Sorafenib (BAY 43-9006): Review of Clinical Development

Ng, Raymond; Chen, Eric X.

doi:10.2174/157488406778249325

Cited by 29 publications

(15 citation statements)

References 31 publications

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“…Whereas nelfinavir is an investigational anti-cancer drug not yet approved for cancer treatment, sorafenib has already been approved for the treatment of renal cell carcinoma [29,30] and hepatocellular carcinoma [31]. It has the further advantage of being a multi-kinase inhibitor with additional anti-angiogenic functions by inhibiting tyrosine kinases [32] and to cooperate with other cytostatic drugs [33]. Sorafenib is currently being tested in at least 10 clinical studies for its potential use in ovarian cancer treatment (http://clinicaltrials.gov).…”

Section: Discussionmentioning

confidence: 99%

Nelfinavir induces mitochondria protection by ERK1/2-mediated mcl-1 stabilization that can be overcome by sorafenib

et al. 2009

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The HIV protease inhibitor nelfinavir is an investigational drug for cancer treatment. We have previously demonstrated induction of apoptosis by nelfinavir even in chemo-resistant ovarian cancer cells. In contrast to the pro-apoptotic effect of nelfinavir on human cancer cells, we noticed a significant upregulation of the anti-apoptotic mitochondrial membrane protein mcl-1 by nelfinavir, resulting in a mitochondria-independent induction of apoptosis. Upregulation of mcl-1 was associated with enhanced phosphorylation of both mcl-1 and of ERK1/2 (extracellular signal-regulated kinases 1/2). ERK1/2 enhanced stability of mcl-1 protein expression by serine-163 phosphorylation. The combination of nelfinavir with sorafenib, a clinically applied inhibitor of the RAS/RAF/ ERK1/2 pathway, inhibited nelfinavir-induced ERK1/2 activation and mcl-1 protein upregulation. Further, the combination of nelfinavir with sorafenib induced mitochondrial membrane potential disruption and resulted in an improved activity of nelfinavir on ovarian cancer cells. Thus, a combination of these two investigational anticancer drugs could be of interest especially because of their unique mechanism of apoptosis induction even in otherwise chemo-resistant human cancer cells.

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Section: Discussionmentioning

confidence: 99%

Nelfinavir induces mitochondria protection by ERK1/2-mediated mcl-1 stabilization that can be overcome by sorafenib

et al. 2009

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“…Sorafenib is an effective and widely used molecular target drug in HCC [53][54][55][56][57]. Besides the classical pathway directly targeting HCC, sorafenib was found to mediate the antitumor effect via macrophages.…”

Section: Dusp1 and Cancer Molecular Target Drugsmentioning

confidence: 99%

Role of DUSP1/MKP1 in tumorigenesis, tumor progression and therapy

et al. 2016

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Dual-specificity phosphatase-1 (DUSP1/MKP1), as a member of the threoninetyrosine dual-specificity phosphatase family, was first found in cultured murine cells. The molecular mechanisms of DUSP1-mediated extracellular signalregulated protein kinases (ERKs) dephosphorylation have been subsequently identified by studies using gene knockout mice and gene silencing technology. As a protein phosphatase, DUSP1 also downregulates p38 MAPKs and JNKs signaling through directly dephosphorylating threonine and tyrosine. It has been detected that DUSP1 is involved in various functions, including proliferation, differentiation, and apoptosis in normal cells. In various human cancers, abnormal expression of DUSP1 was observed which was associated with prognosis of tumor patients. Further studies have revealed its role in tumorigenesis and tumor progression. Besides, DUSP1 has been found to play a role in tumor chemotherapy, immunotherapy, and biotherapy. In this review, we will focus on the function and mechanism of DUSP1 in tumor cells and tumor treatment. Cancer Medicine Open Access 2062

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“…Sorafenib, a small-molecular inhibitor, has been identified to be responsible for the inhibition of the tyrosine kinases VEGFR and PDGFR and rapid accelerated fibrosarcoma (Raf) kinases [53].…”

Section: Sorafenib (Trade Name: Nexavar ò )mentioning

confidence: 99%

Pharmacokinetic Aspects of Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitors

2015

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Scientists have identified the impact of angiogenesis on tumor growth and survival. Among other efficient drugs, several small-molecule tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial growth factor receptor (VEGFR) have been developed and have already been integrated into the treatment of various advanced malignancies. This review provides a compilation of current knowledge on the pharmacokinetic aspects of all VEGFR-TKIs already approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) and of those still under investigation. Additional information on substance metabolism, potential for drug-drug interactions (DDIs), and the need for dose adaptation in patients with predominant renal and/or hepatic impairment has been included. All TKIs introduced in this review were administered orally, allowing for easy drug handling for healthcare professionals and patients. For almost all substances, the maximum plasma concentrations were reached within a short period of time. The majority of the substances showed a high plasma protein binding and their excretion occurred via the feces and, to a lesser extent, via the urine. In most cases, dose adaptation in patients with mild to moderate renal or hepatic impairment is not recommended. Cytochrome P450 (CYP) 3A4 was found to play a crucial role in the drug metabolic processes of many compounds. In order to prevent unwanted DDIs, co-administration of VEGFR TKIs together with CYP3A4 inhibitors or inducers should be avoided. Throughout all TKIs, the data indicate high inter-individual variability. The causes of this are still unclear and require further research to allow for individualization of treatment regimens.

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Sorafenib (BAY 43-9006): Review of Clinical Development

Cited by 29 publications

References 31 publications

Nelfinavir induces mitochondria protection by ERK1/2-mediated mcl-1 stabilization that can be overcome by sorafenib

Nelfinavir induces mitochondria protection by ERK1/2-mediated mcl-1 stabilization that can be overcome by sorafenib

Role of DUSP1/MKP1 in tumorigenesis, tumor progression and therapy

Pharmacokinetic Aspects of Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitors

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