Alteration of the HIF-1α/VEGF Signaling Pathway and Disruption of the Cell Cycle by Second Generation Carbosilan Dendrimers

Abstract

Current therapies against prostate cancer (PCa) disease, such as surgery, radiotherapy, or in last term chemical castration by androgen deprivation, have led to significant reduction of the incidence of PCa throughout the world. Worse prognosis is found in those patients which exhibit castration resistance, relapsing into the disease with even greater aggressiveness. Hypoxia cancer cell adaption has been observed to be closely connected to fatal prognostic tumor features. Therefore, hypoxia adaptive mechanisms of cancer cells have attracted large interest as a relevant biological target for treatment-resistant patients. Dendrimers have been established as a promising nanotechnological tool owing to their beneficial physicochemical features such as multivalency and monodispersity. Herein, we have completed a thorough study to better understand the effect within the cell of the already published ruthenium(II)-N-heterocyclic carbene metallodendrimer (G 2 Ru) that was able to drastically reduce HIF-1α stabilization and exhibited antiproliferative capability against androgen-sensitive (LNCaP) and androgen-resistant prostate cancer cells (LNFLU) in vitro. G 2 Ru, as well as its cationic imidazolium precursor (G 2 P), displayed scavenging properties against intracellular and externally stimulated ROS levels, which would presumably hinder the stabilization of HIF-1α by prolyl hydroxylase (PHD) inhibition. Furthermore, these dendrimers have shown considerably beneficial properties against tumor progression capability in terms of apoptosis, cell cycle, CSCs expression, and epithelial phenotype promotion. Taken all together, in this study we could demonstrate the extraordinary anticancer properties of NHC-based carbosilane dendrimers against androgen-resistant prostate cancer cells in vitro.

Network pharmacology and bioinformatics analysis identifies potential therapeutic targets of Naringenin against COVID-19/LUSC

“…All targets of naringenin were obtained from Nine open-source databases, namely, BATMAN ( 1 ), CTD (326), DGIdb ( 6 ), ETCM ( 44 ), PharmMapper (299), STITCH ( 13 ), Swiss ( 65 ), SymMap ( 65 ), and TCMIP ( 44 ). And 568 targets related to naringenin were acquired after eliminating duplicate targets ( Figure 2A ).…”

“…HIF-1 is a fibroblast master regulator of lipid metabolism that contributes to a tumor-promoting phenotype in lung fibroblasts ( 104 ). Therapy for lung cancer may benefit from focusing on the HIF-1/SCD1 axis in CAFs ( 65 ). HIF-1 is thus a potential target in research against COVID-19/LUSC due to the importance of HIF-1 stabilization in tumor progression.…”