Low Dose of Penfluridol Inhibits VEGF-Induced Angiogenesis

Abstract

Metastasis is considered a major burden in cancer, being responsible for more than 90% of cancer-related deaths. Tumor angiogenesis is one of the main processes that lead to tumor metastasis. Penfluridol is a classic and commonly used antipsychotic drug, which has a great ability to cross the blood–brain barrier. Recent studies have revealed that penfluridol has significant anti-cancer activity in diverse tumors, such as metastatic breast cancer and glioblastoma. Here, we aim to identify the effect of low doses of penfluridol on tumor microenvironment and compare it with its effect on tumor cells. Although low concentration of penfluridol was not toxic for endothelial cells, it blocked angiogenesis in vitro and in vivo. In vitro, penfluridol inhibited VEGF-induced primary endothelial cell migration and tube formation, and in vivo, it blocked VEGF- and FGF-induced angiogenesis in the matrigel plug assay. VEGF-induced VEGFR2 phosphorylation and the downstream p38 and ERK signaling pathways were not affected in endothelial cells, although VEGF-induced Src and Akt activation were abrogated by penfluridol treatment. When cancer cells were treated with the same low concentration of penfluridol, basal Src activation levels were mildly impaired, thus impacting their cell migration and wound healing efficiency. The potential of cancer-induced paracrine effect on endothelial cells was explored, although that did not seem to be a player for angiogenesis. Overall, our data demonstrates that low penfluridol levels, similar to the ones clinically used for anti-psychotic conditions, suppress angiogenic efficiency in the tumor microenvironment.

Coaxially Bioprinted Cell-Laden Tubular-Like Structure for Studying Glioma Angiogenesis

“…In particular, when the two types of cells were cocultured in a 3D hydrogel microenvironment, they showed satisfactory proliferation ability and reached the maximum on day 7. As described previously, VEGF promotes angiogenesis and increases vascular permeability, which plays a pivotal role in tumor angiogenesis (Srivastava et al, 2020). In particular, VEGFA is a major player in physiological and tumor-induced angiogenesis, and numerous human tumors, including GBM, have shown VEGFA overexpression (Andreozzi et al, 2014).…”

The complex relationship between integrins and oncolytic herpes Simplex Virus 1 in high-grade glioma therapeutics

“… 60 , 115 In addition, PF has been shown to modulate the immunosuppressive TME in GBM by lowering the expression of MDSCs and increasing the expression of M1 macrophages 116 as well as regulating angiogenesis by inhibiting the VEGF-signaling pathway in ECs. 117 The specificity of PF as an integrin-targeting drug is not fully understood and therefore would be worthwhile to investigate in order to understand its implications in tumor and immune cells. Additionally, data have not yet been published showing the survival benefits of PF as a single agent in vivo, but the combination of PF with TMZ has shown sensitization of GSCs to the alkylating agent.…”

Fabrication of Vascular Grafts Using Poly(ε-Caprolactone) and Collagen-Encapsuled ADSCs for Interposition Implantation of Abdominal Aorta in Rhesus Monkeys

“…Collagen has been served as a biodegradable scaffold material and extensively employed in research on vascular regeneration studies, supporting and promoting angiogenesis . Prior research has shown that collagen regulates the migration and adhesion of endothelial cells by furnishing cell adhesion sites and facilitating cell-to-cell interactions. , Through binding to cell receptors, collagen initiates a cascade of cellular signaling pathways that impact various functions, including the survival, proliferation, and migration of vascular endothelial cells. , Additionally, collagen can modulate inflammatory responses, contributing to wound healing and the reconstruction of endothelial function . ADSCs are a type of multipotent stem cell found in adipose tissue, possessing the potential for multilineage differentiation.…”

“…30,31 Through binding to cell receptors, collagen initiates a cascade of cellular signaling pathways that impact various functions, including the survival, proliferation, and migration of vascular endothelial cells. 32,33 Additionally, collagen can modulate inflammatory responses, contributing to wound healing and the reconstruction of endothelial function. 34 ADSCs are a type of multipotent stem cell found in adipose tissue, possessing the potential for multilineage differentiation.…”