Vitamin K enhancement of sorafenib-mediated HCC cell growth inhibition in vitro and in vivo.

Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
International Journal of Cancer (Impact Factor: 6.2). 12/2010; 127(12):2949-58. DOI: 10.1002/ijc.25498
Source: PubMed

ABSTRACT The multikinase inhibitor sorafenib is the first oral agent to show activity against human hepatocellular carcinoma (HCC). Apoptosis has been shown to be induced in HCC by several agents, including sorafenib as well as by the naturally occurring K vitamins (VKs). As few nontoxic agents have activity against HCC growth, we evaluated the activity of sorafenib and VKs, both independently and together on the growth of HCC cells in vitro and in vivo. We found that when VK was combined with sorafenib, the concentration of sorafenib required for growth inhibition was substantially reduced. Conversely, VK enhanced sorafenib effects in several HCC cell lines on growth inhibition. Growth could be inhibited at doses of VK plus sorafenib that were ineffective with either agent alone, using vitamins K1, K2 and K5. Combination of VK1 plus sorafenib induced apoptosis on FACS, TUNEL staining and caspase activation. Phospho-extracellular signal-regulated kinase (ERK) levels were decreased as was myeloid cell leukemia sequence 1 (Mcl-1), an ERK target. Sorafenib alone inhibited growth of transplantable HCC in vivo. At subeffective sorafenib doses in vivo, addition of VK1 caused major tumor regression, with decreased phospho-ERK and Mcl-1 staining. Thus, combination of VK1 plus sorafenib strongly induced growth inhibition and apoptosis in rodent and human HCC and inhibited the RAF/mitogen-activated protein kinase kinase/ERK pathway. VK1 alone activated PKA, a mediator of inhibitory Raf phosphorylation. Thus, each agent can antagonize Raf: sorafenib as a direct inhibitor and VK1 through inhibitory Raf phosphorylation. As both agents are available for human use, the combination has potential for improving sorafenib effects in HCC.

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    ABSTRACT: Hepatocellular carcinoma (HCC) is a serious life-threatening malignant disease of liver. Molecular targeted therapies are considered a promising strategy for the treatment of HCC. Sorafenib is the first, and so far the only targeted drug approved by the U.S. Food and Drug Administration (FDA) for clinical therapy of HCC. Despite being effective in some HCC patients, some demerits of sorafenib in the treatment of HCC, such as modest survival benefits, and drug resistance, have also been reported, which highlights the unmet medical need among patients with HCC. Here, we report a novel multikinase inhibitor discovered by us, SKLB-329, which potently inhibits angiogenesis-related kinases including VEGFR1/2/3, and FGFR2, and the Src kinase. SKLB-329 significantly inhibited endothelial cell growth, migration, invasion, and tube formation. It showed potent anti-angiogenic activity in a transgenic zebrafish model. Moreover, SKLB-329 could efficiently restrain the proliferation of HCC cells through down-regulation of Src-mediated FAK and Stat3 activity. In vivo, oral administration of SKLB-329 considerably suppressed the tumor growth in HCC xenograft models (HepG2 and SMMC7721) in a dose-dependent manner. In all of the in vitro and in vivo assays of this investigation, sorafenib was used as a positive control, and in most assays SKLB-329 exhibited a higher potency compared with the positive control. In addition, SKLB-329 also bears favorable pharmacokinetic properties. Collectively, the results of preclinical studies presented here demonstrate that SKLB-329 is a promising drug candidate for HCC treatment. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 05/2014; 135(12). DOI:10.1002/ijc.28944 · 6.20 Impact Factor
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    ABSTRACT: Objective:This study evaluated the feasibility of CT perfusion parameters for the early efficacy prediction of sorafenib in the treatment of hepatocellular carcinoma (HCC) in rats.Methods:CT hepatic perfusion measurements were performed in the livers of 40 rats implanted with rat's HCC. The rats in the experimental group (n=28) were treated by oral gavage with sorafenib (20 mg/d), while the rats in the control group (n=12) were treated by normal saline. Rats were classified into the responder group if the maximum diameter of their tumor had decreased 21 days after treatment, while the other rats were classified into the nonresponder group. Data were analyzed with the Pearson correlation analysis or analysis of variance.Results:CT perfusion was used to depict hemodynamic changes before and after treatment. The arterial liver perfusion (ALP) was significantly decreased in the responder group on day 11 after treatment with sorafenib (from 71.5 ml*min-1*100 ml-1 to 53.4 ml*min-1*100 ml-1), whereas no significant changes were observed in the nonresponder group (p=0.87). The maximum diameter of the tumor was also significantly decreased in the responder group on day 21 after treatment (p=0.042), while the maximum tumor diameter was significantly increased in the control group (p=0.001).Conclusion and Advances in knowledge:CT perfusion could be used to quantitatively analyze the hemodynamic changes the treatment for HCC with sorafenib, which indicates this approach may be developed for the early prediction of treatment efficacy for sorafenib.
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