Synergistic effect of vascular endothelial growth factor and angiopoietin-2 on progression free survival in multiple myeloma

Bhaskar, Archana; Gupta, Ritu; Sreenivas, V.; Rani, Lata; Kumar, Lalit; Sharma, Atul; Sharma, Om Dutt; Sharma, Mehar Chand; Thakur, Sonu Chand

doi:10.1016/j.leukres.2012.12.014

Cited by 14 publications

(9 citation statements)

References 23 publications

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“…In this context miR-96-regulated VEGF and Ang2 play a critical role. Interestingly, studies have shown that VEGF and Ang-2 play a synergistic role in angiogenic stimulation (Bhaskar et al, 2013) and that conversely the dual inhibition of these factors leads to significant vascular failure (Coutelle et al, 2015;Regula et al, 2016). Consistently with our results, some studies have previously described a proangiogenic role of miR-96 in different cancer cell lines by targeting different genes with antiangiogenic functions.…”

Section: Discussionsupporting

confidence: 92%

MicroRNA-96 Promotes Vascular Repair in Oxygen-Induced Retinopathy—A Novel Uncovered Vasoprotective Function

et al. 2020

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Background and Aims: Vascular degeneration is a hallmark in the pathogenesis of oxygen-induced retinopathy (OIR). Dysregulation of microRNAs (miRNAs), key regulators of genes expressions, has been implicated in the regulation of ocular angiogenesis. However, miRNAs specific functions in impaired vascular development during OIR are poorly understood. Herein, we identified miR-96 as one of the most highly expressed miRNAs in the retina and choroid during vascular development and investigated the potential role of miR-96 on microvascular degeneration in a rat OIR model. Methods and Results: Next generation sequencing (NGS) and qRT-PCR analysis showed that miR-96 maintain high levels of expression during ocular vascular development. Nevertheless, miR-96 was significantly downregulated in the retina and choroid of OIR rats (80% O 2 from P5 to P10) during the phase of microvascular degeneration. Similarly, human retinal microvascular endothelial cells (HRMEC) subjected to hyperoxia (80% O 2) showed a significant downregulation of miR-96 evaluated by qPCR. Interestingly, HRMEC supplemented with miR-96 regulated positively the expression of several key angiogenic factors including VEGF and ANG-2. To explore the angiogenic activity of miR-96 on HRMEC, we performed a gain/loss of function study. In a similar way to hyperoxia exposure, we observed a robust angiogenic impairment (tubulogenesis and migration) on HRMEC transfected with an antagomiR-96. Conversely, overexpression of miR-96 stimulated the angiogenic activity of HRMEC and protected against hyperoxia-induced endothelial dysfunction. Finally, we evaluated the potential vasoprotective function of miR-96 in OIR animals. Rat pups intravitreally supplemented with miR-96 mimic (1 mg/kg) displayed a significant preservation of retinal/choroidal microvessels at P10 compared to controls. This result was consistent with the maintenance of physiologic levels of VEGF and ANG-2 in the OIR retina. Conclusion: This study demonstrates that miR-96 regulates the expression of angiogenic factors (VEGF/ANG-2) associated to the maintenance of retinal and choroidal microvasculature during physiological and pathological conditions. Intravitreal

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Section: Discussionsupporting

confidence: 92%

MicroRNA-96 Promotes Vascular Repair in Oxygen-Induced Retinopathy—A Novel Uncovered Vasoprotective Function

et al. 2020

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“…When bound to the receptor, VEGF stimulates endothelial cell (EC) proliferation, increased pulpal blood flow, and capillary hyperpermeability (10). In response to injury, VEGF is mainly secreted by ECs and also pulp fibroblasts and inflammatory cells (11); and elsewhere in the body, the release of VEGF synergistically influences the release of other angiogenic factors including angiopoietins (12,13).…”

Section: Introductionmentioning

confidence: 99%

Vascularity and Angiogenic Signaling in the Dentine-Pulp Complex of Immature and Mature Permanent Teeth

et al. 2019

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This study aimed to examine the protein and gene expression of vascular endothelial growth factor (VEGF) and angiopoietins-1 and 2 in tissue from healthy and inflamed dental pulps. Methods: Permanent teeth with pulps diagnosed as healthy or reversible pulpitis were used for immunohistochemistry (IHC) and gene expression experiments. For IHC, a whole pulp tissue was excavated from the pulp chamber, and it was formalin-fixed and processed for routine IHC with angiogenic markers anti-VEGF, anti-Ang1, and anti-Ang2. Staining was visualized with diaminobenzidine (DAB), and examined using light microscopy. The distribution of markers in healthy and inflamed pulps was qualitatively and quantitatively analyzed. Real-time quantitative polymerase chain reaction (RT qPCR) was used to ascertain the gene expression levels of ANGPT1, ANGPT2, and TEK in the presence of inflammation. Statistical analysis was performed using the Mann-Whitney test with the statistical significance level set at 0.05. Results: There was increased protein and mRNA expression of VEGF and Ang-1 markers in inflamed pulp samples as compared with that in the healthy pulp tissue. IHC demonstrated intense expression of the VEGF protein on endothelial cells (EC) and some non-ECs, and there was significantly more staining on ECs associated with inflamed tissue (P<0.001). Ang-1 and Ang-2 were significantly expressed on ECs and non-ECs (P<0.05). RT qPCR did not show significant differences in gene expression between healthy and inflamed samples although similar trends were observed to IHC. Conclusion: The presence of Ang-1, Ang-2, VEGF, and TEK gene in healthy and mildly inflamed pulp tissue associated with reversible pulpitis indicates that these angiogenic factors may participate in physiological and pathological angiogenesis and healing. The inflammatory process may regulate Ang-1/Ang2/Tie2 signaling; and together with VEGF, these growth factors have an important role in modulating pulp angiogenesis.

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“…The insufficient blood supply of the rapidly growing tumor tissues also induces hypoxia in the central region of the tumor. Hypoxia leads to the activation of hypoxia-inducible factor 1a (HIF-1a), which acts as the transcriptional factor for a variety of essential genes in the hypoxic microenvironment, including those encoding for VEGF and basic fibroblast growth factor (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Tirapazamine Sensitizes Hepatocellular Carcinoma Cells to Topoisomerase I Inhibitors via Cooperative Modulation of Hypoxia-Inducible Factor-1α

Cai

Liu

Zhu

et al. 2014

Molecular Cancer Therapeutics

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Topoisomerase I inhibitors are a class of anticancer drugs with a broad spectrum of clinical activity. However, they have limited efficacy in hepatocellular cancer. Here, we present in vitro and in vivo evidence that the extremely high level of hypoxia-inducible factor-1a (HIF-1a) in hepatocellular carcinoma is intimately correlated with resistance to topoisomerase I inhibitors. In a previous study conducted by our group, we found that tirapazamine could downregulate HIF-1a expression by decreasing HIF-1a protein synthesis. Therefore, we hypothesized that combining tirapazamine with topoisomerase I inhibitors may overcome the chemoresistance. In this study, we investigated that in combination with tirapazamine, topoisomerase I inhibitors exhibited synergistic cytotoxicity and induced significant apoptosis in several hepatocellular carcinoma cell lines. The enhanced apoptosis induced by tirapazamine plus SN-38 (the active metabolite of irinotecan) was accompanied by increased mitochondrial depolarization and caspase pathway activation. The combination treatment dramatically inhibited the accumulation of HIF-1a protein, decreased the HIF-1a transcriptional activation, and impaired the phosphorylation of proteins involved in the homologous recombination repair pathway, ultimately resulting in the synergism of these two drugs. Moreover, the increased anticancer efficacy of tirapazamine combined with irinotecan was further validated in a human liver cancer Bel-7402 xenograft mouse model. Taken together, our data show for the first time that HIF-1a is strongly correlated with resistance to topoisomerase I inhibitors in hepatocellular carcinoma. These results suggest that HIF-1a is a promising target and provide a rationale for clinical trials investigating the efficacy of the combination of topoisomerase I inhibitors and tirapazamine in hepatocellular cancers. Mol Cancer Ther; 13(3); 630-42. Ó2013 AACR.

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Synergistic effect of vascular endothelial growth factor and angiopoietin-2 on progression free survival in multiple myeloma

Cited by 14 publications

References 23 publications

MicroRNA-96 Promotes Vascular Repair in Oxygen-Induced Retinopathy—A Novel Uncovered Vasoprotective Function

MicroRNA-96 Promotes Vascular Repair in Oxygen-Induced Retinopathy—A Novel Uncovered Vasoprotective Function

Vascularity and Angiogenic Signaling in the Dentine-Pulp Complex of Immature and Mature Permanent Teeth

Tirapazamine Sensitizes Hepatocellular Carcinoma Cells to Topoisomerase I Inhibitors via Cooperative Modulation of Hypoxia-Inducible Factor-1α

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