Inhibition of expression of vascular endothelial growth factor and its receptors in pulmonary adenocarcinoma cell by TNP-470 in combination with gemcitabine

Abstract

Angiogenesis is required for solid tumor growth and facilitates tumor progression and metastasis. The inhibition effects of O-(chloroacetyl-carbamoyl) fumagillol (TNP-470), an angiogenesis inhibitor, and gemcitabine, a chemotherapeutic agent, on expression of growth factors were investigated using human pulmonary adenocarcinoma cell line, A549. The A549 cells were divided into four groups: control group, 10 −6 mg/ml gemcitabine treated group, 10 −4 mg/ml TNP-470 treated group and gemcitabine+TNP-470 treated group. The mRNA and protein expression of vascular endothelial growth factor (VEGF) and its receptors, FMS-like tyrosine kinase-1 (FLT-1) and kinase insert domain-containing receptor (KDR), in different groups were measured. The growth of A549 cell cultured with gemcitabine or TNP-470 was inhibited in an almost dose-dependent manner. Although gemcitabine (10 −6 mg/ml) alone and TNP-470 (10 −4 mg/ml) alone had no effect on the mRNA and protein expression of VEGF and its receptors (FLT-1, KDR) in A549 cells compared to the control (P>0.05), 10 −6 mg/ml gemcitabine in combination with 10 −4 mg/ml TNP-470 had significant effect (P<0.01). Moreover, combination of the two drugs significantly inhibited the mRNA expression of VEGF, FLT-1 and KDR compared to either drug alone (P<0.05). This study suggests that combined treatment with TNP-470 plus gemcitabine may augment the antiangiogenic and antineoplastic effects in lung cancer cells in vitro.

Hyperoxia enhances VEGF release from A549 cells via post-transcriptional processes

“…Treatment of cells with heparinase to dissociate VEGF from heparin/heparan sulfate-binding sites revealed a reserve of VEGF in the hyperoxia-treated cells. As A549 cells are known to express both VEGFR1 and VEGFR2 protein, the results of the present study could reflect a shift in VEGF binding from receptors to heparin moieties [38]. Indeed hyperoxia has been shown to reduce VEGFR1 and VEGFR2 expression in the lungs of rats [39].…”

Inhibitory effects of TNP-470 in combination with BCNU on tumor growth of human glioblastoma xenografts

“…Studies on xenografts of human gastric cancer cells, pulmonary adenocarcinoma cells and prostate cancer cells showed that the combination therapy of TNP-470 and cytotoxic drug can improve the clinical efficacy, reduce drug dosage and toxicity and adverse drug reactions [23][24][25][26] . Up to present, few reports on TNP-470 in combination with other treatment methods in the treatment of human glioma cell xenografts are available.…”

Synergistic inhibitory effect of gemcitabine and angiotensin type-1 receptor blocker, losartan, on murine pancreatic tumor growth via anti-angiogenic activities

“…Pre-clinical evidence indicated that combining antiangiogenic agents with a conventional chemotherapeutic agent therapy results in additive or even synergistic antitumoral effect (12,29,30). Several studies have shown that the combination of newly developed anti-angiogenic agents (DC101, SU5416 and TNP-470) and GEM inhibited the tumor growth and angiogenesis synergistically in pancreatic cancer experimental models (31). Although several anti-angiogenic agents have already been employed in the clinical practice, these newly developed agents frequently induce severe side effects such as perforation of the gastrointestinal tract and hand-foot syndrome (32,33).…”