ERK/TGF-b Promote migration, invasion, and angiogenesis [32] aVb5 KRAS V12 /fibrinogen-integrin aVb5 Activate HSC [71] POSTN/integrin aVb5/FAK/STAT3/ POSTN circuit Promote HCC cells proliferation [70] aMb2 M2 exos/integrin aMb2/MMP9 Support HCC cells migration [72] b3 TGF-b1/H 2 O 2 /HOCl Induction of metastatic phenotype of HCC [73] b4 Integrin b4/Slug/AKT/Sox2-Nanog Promote HCC cells invasion and EMT [74] Integrin b4/EGFR/FAK/AKT Promote HCC lung metastases [29] ZKSCAN3/integrin b4/FAK/AKT Promote HCC cells EMT [75] ADAM17: ADAM metallopeptidase domain SERPINA5/fibronectin-integrin b1 Inhibit tumor cells migration [77] a1b1 ANGPTL1-integrin a1b1/FAK/Src/JAK/STAT3 Suppress HCC angiogenesis and metastasis [78] a3b1 DPT/integrin a3b1/Rho GTPase Inhibit HCC metastasis [30] a4b1 SPON2/integrin a4b1/Rho GTPase-Hippo pathways Promote M1-like macrophage recruitment [75] a5b1 Fibulin-5-integrin a5b1 Block HCC angiogenesis [79] HM-3-HSA/HUVEC-integrin a5b1 Exhibit potent anti-angiogenesis and antitumor activity in HCC [80] a6 CCN1/integrin a6/ROS/p53 Inhibit the compensatory proliferation of HCC [81] aVb3 HM-3-HSA/HUVEC-Integrin aVb3 Exhibit potent anti-angiogenesis and antitumor activity in HCC [80] Fibulin-5-integrin aVb3 Inhibit HCC adhesion, migration, and invasion [79] aVb5 Fibulin-5-integrin aVb5 Inhibit HCC adhesion, migration, and invasion [79] b3 NDRG1/integrin b3 Inhibit the proliferation and invasion of HCC [82] a9 Integrin a9/FAK/Src-Rac1/RhoA signaling Prevent HCC cells migration and invasion…”

Section: Function Of Integrins In Hccmentioning

confidence: 99%

Integrins in human hepatocellular carcinoma tumorigenesis and therapy

Gao

Sun

Fang

2023

Chinese Medical Journal

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Integrins are a family of transmembrane receptors that connect the extracellular matrix and actin skeleton, which mediate cell adhesion, migration, signal transduction, and gene transcription. As a bi-directional signaling molecule, integrins can modulate many aspects of tumorigenesis, including tumor growth, invasion, angiogenesis, metastasis, and therapeutic resistance. Therefore, integrins have a great potential as antitumor therapeutic targets. In this review, we summarize the recent reports of integrins in human hepatocellular carcinoma (HCC), focusing on the abnormal expression, activation, and signaling of integrins in cancer cells as well as their roles in other cells in the tumor microenvironment. We also discuss the regulation and functions of integrins in hepatitis B virus-related HCC. Finally, we update the clinical and preclinical studies of integrin-related drugs in the treatment of HCC.

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“…35,36 Endothelial cells also participate in the process of angiogenesis which can be detected by multiple methods, including cell migration, invasion, and tube formation. 37,38 Moreover, data from cardiovascular outcome trials have shown that patients received a treatment with SGLT2 inhibitors have a lower risk of adverse cardiovascular events than those allocated to placebo. [39][40][41] Consistently, fundamental studies conducted on animals and cells have demonstrated that SGLT2 inhibitors protect endothelium and reduce cardiovascular damage.…”

Section: Ctrl Controlmentioning

confidence: 99%

Dapagliflozin improves pancreatic islet function by attenuating microvascular endothelial dysfunction in type 2 diabetes

Yang

et al. 2022

Diabetes Metabolism Res

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Aims Sodium‐glucose co‐transporter 2 inhibitors, including dapagliflozin, improve ß cell function in type 2 diabetic individuals. Whether dapagliflozin can protect islet microvascular endothelial cells (IMECs) and thus contribute to the improvement of ß cell function remains unknown. Materials and Methods The db/db mice were treated with dapagliflozin or vehicle for 6 weeks. ß cell function, islet capillaries and the levels of inflammatory chemokines in IMECs were detected. The mouse IMEC cell line MS‐1 cells were incubated with palmitate and/or dapagliflozin for 24 h. Angiogenesis and inflammatory chemokine levels were evaluated, and the involved signalling pathways were analysed. The mouse ß cell line MIN6 cells, in the presence or absence of co‐culture with MS‐1 cells, were treated with palmitate and/or dapagliflozin for 24 h. The expression of ß cell specific markers and insulin secretion in MIN6 cells were determined. Results Dapagliflozin significantly improved ß cell function, increased islet capillaries and decreased the levels of inflammatory chemokines of IMECs in db/db mice. In the palmitate‐treated MS‐1 cells, angiogenesis was enhanced and the levels of inflammatory chemokines were downregulated by dapagliflozin. Either a PI3K inhibitor or mTOR inhibitor eliminated the dapagliflozin‐mediated effects. Importantly, dapagliflozin attenuated the palmitate‐induced downregulation of ß cell function‐related gene expression and insulin secretion in MIN6 cells co‐cultured with MS‐1 cells but not in those on mono‐culture. Conclusions Dapagliflozin restores islet vascularisation and attenuates the inflammation of IMECs in type 2 diabetic mice. The dapagliflozin‐induced improvement of ß cell function is at least partially accounted for by its beneficial effects on IMECs in a PI3K/Akt‐mTOR‐dependent manner.

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HM-3-HSA exhibits potent anti-angiogenesis and antitumor activity in hepatocellular carcinoma

Cited by 7 publications

References 37 publications

Preclinical anti‐angiogenic and anti‐cancer activities of BAY1143269 in glioblastoma via targeting oncogenic protein expression

Preclinical anti‐angiogenic and anti‐cancer activities of BAY1143269 in glioblastoma via targeting oncogenic protein expression

Integrins in human hepatocellular carcinoma tumorigenesis and therapy

Dapagliflozin improves pancreatic islet function by attenuating microvascular endothelial dysfunction in type 2 diabetes

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