Antiangiogenic treatment with Sunitinib ameliorates inflammatory infiltrate, fibrosis, and portal pressure in cirrhotic rats

Abstract

Liver cirrhosis is a very complex disease in which several pathological processes such as inflammation, fibrosis, and pathological angiogenesis are closely integrated. We hypothesized that treatment with pharmacological agents with multiple mechanisms of action will produce superior results to those achieved by only targeting individual mechanisms. This study thus evaluates the therapeutic use of the multitargeted receptor tyrosine kinase inhibitor Sunitinib (SU11248). The in vitro effects of SU11248 were evaluated in the human hepatic stellate cell line LX-2 by measuring cell viability. The in vivo effects of SU11248 treatment were monitored in the livers of cirrhotic rats by measuring angiogenesis, inflammatory infiltrate, fibrosis, ␣-smooth muscle actin (␣-SMA) accumulation, differential gene expression by microarrays, and portal pressure. Cirrhosis progression was associated with a significant enhancement of vascular density and expression of vascular endothelial growth factor-A, angiopoietin-1, angiopoietin-2, and placental growth factor in cirrhotic livers. The newly formed hepatic vasculature expressed vascular cellular adhesion molecule 1 and intercellular adhesion molecule 1. Interestingly, the expression of these adhesion molecules was adjacent to areas of local inflammatory infiltration. SU11248 treatment resulted in a significant decrease in hepatic vascular density, inflammatory infiltrate, ␣-SMA abundance, LX-2 viability, collagen expression, and portal pressure. Conclusion: These results suggest that multitargeted therapies against angiogenesis, inflammation, and fibrosis merit consideration in the treatment of cirrhosis. (HEPATOLOGY 2007;46:1919-1926

Aquaporin-1 Promotes Angiogenesis, Fibrosis, and Portal Hypertension Through Mechanisms Dependent on Osmotically Sensitive MicroRNAs

“…Indeed, most strategies targeting angiogenic molecules have shown benefit in preclinical animal models of liver disease. 11,[31][32][33][34] In this context, our study extends the current knowledge of an emerging anti-angiogenic target, AQP1, by providing direct in vivo evidence that AQP1 regulates the angiogenesis, fibrosis, and portal hypertension that occurs after BDL; and defining a novel, molecular, fine-tuning mechanism involving osmotically sensitive miRs that may contribute to the pathological overexpression of AQP1 during cirrhosis. We previously demonstrated that AQP1 is overexpressed in the angiogenic neovasculature within fibrotic septa in human cirrhosis and in CCl 4 -induced liver injury in C57 black mice.…”

Targeting Liver Fibrosis

“…Drug repositioning is the effort to develop treatments by finding novel applications for drugs that are already in clinical use for other indications. 56 Examples for liver fibrosis are immunosuppressants such as rapamycin, 57 antidiabetic glitazones, 58 the antiparasitic drug halofuginone, 59,60 the tyrosine kinasetargeted anticancer drugs sunitinib, 61 or imatinib mesylate (Gleevec), 62 and blockers of the angiotensin system. 6 Because the clinical safety and efficacy profile is already known for these agents, drug repositioning offers the chance of a "fast track" introduction of novel treatments into clinical practice.…”

Inhibition of receptor tyrosine kinases restores immunocompetence and improves immune-dependent chemotherapy against experimental leishmaniasis in mice

“…Receptor tyrosine kinase inhibitors (RTKIs) are playing a growing role in the treatment of cancer, either as monotherapy or in combination with other anticancer drugs (1)(2)(3). Inhibition of changes in vasculature are well-documented outcomes of RTKI treatment (3)(4)(5), with the inhibitory effects of these drugs initially attributed to the blockade of VEGFRs and PDGFR (6).…”

“…Inhibition of changes in vasculature are well-documented outcomes of RTKI treatment (3)(4)(5), with the inhibitory effects of these drugs initially attributed to the blockade of VEGFRs and PDGFR (6). However, recent evidence suggests that the multitarget capabilities of RTKIs may underlie their beneficial effects in the treatment of chronic inflammation (3).…”

“…Inhibition of changes in vasculature are well-documented outcomes of RTKI treatment (3)(4)(5), with the inhibitory effects of these drugs initially attributed to the blockade of VEGFRs and PDGFR (6). However, recent evidence suggests that the multitarget capabilities of RTKIs may underlie their beneficial effects in the treatment of chronic inflammation (3). Although drugs of this class have not been evaluated to date for efficacy in an infectious disease setting, their established pharmacokinetic and safety profiles and ready availability could lead to a significant and rapid impact on the treatment and control of major globally important diseases.…”