The vascular disrupting activity of OXi8006 in endothelial cells and its phosphate prodrug OXi8007 in breast tumor xenografts

Strecker, Tracy E.; Odutola, Samuel O.; Lopez, Ramona; Cooper, Morgan S.; Tidmore, Justin K.; Charlton-Sevcik, Amanda K.; Li, Li; MacDonough, Matthew T.; Hadimani, Mallinath B.; Ghatak, Anjan; Liu, Li; Chaplin, David J.; Mason, Ralph P.; Pinney, Kevin G.; Trawick, Mary Lynn

doi:10.1016/j.canlet.2015.08.021

Cited by 28 publications

(37 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Given this effect, to better underlie the functional activity of the drug, we investigated the capability of HUVEC cells to adhere to the substrate. TR-764 alone, as reported for other VDAs14, was able to induce an increase in cell adhesion (Fig. 4B).…”

Section: Resultssupporting

confidence: 82%

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

Porcù

Persano

Ronca

et al. 2016

Sci Rep

View full text Add to dashboard Cite

Tubulin binding agents (TBAs) are commonly used in cancer therapy as antimitotics. It has been described that TBAs, like combretastatin A-4 (CA-4), present also antivascular activity and among its derivatives we identified TR-764 as a new inhibitor of tubulin polymerization, based on the 2-(alkoxycarbonyl)-3-(3′,4′,5′-trimethoxyanilino)benzo[b]thiophene molecular skeleton. The antiangiogenic activity of TR-764 (1–10 nM) was tested in vitro on human umbilical endothelial cells (HUVECs), and in vivo, on the chick embryo chorioallantoic membrane (CAM) and two murine tumor models. TR-764 binding to tubulin triggers cytoskeleton rearrangement without affecting cell cycle and viability. It leads to capillary tube disruption, increased cell permeability, and cell motility reduction. Moreover it disrupts adherens junctions and focal adhesions, through mechanisms involving VE-cadherin/β-catenin and FAK/Src. Importantly, TR-764 is active in hypoxic conditions significantly reducing HIF-1α. In vivo TR-764 (1–100 pmol/egg) remarkably blocks the bFGF proangiogenic activity on CAM and shows a stronger reduction of tumor mass and microvascular density both in murine syngeneic and xenograft tumor models, compared to the lead compound CA-4P. Altogether, our results indicate that TR-764 is a novel TBA with strong potential as both antivascular and antitumor molecule that could improve the common anticancer therapies, by overcoming hypoxia-induced resistance mechanisms.

show abstract

Section: Resultssupporting

confidence: 82%

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

Porcù

Persano

Ronca

et al. 2016

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Vascular disrupting agents (VDAs) are potential anti-cancer agents that selectively destroy the pre-existing tumor vasculature and cause rapid and pronounced shutdown of blood flow in tumors, resulting in a large area of tumor ischemia and central necrosis 1 , 2 . VDAs have been shown to possess potential preclinical activity in many types of cancer, including ovarian cancer, non-small cell lung carcinoma and sarcoma 3 .…”

Section: Introductionmentioning

confidence: 99%

Desacetylvinblastine Monohydrazide Disrupts Tumor Vessels by Promoting VE-cadherin Internalization

et al. 2018

View full text Add to dashboard Cite

Vinca alkaloids, the well-known tubulin-binding agents, are widely used for the clinical treatment of malignant tumors. However, little attention has been paid to their vascular disrupting effects, and the underlying mechanisms remain largely unknown. This study aims to investigate the vascular disrupting effect and the underlying mechanisms of vinca alkaloids.Methods: The capillary disruption assay and aortic ring assay were performed to evaluate the in vitro vascular disrupting effect of desacetylvinblastine monohydrazide (DAVLBH), a derivate of vinblastine, and the in vivo vascular disrupting effect was assessed on HepG2 xenograft model using magnetic resonance imaging, hematoxylin and eosin staining and immunohistochemistry. Tubulin polymerization, endothelial cell monolayer permeability, western blotting and immunofluorescence assays were performed to explore the underlying mechanisms of DAVLBH-mediated tumor vascular disruption.Results: DAVLBH has potent vascular disrupting activity both in vitro and in vivo. DAVLBH disrupts tumor vessels in a different manner than classical tubulin-targeting VDAs; it inhibits microtubule polymerization, promotes the internalization of vascular endothelial cadherin (VE-cadherin) and inhibits the recycling of internalized VE-cadherin to the cell membrane, thus increasing endothelial cell permeability and ultimately resulting in vascular disruption. DAVLBH-mediated promotion of VE-cadherin internalization and inhibition of internalized VE-cadherin recycling back to the cell membrane are partly dependent on inhibition of microtubule polymerization, and Src activation is involved in DAVLBH-induced VE-cadherin internalization.Conclusions: This study sheds light on the tumor vascular disrupting effect and underlying mechanisms of vinca alkaloids and provides new insight into the molecular mechanism of tubulin-targeting VDAs.

show abstract

“…Chemical modification can be considered for currently abandoned compounds or newly developed ones beyond the drug‐likeness space. Drug latentiation and pro‐drug formation is a classical approach to circumvent structure‐related problems via esterification, amidation, benzylation of carboxylic acid or hydroxy/amino functional groups as well as salt formation . Other chemical modification strategies include chemical substitutions to reduce molecular weight and conjugation to carrier molecule…”

Section: Chemical and Pharmaceutical Solutionsmentioning

confidence: 99%

Chemical structure modifications and nano‐technology applications for improving ADME‐Tox properties, a review

Farouk

Shamma

2019

Archiv der Pharmazie

View full text Add to dashboard Cite

The chemical structure of a drug molecule affects its physicochemical properties and subsequent biological activities. Many pharmacologically active molecules fail to reach the market or have an inconvenient route of administration due to their chemical structure. This is especially important with the recent tendency to develop drug candidates beyond the drug-likeness space for addressing difficult targets such as protein-protein interfaces. The objective of this review is to discuss chemical and pharmaceutical approaches for circumventing structure-related problems and achieving acceptable ADME-Tox properties. The chemical structure-associated limitations are critically discussed. Chemical modifications and pharmaceutical technology applications for improving drug-likeness are illustrated. Attention is paid to modern therapeutic candidates and targets. In conclusion, chemical modifications as well as nanotechnology applications can be used effectively to enhance absorption, permeability, and selective distribution to a body compartment, to improve drug specificity, to limit off-target toxicity as well as to enhance stability and to protect against metabolism. The nano-technology-based solutions are relatively easier to develop over a new molecular entity, but adopting the chemical approach is more established in terms of safety, quality control, and regulatory assessment methods. K E Y W O R D Sblood-brain barrier, cancer tissue delivery, drug delivery, drug targeting, protein-protein interaction

show abstract

The vascular disrupting activity of OXi8006 in endothelial cells and its phosphate prodrug OXi8007 in breast tumor xenografts

Cited by 28 publications

References 44 publications

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

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

Desacetylvinblastine Monohydrazide Disrupts Tumor Vessels by Promoting VE-cadherin Internalization

Chemical structure modifications and nano‐technology applications for improving ADME‐Tox properties, a review

Contact Info

Product

Resources

About