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A novel angiogenesis inhibitor impairs lovo cell survival via targeting against human VEGFR and its signaling pathway of phosphorylation.

ABSTRACT: Colorectal cancer represents the fourth commonest malignancy, and constitutes a major cause of significant morbidity and mortality among other diseases. However, the chemical therapy is still under development. Angiogenesis plays an important role in colon cancer development. We developed HMQ18-22 (a novel analog of taspine) with the aim to target angiogenesis. We found that HMQ18-22 significantly reduced angiogenesis of chicken chorioallantoic membrane (CAM) and mouse colon tissue, and inhibited cell migration and tube formation as well. Then, we verified the interaction between HMQ18-22 and VEGFR2 by AlphaScreen P-VEGFR assay, screened the targets on angiogenesis by VEGF Phospho Antibody Array, validated the target by western blot and RNAi in lovo cells. We found HMQ18-22 could decrease phosphorylation of VEGFR2(Tyr(1214)), VEGFR1(Tyr(1333)), Akt(Tyr(326)), protein kinase C? (PKC?) (Tyr(657)) and phospholipase-C?-1 (PLC?-1) (Tyr(771)). Most importantly, HMQ18-22 inhibited proliferation of lovo cell and tumor growth in a human colon tumor xenografted model of athymic mice. Compared with normal lovo cells proliferation, the inhibition on proliferation of knockdown cells (VEGFR2, VEGFR1, Akt, PKC? and PLC?-1) by HMQ18-22 decreased. These results suggested that HMQ18-22 is a novel angiogenesis inhibitor and can be a useful therapeutic candidate for colon cancer intervention.

SUBMITTER: Zhang YM

PROVIDER: S-EPMC3481133 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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A novel angiogenesis inhibitor impairs lovo cell survival via targeting against human VEGFR and its signaling pathway of phosphorylation.

Zhang Y M YM Dai B L BL Zheng L L Zhan Y Z YZ Zhang J J Smith W W WW Wang X L XL Chen Y N YN He L C LC

Cell death & disease 20121011

Colorectal cancer represents the fourth commonest malignancy, and constitutes a major cause of significant morbidity and mortality among other diseases. However, the chemical therapy is still under development. Angiogenesis plays an important role in colon cancer development. We developed HMQ18-22 (a novel analog of taspine) with the aim to target angiogenesis. We found that HMQ18-22 significantly reduced angiogenesis of chicken chorioallantoic membrane (CAM) and mouse colon tissue, and inhibite ...[more]

PMID: 23059825

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Project description:BackgroundLenvatinib is an oral inhibitor of multiple receptor tyrosine kinases (RTKs) targeting vascular endothelial growth factor receptor (VEGFR1-3), fibroblast growth factor receptor (FGFR1-4), platelet growth factor receptor ? (PDGFR ?), RET and KIT. Antiangiogenesis activity of lenvatinib in VEGF- and FGF-driven angiogenesis models in both in vitro and in vivo was determined. Roles of tumor vasculature (microvessel density (MVD) and pericyte coverage) as biomarkers for lenvatinib were also examined in this study.MethodWe evaluated antiangiogenesis activity of lenvatinib against VEGF- and FGF-driven proliferation and tube formation of HUVECs in vitro. Effects of lenvatinib on in vivo angiogenesis, which was enhanced by overexpressed VEGF or FGF in human pancreatic cancer KP-1 cells, were examined in the mouse dorsal air sac assay. We determined antitumor activity of lenvatinib in a broad panel of human tumor xenograft models to test if vascular score, which consisted of high MVD and low pericyte coverage, was associated with sensitivity to lenvatinib treatment. Vascular score was also analyzed using human tumor specimens with 18 different types of human primary tumors.ResultLenvatinib inhibited VEGF- and FGF-driven proliferation and tube formation of HUVECs in vitro. In vivo angiogenesis induced by overexpressed VEGF (KP-1/VEGF transfectants) or FGF (KP-1/FGF transfectants) was significantly suppressed with oral treatments of lenvatinib. Lenvatinib showed significant antitumor activity in KP-1/VEGF and five 5 of 7 different types of human tumor xenograft models at between 1 to 100?mg/kg. We divided 19 human tumor xenograft models into lenvatinib-sensitive (tumor-shrinkage) and relatively resistant (slow-growth) subgroups based on sensitivity to lenvatinib treatments at 100?mg/kg. IHC analysis showed that vascular score was significantly higher in sensitive subgroup than relatively resistant subgroup (p?<?0.0004). Among 18 types of human primary tumors, kidney cancer had the highest MVD, while liver cancer had the lowest pericyte coverage, and cancers in Kidney and Stomach had highest vascular score.ConclusionThese results indicated that Lenvatinib inhibited VEGF- and FGF-driven angiogenesis and showed a broad spectrum of antitumor activity with a wide therapeutic window. MVD and pericyte-coverage of tumor vasculature might be biomarkers and suggest cases that would respond for lenvatinib therapy.

Project description:Background and Objective: Cerebral infarction (CI) is a severe neurological disorder caused by localized disruption of blood supply to brain tissue, leading to high rates of disability and mortality. Circular RNAs (circRNAs), highly expressed in the brain, have been identified as potential therapeutic targets for CI. Although acupuncture has been shown to promote neurological recovery, the precise molecular mechanisms, particularly the role of circRNAs in regulating angiogenesis, remain insufficiently understood. This study is the first to demonstrate that electroacupuncture (EA) promotes angiogenesis by regulating the circRNA_011971/miR-196c-5p/ARL13B axis, enhancing the proliferation and migration of brain microvascular endothelial cells (BMECs), and accelerating angiogenesis. These findings provide new insights into the molecular mechanisms of acupuncture treatment for CI and identify potential therapeutic targets. Methods: Male Wistar rats were used to establish a cerebral infarction model via middle cerebral artery occlusion (MCAO). The rats were divided into a model group, an EA treatment group, and a control group. Immediately after MCAO induction, the EA group received acupuncture at the GV26 acupoint. Neurological deficits were assessed using the modified Neurological Severity Score (mNSS), and infarct volumes were measured using TTC staining. Immunofluorescence double staining was performed to detect angiogenesis markers CD31 and Ki67 in the peri-infarct area. CircRNA expression profiles in brain tissue were obtained through circRNA microarray analysis, and key circRNAs were validated via qRT-PCR and fluorescence in situ hybridization (FISH). In BMECs, circRNA_011971 knockdown was achieved using shRNA, and its biological functions were assessed through CCK8, wound healing, and transwell assays. The expression levels of Arl13b, VEGFA, and VEGFR2 were measured using qRT-PCR and Western blot after circRNA_011971 knockdown or overexpression. Molecular interactions among circRNA_011971, miR-196c-5p, and ARL13B were explored using dual-luciferase reporter assays, RNA immunoprecipitation (RIP), and co-immunoprecipitation (Co-IP). Results: Compared to the untreated group, the EA group exhibited significantly smaller infarct volumes, suggesting immediate EA treatment at GV26 following infarction can effectively limit infarct progression. Immunofluorescence analysis revealed a marked increase in the co-expression of CD31 and Ki67 in the peri-infarct region of the EA-treated rats, indicating enhanced angiogenesis. CircRNA microarray analysis showed that circRNA_011971 was significantly upregulated following ischemia and downregulated after EA treatment. In BMECs, circRNA_011971 knockdown inhibited cell proliferation, migration, and invasion, whereas its overexpression promoted these processes. Further mechanistic studies revealed that EA downregulated rno_circ_011971 expression, lifting its inhibition on miR-196c-5p and activating the ARL13B/VEGF signaling pathway, thereby significantly promoting angiogenesis. This study discover a molecular mechanism by which EA regulates post-CI angiogenesis through the circRNA/miRNA axis for the first time, offering new potential targets for acupuncture therapy. Conclusion: EA improves neurological function, reduces infarct size, and promotes angiogenesis, potentially through regulating of VEGFR via the rno_circ_011971/miR-196c-5p/ARL13B axis.

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A novel angiogenesis inhibitor impairs lovo cell survival via targeting against human VEGFR and its signaling pathway of phosphorylation.

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A novel angiogenesis inhibitor impairs lovo cell survival via targeting against human VEGFR and its signaling pathway of phosphorylation.

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