Celecoxib and octreotide synergistically ameliorate portal hypertension via inhibition of angiogenesis in cirrhotic rats

Abstract

Abnormal angiogenesis is critical for portal hypertension in cirrhosis. Except for etiological treatment, no efficient medication or regime has been explored to treat the early stage of cirrhosis when angiogenesis is initiated or overwhelming. In this study, we explored an anti-angiogenesis effort through non-cytotoxic drugs octreotide and celecoxib to treat early stage of cirrhotic portal hypertension in an animal model. Peritoneal injection of thioacetamide (TAA) was employed to induce liver cirrhosis in rats. A combination treatment of celecoxib and octreotide was found to relieve liver fibrosis, portal venous pressure, micro-hepatic arterioportal fistulas, intrahepatic and splanchnic angiogenesis. Celecoxib and octreotide exerted their anti-angiogenesis effect via an axis of cyclooxygenase-2/prostaglandin E2/EP-2/somatostatin receptor-2, which consequently down-regulated phosphorylation of extracellular signal-regulated kinase (p-ERK)–hypoxia-inducible factor-1α (HIF-1α)–vascular endothelial growth factor (VEGF) integrated signaling pathways. In conclusions, combination of celecoxib and octreotide synergistically ameliorated liver fibrosis and portal hypertension of the cirrhotic rats induced by TAA via the inhibition of intrahepatic and extrahepatic angiogenesis. The potential mechanisms behind the regimen may due to the inactivation of p-ERK–HIF-1α–VEGF signaling pathway.Electronic supplementary materialThe online version of this article (doi:10.1007/s10456-016-9522-9) contains supplementary material, which is available to authorized users.

Hepatoprotectivity of Panduratin A against liver damage: In vivo demonstration with a rat model of cirrhosis induced by thioacetamide

“…Upon an insult, various grades of liver damage have been reported to be similar to the TAA intoxication in experimental animals including cell necrosis and nodular cirrhosis . HSCs acquire highly proliferative catalog generating fibrillar collagen within the injured liver .…”

Consensus guidelines for the use and interpretation of angiogenesis assays

“…These assays have been instrumental in the study of vascular biology in growth and development [6–8] but also play a key role in the design, development, and evaluation of drugs that positively or negatively modulate vessel function for the treatment of many diseases [9–11]. Some examples of where the use of such bioassays has been imperative are: (1) the development of angiostatic drugs for the treatment of cancer, ocular diseases, and other pathologic conditions where angiogenesis is implicated and also angiogenic treatment strategies in ischemic cardiovascular disease [12, 13], (2) screening of natural anti-angiogenic compounds [14], (3) the efforts to design combination therapies including angiogenesis inhibitors [15–20], (4) the unraveling of mechanisms regulating lymphangiogenesis [21, 22], (5) the interrelationship of angiogenesis and immunity [23–25], (6) the development of imaging as diagnostic strategy [26], (7) the study of drug resistance mechanisms [27–29], (8) development of compounds and strategies for the revascularization of ischemic injuries [30, 31], and (9) to improve the vascular fitness in aging vessels [32, 33]. The current paper describes a large collection of assays and techniques for the evaluation of angiogenesis and aims at explaining their respective advantages and limitations.…”

Adjuvant celecoxib and lanreotide following transarterial chemoembolisation for unresectable hepatocellular carcinoma: a randomized pilot study

“…The potential mechanisms behind the regimen may due to the inactivation of p-ERK - HIF-1α/VEGF, endothelial nitric oxide synthase, MAPK - ERK, JNK - p38, and TGF-β1/Smads integrated signaling pathways, which are involved in the cross-talk of COX-2 and SST signal transduction. The synergistic outcome of SSTA and COX-2 inhibitor led to a higher efficiency in inhibition of p-ERK, HIF-1α, VEGF and angiogenesis than either one alone [ 15 – 17 , 21 – 23 ].…”

“…Besides chronic inflammation plays a stimulatory role in the fibrosis, proinflammatory conditions promote HCC onset and progression via activation of Wnt and EGFR signaling pathways [ 24 ]. Celecoxib and octreotide may ameliorate liver fibrosis in the cirrhotic rats model via the inhibition of intrahepatic and extrahepatic inflammation, and angiogenesis [ 23 , 25 , 26 ]. Also, celecoxib could inhibit the epithelial-mesenchymal transition of hepatocytes by reduction of intrahepatic inflammation, preservation of normal basement matrix and inhibition of TGF-β1/Smad pathway [ 27 ].…”