Antitumor and vascular disrupting effects of ombrabulin in hepatocellular carcinoma

Abstract

Hepatocellular Carcinoma (HCC) the fifth most common cancer and the third leading cause of death among cancer worldwide. Curative treatments such as liver resection and liver transplantation are generally used in treating early-stage HCC patients. However, only 10% to 30% of HCC patients are eligible for the surgery, which is due to the asymptomatic characteristic of HCC, most HCC patients are diagnosed at late stage. Palliative treatment such as TAE, TACE and Sorafenib provide them options to maintain their quality of life and extend their survival. Nevertheless, current treatments provides limited benefits to them as efficacy remains unsatisfactory. Therefore, there is a great need to develop new palliative treatments and explore new agents for the treatment of HCC.

The aim of this study is to investigate the efficacy of a new therapeutic agent, Ombrabulin, in the treatment of HCC. Angiogenesis in HCC has been well-studied for many years as many studies proved that angiogeneisis plays an important role in the progression and development of HCC. Angiogenesis can also affect the prognosis and efficacy of treatments in HCC. As a result, antiangiogenesis and vascular disrupting agents have become new target in the therapaies of HCC. Ombrabulin is a synthetic vascular disrupting agent, which can inhibit tubulin polymerization in endothelial cells, causing cytoskeleton disorganization in endothelial cells. Endothelial cells will then detach from the basement membrane and eventually lead to vascular shutdown. This study demonstrated for the first time that Ombrabulin could selectively inhibit human umbilical vein endothelial cell (HUVEC) growth in vitro; particularly the early-form of HUVEC, which represent immature endothelial cell in neovasculature. Furthermore, this study also demonstrated the antiangiogenic effect of Ombrabulin on endothelial cells. By F-actin staining, it was shown that Ombrabulin caused changes in HUVECs morphology, which supported that Ombrabulin could lead to distortion in cytoskeleton.

In vivo study demonstrated the early effect and long term effect of Ombrabulin. For the first part of the in vivo study, Nude mice were treated with single-dose of Ombrabulin for one week. Hoechst 33342, anti-CD34 staining and PCNA staining were carried out to study the functional effect of Ombrabulin and the combination effect with Sorafenib in vivo. Mice treated with Ombrabulin resulted in decreased blood perfusion, microvessel density and tumor cell proliferation, and tumor necrosis was also observed. In the combination with Sorafenib, it did not show synergistic effect in both tumor cell proliferation and microvessel density.

For the second part of the in vivo study, nod scid mice were treated with multiple doses of Ombrabulin for three weeks to study the long term effect of Ombrabulin. Mice treated with Ombrabulin resulted in significantly smaller tumor size, demonstrating its antitumor efficacy in HCC. Furthermore, combination treatment of Sorafenib and Ombrabulin in vivo could enhance the efficacy of the treatment of HCC.

In conclusion, Ombrabulin has vascular disrupting and antitumor effects, which could efficiently suppress HCC tumor growth in vivo. These results suggest that Ombrabulin could be a promising vascular disrupting agent in treating HCC. Combination with sorafenib should be further explored in clinical studies to demonstrate the synergistic antitumor effects in HCC patients.