c-Met-Akt pathway-mediated enhancement of inhibitory c-Raf phosphorylation is involved in vitamin K1 and sorafenib synergy on HCC growth inhibition

Carr, Brian I.; Wang, Ziqiu; Wang, Meifang; Cavallini, A; D’Alessandro, Rosalba; Refolo, Maria Gratzia

doi:10.4161/cbt.12.6.16053

Cited by 23 publications

(18 citation statements)

References 27 publications

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“…However, despite the availability of these targeted kinase inhibitors, drug toxicity and resistance and subsequent disease relapse remain a problem in HCC management. Several studies have aimed at improving the actions of these systemic drugs and at reducing their toxicity, such as by targeting parallel pathways [ 7 ] or by combination with Vitamins K (VKs) [ 8 – 9 ]. VKs are fat-soluble vitamins with minimal toxicity, that play a major role not only in blood coagulation and bone metabolism [ 10 ], but also have anti-tumor activity in different experimental tumor types [ 11 – 13 ].…”

Section: Introductionmentioning

confidence: 99%

IGF-1R tyrosine kinase inhibitors and Vitamin K1 enhance the antitumor effects of Regorafenib in HCC cell lines

et al. 2017

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The recent RESORCE trial showed that treatment with Regorafenib after Sorafenib failure provided a significant improvement in overall survival in HCC patients. Preclinical and clinical trial data showed that Regorafenib is a more potent drug than Sorafenib. In this study we aimed at improving Regorafenib actions and at reducing its toxicity, by targeting parallel pathways or by combination with Vitamins K (VKs). We investigated the effects of Regorafenib administrated at low concentrations and in combination with either VK1 and/or with GSK1838705A or OSI-906, two IGF1-R inhibitors, on HCC cell growth and motility. Our results showed that both IGF1-R inhibitors potentiated the antiproliferative and pro-apoptotic effects of Regorafenib and/or VK1 in HCC cell lines. Moreover we provide evidence that the combined treatment with IG1-R antagonists and Regorafenib (and/or VK1) also caused a significant reduction and depolymerization of actin resulting in synergistic inhibition exerted on cell migration. Thus, simultaneous blocking of MAPK and PI3K/Akt cascades with IGF1-R inhibitors plus Regorafenib could represent a more potent approach for HCC treatment.

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Section: Introductionmentioning

confidence: 99%

IGF-1R tyrosine kinase inhibitors and Vitamin K1 enhance the antitumor effects of Regorafenib in HCC cell lines

et al. 2017

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“…It has been shown that vitamin Ks could inhibit the growth of various types of cancer cells in vitro as a single agent or in combination with other chemotherapy [16,17]. Recent studies have shown that VK1 can enhance the effects of sorafenib-mediated hepatocellular carcinoma cell growth inhibition through inhibiting the density-enhanced phosphatase 1 (DEP-1)-regulated c-Met-Akt pathway [18]. However, the combinational effect of sorafenib and VK1 on glioma cells has not been studied so far.…”

Section: Introductionmentioning

confidence: 99%

Vitamin K1 enhances sorafenib-induced growth inhibition and apoptosis of human malignant glioma cells by blocking the Raf/MEK/ERK pathway

Zhou

Wang

et al. 2012

World J Surg Onc

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BackgroundThe combined effects of anticancer drugs with nutritional factors against tumor cells have been reported previously. This study characterized the efficacy and possible mechanisms of the combination of sorafenib and vitamin K1 (VK1) on glioma cell lines.MethodsWe examined the effects of sorafenib, VK1 or their combination on the proliferation and apoptosis of human malignant glioma cell lines (BT325 and U251) by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, flow cytometry and 4′,6-diamidino-2-phenylindole (DAPI) assay. The signaling pathway changes were detected by western blotting.ResultsSorafenib, as a single agent, showed antitumor activity in a dose-dependent manner in glioma cells, but the effects were more pronounced when used in combination with VK1 treatment. Sorafenib in combination with VK1 treatment produced marked potentiation of growth inhibition and apoptosis, and reduced expression of phospho-mitogen-activated protein kinase kinase (MEK) and phospho-extracellular signal-regulated kinase (ERK). Furthermore, the expression levels of antiapoptotic proteins Bcl-2 and Mcl-1 were significantly reduced.ConclusionsOur findings indicated that VK1 enhanced the cytotoxicity effect of sorafenib through inhibiting the Raf/MEK/ERK signaling pathway in glioma cells, and suggested that sorafenib in combination with VK1 maybe a new therapeutic option for patients with gliomas.

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“…In a recent study, the combination of K vitamins with Sorafenib induced c-Raf phosphorylation at two serine residues, Ser-43 and Ser-259 and this significantly inhibited HCC growth (Carr et al 2011). The authors found that vitamin K1 enhanced sorafenib-induced c-Met phosphorylation at Tyr-1349, and consequently induced phosphorylation of PI3K-Akt.…”

Section: A Case For Better Animal Modelsmentioning

confidence: 97%

“…The authors found that vitamin K1 enhanced sorafenib-induced c-Met phosphorylation at Tyr-1349, and consequently induced phosphorylation of PI3K-Akt. These findings suggested that the c-Met-PI3K-Akt signaling pathway to inhibit c-Raf phosphorylation may play a central role in inhibiting HCC cell growth when vitamin K1 is used in combination with Sorafenib (Carr et al 2011).…”

Section: A Case For Better Animal Modelsmentioning

confidence: 97%

Hepatocellular Carcinoma

Aravalli¹,

Steer²

2014

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c-Met-Akt pathway-mediated enhancement of inhibitory c-Raf phosphorylation is involved in vitamin K1 and sorafenib synergy on HCC growth inhibition

Cited by 23 publications

References 27 publications

IGF-1R tyrosine kinase inhibitors and Vitamin K1 enhance the antitumor effects of Regorafenib in HCC cell lines

IGF-1R tyrosine kinase inhibitors and Vitamin K1 enhance the antitumor effects of Regorafenib in HCC cell lines

Vitamin K1 enhances sorafenib-induced growth inhibition and apoptosis of human malignant glioma cells by blocking the Raf/MEK/ERK pathway

Hepatocellular Carcinoma

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