Azithromycin effectively inhibits tumor angiogenesis by suppressing vascular endothelial growth factor receptor 2-mediated signaling pathways in lung cancer

Abstract

Tumor angiogenesis is essential during lung cancer development and targeting angiogenesis may possess a potential therapeutic value. The present study demonstrates that azithromycin, a Food and Drug Administration-approved antibiotic drug, is a novel tumor angiogenesis inhibitor. Azithromycin inhibits capillary network formation of human lung tumor associated-endothelial cells (HLT-ECs) in vitro and in vivo. It significantly inhibits HLT-EC adhesion and vascular endothelial growth factor (VEGF)-induced proliferation of HLT-ECs in a dose-dependent manner without affecting migration. In addition, azithromycin induces apoptosis of HLT-ECs even in the presence of VEGF. Notably, azithromycin inhibits proliferation and induces apoptosis in multiple lung cancer cell lines to a significantly reduced extent compared with in HLT-ECs, suggesting that HLT-ECs are more susceptible to azithromycin treatment. In a lung tumor xenograft model, azithromycin significantly inhibits tumor growth and its anti-tumor activities are achieved by suppressing angiogenesis. Notably, the inhibitory effects of azithromycin on angiogenesis are associated with its ability to suppress VEGF-induced activation of VEGF receptor 2 (VEGFR2), phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), focal adhesion kinase, and disruption of focal adhesion assembly and actin stress fiber formation in HLT-ECs. The present study identifies that azithromycin targets VEGFR2-mediated focal adhesion and PI3K/Akt signaling pathways in HLT-ECs, leading to the suppression of angiogenesis and lung tumor growth.

Utilizing network pharmacology to explore the underlying mechanism of Radix Salviae in diabetic retinopathy

“…KDR modulates angiogenic responses such as endothelial cell migration and proliferation. VEGF acts through high-affinity receptors and some consist of KDR [34].…”

Identification and genetic validation of drug-comorbidity interactions in type 2 diabetes using data-driven disease trajectory analysis

“…Bacitracin, azithromycin, and lidocaine protected against 'Neoplasm excl. benign' (HR=0.67, adjusted p=0.016; HR=0.72, adjusted p=0.00041; HR=0.80, adjusted p=0.029; respectively) [39][40][41] . Clopidogrel and hydroxyzine were protective against 'Retinal detachments; defects; vascular occlusion; and retinopathy' (HR=0.80, adjusted p=0.025; HR=0.52, adjusted p=0.017; respectively) 42,43 .…”

Manipulation of immune‒vascular crosstalk: new strategies towards cancer treatment

“…Here we reviewed the strategies to enhance delivery efficiency and efficacy of nanomedicine by focusing on normalization of vasculature and the enhancement of extravasation of nanomedicine into tumors. By presenting insights into the basics of nanomedicine–vasculature interactions in tumors, we hope it would provide novel strategies to engineer cancer nanomedicine to accelerate their translation and fulfill the promises of this field ( Table 2 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 ).…”

“… Target/strategy Cargo/engineered nanoparticle Ref. Nanomedicine to normalize tumor vasculature Angiogenesis signalling pathway VEGFA-VEGFR2 Knockdown of VEGFA by: siRNA/PLCP 94 siRNA/PEI-SWNTs 95 shRNA/dtACPP-modified PEG-DGL 96 Inhibition of VEGFR2 by: Antibody/MSV 97 Ang2 Knockdown of Ang2 by: siRNA/chitosan magnetic nanoparticles 98 Blockage of Ang2-Tie2 interaction by: T4 peptide (K(DEAP)-AAN-NLLMAAS)/PEG 99 PDGF PDGF/PLGA–pSi-ES 100 Immune-associated cell populations and signalling: TAMs Targeting TAMs-specific ligands by: MTX/FOLR2 conjugated G5-dendrimer 101 HA/Mannose receptor conjugated MnO 2 NPs 102 siVEGF/M2pep conjugated AuNPs 103 Enhance extravasation of nanomedicine into tumor Transcytosis-based delivery Adsorptive-mediated transcytosis (AMT) CPT/PBEAGA zwitterionic polymer 104 Receptor-mediated transcytosis (RMT) Targeting iRGD/integrins α v by: siPLK1 and miR-200c/iRGD conjugated MSN 105 CA4 and DOX/iRGD conjugated MSN 106 Targeting GD16/Dll4 by: PTX/GD16 conjugated aldehyde-PEG-PLA and MPEG-PLA block copolymers 107 Immune cell-based delivery PTX/cationic liposomes (PTX-CL)-NEs to form PTX-CL/NEs …”