title: Vitamin K enhancement of sorafenib-mediated HCC cell growth inhibition in vitro and in vivo.
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.
authors.affiliation: Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Wei
authors.forename: Meifang
authors.initials: M
authors.lastname: Wang
authors.forename: Terry
authors.initials: T
authors.lastname: Hyslop
authors.forename: Ziqiu
authors.initials: Z
authors.lastname: Wang
authors.forename: Brian I
authors.initials: BI
authors.lastname: Carr
mesh_terms: D000818:Animals; D000933:Antifibrinolytic Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects*; D001557:Benzenesulfonates / Q000494:pharmacology*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D000077157:Sorafenib; D014812:Vitamin K / Q000494:pharmacology*; D048490:raf Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000933:Antifibrinolytic Agents; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D014812:Vitamin K; D009536:Niacinamide; D000077157:Sorafenib; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases