The Novel Antitubulin Agent TR-764 Strongly Reduces Tumor Vasculature and Inhibits HIF-1α Activation

Porcù, Elena; Persano, Luca; Ronca, Roberto; Mitola, Stefania; Bortolozzi, Roberta; Romagnoli, Romeo; Oliva, Paola; Basso, Giuseppe; Viola, Giampietro

doi:10.1038/srep27886

Cited by 9 publications

(13 citation statements)

References 43 publications

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“…Fig. S3A) [38,39]. As a further confirmation, we observed a strong impairment of GBM cell migration across transwell inserts upon BMP9 treatment ( Fig.…”

Section: Bmp9 Impairs Cell Proliferation Migration and Invasion In Vsupporting

confidence: 72%

“…Capillary tube formation assay 3 × 10 4 GBM cells were pre-treated for 10 days with BMP9 every other day at 30 ng/ml and then seeded over Matrigel matrix (Basement membrane matrix, BD Biosciences, Franklin Lakes, NJ) to allow the capillary tubes to form within 24 h, as previously described [39]. Images were acquired with a Nikon SMZ1500 microscope (Nikon, Melville, NY) and then analyzed by using ImageJ software (Angiogenesis plug-in; https://imagej.nih.gov) and accounting for the number of meshes and branches of the capillary structures, as described [38].…”

Section: Flow Cytometry and Immunofluorescence Of Cultured Cellsmentioning

confidence: 99%

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BMP9 counteracts the tumorigenic and pro-angiogenic potential of glioblastoma

et al. 2018

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Glioblastoma multiforme (GBM) is a highly vascularized and aggressive brain tumor, with a strong ability to disseminate and invade the surrounding parenchyma. In addition, a subpopulation of GBM stem cells has been reported to possess the ability to transdifferentiate into tumor-derived endothelial cells (TDECs), supporting the resistance to anti-angiogenic treatments of newly formed blood vessels. Bone Morphogenetic Protein 9 (BMP9) is critically involved in the processes of cancer cell differentiation, invasion and metastasis, representing a potential tool in order to impair the intrinsic GBM aggressiveness. Here we demonstrate that BMP9 is able to trigger the activation of SMADs in patient-derived GBM cells, and to strongly inhibit proliferation and invasion by reducing the activation of PI3K/AKT/MAPK and RhoA/Cofilin pathways, respectively. Intriguingly, BMP9 treatment is sufficient to induce a strong differentiation of GBM stem-like cells and to significantly counteract the already reported process of GBM cell transdifferentiation into TDECs not only in in vitro mimicked TDEC models, but also in vivo in orthotopic xenografts in mice. Additionally, we describe a strong BMP9-mediated inhibition of the whole angiogenic process engaged during GBM tumor formation. Based on these results, we believe that BMP9, by acting at multiple levels against GBM cell aggressiveness, can be considered a promising candidate, to be further developed, for the future therapeutic management of GBM.

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“…Fig. S3A) [38,39]. As a further confirmation, we observed a strong impairment of GBM cell migration across transwell inserts upon BMP9 treatment ( Fig.…”

Section: Bmp9 Impairs Cell Proliferation Migration and Invasion In Vsupporting

confidence: 72%

Section: Flow Cytometry and Immunofluorescence Of Cultured Cellsmentioning

confidence: 99%

BMP9 counteracts the tumorigenic and pro-angiogenic potential of glioblastoma

et al. 2018

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“…Endothelial cell vessel formation was carried out as described (Porcu et al, 2016). EA.hy926 human endothelial cells were seeded on Matrigel (BD Biosciences, San Jose, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

Network Pharmacology-Guided Development of a Novel Integrative Regimen to Prevent Acute Graft-vs.-Host Disease

et al. 2018

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Lapses in the graft-vs.-host disease (GVHD) prophylaxis and side effects of current standard care following allogeneic hematopoietic stem cell transplantation (allo-HSCT) call for novel regimens. Traditional approaches targeting T cells showed limited success in preventing acute GVHD (aGVHD). System medicine showed promising results treating complex diseases such as sepsis and multi-organ dysfunction syndrome (MODS). Adapting established network pharmacology analysis methods, we aimed to develop novel integrative regimens to prevent aGVHD. Our network pharmacology analysis predicted that Xuebijing injection (XBJ) targets a series of key node proteins in aGVHD network. It also unveiled that Salviae miltiorrhizae (Danshen), an herb in Xuebijing formula, which prevented aGVHD in rats, shares five out of six key GVHD node proteins targeted by XBJ. Interestingly, network pharmacology analysis indicated Xuebijing may share multiple aGVHD targets with Cyclosporin A (CsA), a first-line drug for preventing aGVHD in the clinic. Based on current information, we hypothesized that combination of XBJ and CsA may yield superior results in aGVHD prevention than either drug alone. We performed in vitro and in vivo assays to validate the predictions by the network pharmacology analysis. In vitro assays revealed XBJ prevented platelet aggregation and NF-κB nuclear translocation in macrophages. XBJ also promoted angiogenesis in tube-formation assay. Importantly, the combination of CsA and XBJ was effective in rescuing mice subjected to lethal GVHD. XBJ contributed to the rescue through preventing NF-κB nuclear translocation, attenuating inflammation and maintaining viability of macrophages. Overall, network pharmacology is a powerful tool to develop novel integrative regimens. Combination of XBJ and CsA may shed light on preventing aGVHD.

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“…Derivative 6g had antivascular effects in vitro. Recent antitumor strategies have included the use of chemotherapeutics with antiangiogenic or antivascular drugs to increase the efficacy of the treatment, 4 and, in this context, many tubulin binding agents show antivascular effects against tumor endothelium, [46][47][48][49] including CA-4. For that reason, we evaluated 6g for its effects on endothelial cells…”

Section: Molecular Modelingmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of 6-Substituted Thieno[3,2-d]pyrimidine Analogues as Dual Epidermal Growth Factor Receptor Kinase and Microtubule Inhibitors

et al. 2019

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The clinical evidence for the success of tyrosine kinase inhibitors in combination with microtubule-targeting agents prompted us to design and develop single agents that possess both epidermal growth factor receptor (EGFR) kinase and tubulin polymerization inhibitory properties. A series of 6-aryl/heteroaryl-4-(3′,4′,5′-trimethoxyanilino)thieno[3,2-d]pyrimidine derivatives were discovered as novel dual tubulin polymerization and EGFR kinase inhibitors. The 4-(3′,4′,5′-trimethoxyanilino)-6-(p-tolyl)thieno[3,2-d]pyrimidine derivative 6g was the most potent compound of the series as an antiproliferative agent, with half-maximal inhibitory concentration (IC50) values in the single- or double-digit nanomolar range. Compound 6g bound to tubulin in the colchicine site and inhibited tubulin assembly with an IC50 value of 0.71 μM, and 6g inhibited EGFR activity with an IC50 value of 30 nM. Our data suggested that the excellent in vitro and in vivo profile of 6g may be derived from its dual inhibition of tubulin polymerization and EGFR kinase.

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The Novel Antitubulin Agent TR-764 Strongly Reduces Tumor Vasculature and Inhibits HIF-1α Activation

Cited by 9 publications

References 43 publications

BMP9 counteracts the tumorigenic and pro-angiogenic potential of glioblastoma

BMP9 counteracts the tumorigenic and pro-angiogenic potential of glioblastoma

Network Pharmacology-Guided Development of a Novel Integrative Regimen to Prevent Acute Graft-vs.-Host Disease

Design, Synthesis, and Biological Evaluation of 6-Substituted Thieno[3,2-d]pyrimidine Analogues as Dual Epidermal Growth Factor Receptor Kinase and Microtubule Inhibitors

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