Apatinib inhibits VEGF signaling and promotes apoptosis in intrahepatic cholangiocarcinoma

Peng, Hong; Zhang, Qiuyang; Li, Jiali; Zhang, Ning; Hua, Yunpeng; Xu, Lixia; Deng, Yong; Lai, Jiaming; Peng, Zhenwei; Peng, Baogang; Chen, Minhu; Peng, Sui

doi:10.18632/oncotarget.7948

Cited by 117 publications

(96 citation statements)

References 23 publications

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“…32 Recent studies have reported the possible molecular mechanisms involved in the direct anticancer action of apatinib in various cancer cell lines. [33][34][35] These findings suggested that apatinib may also have the potential to directly suppress HCC cell growth. As shown in the present study, the expression of VEGFR-2 was markedly higher in 6 HCC cell lines compared to normal controls.…”

Section: Discussionmentioning

confidence: 90%

“…VEGF/VEGFR signaling is required in tumor cells to stimulate their proliferation and invasive growth in an autocrine and angiogenesis‐dependent manner . Recent studies have reported the possible molecular mechanisms involved in the direct anticancer action of apatinib in various cancer cell lines . These findings suggested that apatinib may also have the potential to directly suppress HCC cell growth.…”

Section: Discussionmentioning

confidence: 99%

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Apatinib targets both tumor and endothelial cells in hepatocellular carcinoma

Yang

Qin

2018

Cancer Medicine

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Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed malignancies worldwide with poor prognosis and tends to be hypervascular. Aberrant expression of the vascular endothelial growth factor 2 (VEGFR‐2) has been implicated in the progression of HCC and represents a valid target for anticancer therapy. Apatinib, a small molecule inhibitor of VEGFR‐2 tyrosine kinase, shows strong antitumor activity in various tumors. This study is designed to evaluate the activity of apatinib on both human umbilical vein vascular endothelial cells (HUVECs) and HCC cell lines (in vitro and in vivo), and also to investigate the characteristics and possible mechanisms underlying these effects by molecular biology methods. Following the results in our study, apatinib inhibited phosphorylation of VEGFR‐2 in HUVECs and blocked in vitro endothelial cell migration and tube formation. Concentration‐dependent antiproliferative effects of apatinib were also observed in all 6 HCC cell lines including SK‐Hep‐1, HepG2, Hep3B, Huh‐7, PLC/PRF/5, SMMC‐7721. Moreover, response to apatinib of HCC cell lines was significantly correlated with VEGFR‐2 expression level. Additionally, apatinib significantly inhibit VEGF‐triggered VEGFR‐2 phosphorylation and activation of downstream signaling molecules such as Akt and ERK1/2 in HCCs. Apatinib can also induce a cell cycle arrest at G2/M phase and promote HCC apoptosis tested in vitro. In vivo data showed that apatinib can effectively inhibit tumor growth, decreased angiogenesis, as well as induced HCC apoptosis (in some tumors), and thus prolonged animal survival in a mouse xenograft model of human HCC. Our findings suggested that apatinib is a highly potent, oral active anti‐angiogenic, and anti‐HCC agent. The results from current study provide a clear biological rationale to evaluate apatinib as a new agent in HCC in clinical setting, especially for the VEGFR‐2 overexpression ones.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Apatinib targets both tumor and endothelial cells in hepatocellular carcinoma

Yang

Qin

2018

Cancer Medicine

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“…Apatinib, also known as YN968D1, is a small molecule TKI that mainly targets VEGFR‐2 through the intracellular ATP‐binding site that inhibits all VEGF‐stimulated endothelial cell migration and proliferation, decreases tumor microvascular density, and promotes apoptosis . On 17 October 17, 2014, apatinib was approved by the cFDA as a third or subsequent‐line therapy for advanced or metastatic chemo‐refractory gastric cancer .…”

Section: Discussionmentioning

confidence: 99%

“…44,45 Apatinib, also known as YN968D1, is a small molecule TKI that mainly targets VEGFR-2 through the intracellular ATP-binding site that inhibits all VEGF-stimulated endothelial cell migration and proliferation, decreases tumor microvascular density, and promotes apoptosis. [46][47][48] On 17 October 17, 2014, apatinib was approved by the cFDA as a third or subsequent-line therapy for advanced or metastatic chemo-refractory gastric cancer. 49 Both preclinical and clinical studies have shown that apatinib has promising efficacy, convenient oral administration methods, and manageable AEs in the treatment of a variety of solid tumors.…”

Section: Discussionmentioning

confidence: 99%

Clinical investigation of the efficacy and toxicity of apatinib (YN968D1) in stage III/IV non‐small cell lung cancer after second‐line chemotherapy treatment: A retrospective study

Zhang

Huang

et al. 2018

Thoracic Cancer

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BackgroundThis study was designed to assess the clinical efficacy and toxicity of apatinib (YN968D1) as third or subsequent‐line treatment for stage III/IV non‐small cell lung cancer (NSCLC).MethodsA total of 100 patients with advanced NSCLC who were treated with apatinib at a daily dose of 250/425/500 mg at Shandong Cancer Hospital from January 2016 to June 2018 were enrolled in our study. The objective response, disease control, and median progression‐free survival rates were reviewed and evaluated. Univariate and multivariate analyses were performed to determine the prognostic factors. The main adverse events were evaluated per the Common Terminology Criteria for Adverse Events version 4.0.ResultsAll patients were assessable for response. No complete responses were observed, 11 patients achieved a partial response, and 56 showed stable disease. The objective response rate was 11.0%, the disease control rate was 67.0%, and the median progression‐free survival was 2.93 months (95% confidence interval 2.07–3.87). In Cox regression analysis, the Eastern Cooperative Oncology Group performance status score (hazard ratio 1.799; P < 0.05) and smoking history (hazard ratio 1.958; P < 0.05) were predictive indicators for apatinib treatment efficacy. Treatment‐related adverse events were tolerated, predictable, reversible, and controllable.ConclusionApatinib was found to be both effective and safe in advanced NSCLC patients without a genetic driver mutation who experienced progression after two or more lines of chemotherapy treatment.

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“…Apatinib was obtained from Jiangsu Hengrui Medicine Co. Purified water was produced by a Milli-Q system (Millipore). [1,[2][3][4][5][6][7][8][9][10][11][12][13] C 2 ] Myristic acid, methoxyamine hydrochloride (purity 98%), alkane solution (C8-C40), and pyridine (99.8% GC) were purchased from Sigma-Aldrich. MSTFA (N-methyl-N-trimethylsilyltrifluoroacetamide) and 1% TMCS (trimethylchlorosilane) were obtained from Pierce Chemical Company.…”

Section: Reagents and Chemicalsmentioning

confidence: 99%

Apatinib induces 3‐hydroxybutyric acid production in the liver of mice by peroxisome proliferator‐activated receptor α activation to aid its antitumor effect

Feng

Wang

et al. 2019

Cancer Science

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Apatinib, an antiangiogenic agent, shows efficient antitumor activity in a broad range of malignancies. Considering tumor is a type of metabolic disease, we investigated the metabolomics changes in serum and tumor after apatinib treatment and the molecular mechanism of characteristic changes associated with its antitumor efficacy. Molecules in serum and tumor tissue were extracted and analyzed by a gas chromatography‐mass spectrometry metabolic platform. Apatinib significantly inhibited e tumor growth and alleviated metabolic rearrangement in both serum and tumor of A549 xenograft mice. Among these endogenous metabolites, 3‐hydroxybutyric acid (3‐HB) was significantly increased in serum, tumor and liver after apatinib treatment. Interestingly, giving exogenous 3‐HB also inhibited tumor growth. Gene expression, dual luciferase reporter gene assay and molecular docking analysis all indicated that apatinib could induce 3‐HB production through the dependent activation of peroxisome proliferator‐activated receptor α (PPARα) and promotion of fatty acid utilization in the liver. Therefore, increased content of 3‐HB induced by PPARα activation in the liver partially contributed to the antitumor effect of apatinib. It may provide clues to another potential mechanism underlying the antitumor effect of apatinib besides its antiangiogenic effect through inhibiting vascular endothelial growth factor receptor 2.

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Apatinib inhibits VEGF signaling and promotes apoptosis in intrahepatic cholangiocarcinoma

Cited by 117 publications

References 23 publications

Apatinib targets both tumor and endothelial cells in hepatocellular carcinoma

Apatinib targets both tumor and endothelial cells in hepatocellular carcinoma

Clinical investigation of the efficacy and toxicity of apatinib (YN968D1) in stage III/IV non‐small cell lung cancer after second‐line chemotherapy treatment: A retrospective study

Apatinib induces 3‐hydroxybutyric acid production in the liver of mice by peroxisome proliferator‐activated receptor α activation to aid its antitumor effect

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