Resveratrol Promotes Tumor Microvessel Growth via Endoglin and Extracellular Signal-Regulated Kinase Signaling Pathway and Enhances the Anticancer Efficacy of Gemcitabine against Lung Cancer

Abstract

The synergistic anticancer effect of gemcitabine (GEM) and resveratrol (RSVL) has been noted in certain cancer types. However, whether the same phenomenon would occur in lung cancer is unclear. Here, we uncovered the molecular mechanism by which RSVL enhances the anticancer effect of GEM against lung cancer cells both in vitro and in vivo. We established human lung adenocarcinoma HCC827 xenografts in nude mice and treated them with GEM and RSVL to detect their synergistic effect in vivo. Tumor tissue sections from nude mice were subjected to hematoxylin and eosin staining for blood vessel morphological observation, and immunohistochemistry was conducted to detect CD31-positive staining blood vessels. We also established the HCC827-human umbilical vein endothelial cell (HUVEC) co-culture model to observe the tubule network formation. Human angiogenesis antibody array was used to screen the angiogenesis-related proteins in RSVL-treated HCC827. RSVL suppressed the expression of endoglin (ENG) and increased tumor microvessel growth and blood perfusion into tumor. Co-treatment of RSVL and GEM led to more tumor growth suppression than treatment of GEM alone. Mechanistically, using the HCC827-HUVEC co-culture model, we showed that RSVL-suppressed ENG expression was accompanied with augmented levels of phosphorylated extracellular signal-regulated kinase (ERK) 1/2 and increased tubule network formation, which may explain why RSVL promoted tumor microvessel growth in vivo. RSVL promoted tumor microvessel growth via ENG and ERK and enhanced the anticancer efficacy of GEM. Our results suggest that intake of RSVL may be beneficial during lung cancer chemotherapy.

Comprehensive bioinformatics analysis to identify a novel cuproptosis-related prognostic signature and its ceRNA regulatory axis and candidate traditional Chinese medicine active ingredients in lung adenocarcinoma

“…At the same time, resveratrol can induce apoptosis and autophagy of lung adenocarcinoma cells by up-regulating the P53 level ( Fan et al, 2020 ). When used in combination with gemcitabine (GEM), resveratrol has synergistic anticancer effects ( Qin et al, 2020 ). Genistein exists in various plants for human and animal consumption, and it can inhibit the proliferation and induce apoptosis of A549 cells ( Zhang et al, 2018 ).…”

Cytochrome P450 27C1 Level Dictates Lung Cancer Tumorigenicity and Sensitivity towards Multiple Anticancer Agents and Its Potential Interplay with the IGF-1R/Akt/p53 Signaling Pathway

“…As previously described, diluted primary antibodies targeting CYP27C1 (1:800, GTX45438, Gene Tex, Irvine, CA, USA), beta-actin (1:, A5441, Sigma Aldrich, St. Louis, MO, USA), phospho-tyrosine (1:2000, #9416, Cell Signaling Technology, Danvers, MA, USA), ERK1/2 (1:1000, #9102, Cell Signaling Technology), phosphorylated ERK1/2 Thr202/Tyr204 (1:2000, #4370, Cell Signaling Technology), Akt (1:1000, #4691, Cell Signaling Technology), phospho-Akt Ser473 (1:1000, #9271, Cell Signaling Technology), and p53 (1: 1000, sc-6243, Santa Cruz Biotechnology) were applied to probe the protein on PVDF membrane at four degrees Celsius overnight, following by the reaction with secondary anti-mouse or anti-rabbit antibodies at room temperature for two hours. Targeted proteins were detected using Enhanced Chemiluminescence Detection Reagents (GE Healthcare, Boston, MA, USA) and capture by Chemiluminescent Imaging System (Tanon 5200, Shanghai, China) [ 60 ]. Grey scales were analyzed by Gel-Pro ANALYZER.…”

“…Stable CYP27C1-knockdown A549 and H1975 cells, stable CYP27C1-overexpressed H460 cells, and the corresponding control cells were seeded in 96-well plates. Cell viability was tested by a 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay at 12,24,36,48,60,72,84, and 96 h after cell seeding, following the manufacturer's protocol (Promega, Madison, WI, USA), and the absorbance was measured by a microplate photometer (Thermo Fisher Scientific, Waltham, MA, USA) at 492 nm.…”

Novel Angiogenic Regulators and Anti-Angiogenesis Drugs Targeting Angiogenesis Signaling Pathways: Perspectives for Targeting Angiogenesis in Lung Cancer

“…Qin et al. ( 95 ) recently showed that Resveratrol (RSVL) combined with Gemcitabine (GEM) has stronger tumor growth inhibition than GEM alone. In terms of mechanism, this study suggests that RSVL promotes tumor microvascular growth by down-regulating expression of endothelin and activating the ERK signaling pathway, leading to increased blood perfusion and increased drug entry into the tumor, ultimately enhancing the anticancer effect of GEM.…”