PTPN11 (SHP2) Is Indispensable for Growth Factors and Cytokine Signal Transduction During Bovine Oocyte Maturation and Blastocyst Development.

This study was aimed to investigate the role of SHP2 (Src-homology-2-containing phosphotyrosine phosphatase) in intricate signaling networks invoked by bovine oocyte to achieve maturation and blastocyst development. PTPN11 (Protein Tyrosine Phosphatase, non-receptor type 11) encoding protein SHP2, a positive transducer of RTKs (Receptor Tyrosine Kinases) and cytokine receptors, can play a significant role in bovine oocyte maturation and embryo development, but this phenomenon has not yet been explored. Here, we used different growth factors, cytokines, selective activator, and a specific inhibitor of SHP2 to ascertain its role in bovine oocyte developmental stages in vitro. We found that SHP2 became activated by growth factors and cytokines treatment and was highly involved in the activation of oocyte maturation and embryo development pathways. Activation of SHP2 triggered MAPK (mitogen-activated protein kinases) and PI3K/AKT (Phosphoinositide 3-kinase/Protein kinase B) signaling cascades, which is not only important for GVBD (germinal vesical breakdown) induction but also for maternal mRNA translation. Inhibition of phosphatase activity of SHP2 with PHPS1 (Phenylhydrazonopyrazolone sulfonate 1) reduced oocytes maturation as well as bovine blastocyst ICM (inner cell mass) volume. Supplementation of LIF (Leukemia Inhibitory Factor) to embryos showed an unconventional direct relation between p-SHP2 and p-STAT3 (Signal transducer and activator of transcription 3) for blastocyst ICM development. Other than growth factors and cytokines, cisplatin was used to activate SHP2. Cisplatin activated SHP2 modulate growth factors effect and combine treatment significantly enhanced quality and rate of developed blastocysts.

Electropharmacological effects of intracellular Ca2+ handling modulator caldaret on the heart assessed in the halothane-anesthetized dogs.

We analyzed how the enhancement of net sarcoplasmic reticulum (SR) Ca2+ uptake may affect cardiac electrophysiological properties in vivo by using caldaret which can decrease SR diastolic Ca2+ leak, enhance SR Ca2+ reuptake and inhibit reverse-mode Na+/Ca2+ exchanger. Caldaret in doses of 0.5, 5 and 50 µg/kg was intravenously administered over 10 min to the halothane-anesthetized beagle dogs (n = 5), attaining pharmacologically active plasma concentration. The low and middle doses of caldaret increased the ventricular contraction, which could be explained by its on-target pharmacological activities. The high dose enhanced the sinus automaticity followed by its suppression in addition to the increase of the total peripheral resistance, which may be unfavorable for treating diastolic heart failure. The low and middle doses enhanced the atrioventricular conduction, which may have some potential for predisposing the atria to the onset of atrial fibrillation via an induction of mitral and/or tricuspid regurgitation. The middle and high doses of caldaret prolonged the ventricular effective refractory period without altering the intraventricular conduction or repolarization period, which may prevent the onset of ventricular arrhythmias. Thus, modulation of intracellular Ca2+ handling by caldaret can induce not only inotropic effect, but also various electrophysiological actions on the in situ heart.

The STAT3 inhibitor S3I-201 suppresses fibrogenesis and angiogenesis in liver fibrosis.

Liver fibrosis is a common pathological response to chronic hepatic injury. STAT3 is actively involved in the fibrogenesis and angiogenesis seen in liver fibrosis. S3I-201 (NSC 74859) is a chemical inhibitor of STAT3 activity, which blocks the dimerization of STAT3, STAT3-DNA binding and transcription activity. This study evaluated the effects of S3I-201 against liver fibrosis. S3I-201 inhibited the proliferation, migration, and actin filament formation in primary human hepatic stellate cells (HSCs), as well as the expression of α-SMA, collagen I and TIMP1 in both primary HSC and in a CCl4-induced fibrosis mouse model. S3I-201 induced both apoptosis and cell cycle arrest in the HSC cell line (LX-2). S3I-201 inhibited the expression of fibrogenesis factors TGFß1 and TGFßRII, as well as the downstream phosphorylation of Smad2, Smad3, Akt and ERK induced by TGFß1. In addition to fibrogenesis, both in vitro and in vivo assays showed that S3I-201 inhibited angiogenesis through expression suppression of VEGF and VEGFR2. Moreover, S3I-201 also had a synergistic effect with sorafenib, an FDA approved liver cancer drug, in the proliferation, apoptosis, angiogenesis and fibrogenesis of HSC. S3I-201 suppressed liver fibrosis through multiple mechanisms, and combined with sorafenib, S3I-201 could be a potentially effective antifibrotic agent.

NXY-059, a Failed Stroke Neuroprotectant, Offers No Protection to Stem Cell-Derived Human Neurons.

BACKGROUND: Developing new medicines is a complex process where understanding the reasons for both failure and success takes us forward. One gap in our understanding of most candidate stroke drugs before clinical trial is whether they have a protective effect on human tissues. NXY-059 is a spin-trap reagent hypothesized to have activity against the damaging oxidative biology which accompanies ischemic stroke. Re-examination of the preclinical in vivo dataset for this agent in the wake of the failed SAINT-II RCT highlighted the presence of a range of biases leading to overestimation of the magnitude of NXY-059's effects in laboratory animals. Therefore, NXY-059 seemed an ideal candidate to evaluate in human neural tissues to determine whether human tissue testing might improve screening efficiency. MATERIALS AND METHODS: The aim of this randomized and blinded study was to assess the effects of NXY-059 on human stem cell-derived neurons in the presence of ischemia-like injury induced by oxygen glucose deprivation or oxidative stress induced by hydrogen peroxide or sodium nitroprusside. RESULTS: In MTT assays of cell survival, lactate dehydrogenase assays of total cell death and terminal deoxynucleotidyl transferase dUTP nick end labeling staining of apoptotic-like cell death, NXY-059 at concentrations ranging from 1 µm to 1 mm was completely without activity. Conversely an antioxidant cocktail comprising 100 µm each of ascorbate, reduced glutathione, and dithiothreitol used as a positive control provided marked neuronal protection in these assays. CONCLUSION: These findings support our hypothesis that stroke drug screening in human neural tissues will be of value and provides an explanation for the failure of NXY-059 as a human stroke drug.

Direct determination of surfactant effects on the uptake of gaseous parent and alkylated PAHs by crop leaf surfaces.

The partitioning of atmospheric polycyclic aromatic hydrocarbons (PAHs) into crop systems raises concerns about their potential harm to ecosystem and human health. To assess parent and alkylated PAHs accumulation accurately, the uptake of individual 7-isopropyl-1-methylphenanthrene (Retene), 3-methyl-phenanthrene (3-MP) and phenanthrene (Phe) by living maize, soybean and potato leaf surfaces, as well as the effects of cationic cetyltrimethylammonium bromide (CTMAB) and anionic sodium dodecyl benzene sulfonate (SDBS), were examined in situ using fiber-optic fluorimetry. For each of three PAH chemicals, the uptake achieved equilibrium between the air and living crop leaf surfaces within the 120-h monitoring period. There is inter-chemical and inter-species variability in terms of both the time required reaching equilibrium, the equilibrated adsorption concentration (EAC) and the overall air-surfaces mass transfer coefficient (kAS). The EAC of the three PAHs for each of the three crops' leaf surfaces increased with the number of alkyl substitutions on the aromatic ring. For any given PAHs, the EAC values followed the sequence of potato > soybean > maize, which was dominantly controlled by their leaf surface polarity index ((O+N)/C). The presence of CTMAB and SDBS increased the EAC of PAHs in the three crops' leaf surfaces by 6.5-17.1%, due to the plasticizing effect induced by the surface-sorbed surfactants, and the enhancement degree was closely associated with leaf-wax content and lg KOW values of PAHs. In addition, the two surfactants promoted the kAS values of the three chemicals by 7.7-23.3%. These results demonstrated that surfactants promoted the uptake of PAHs onto the crop leaf surfaces, potentially threatening the agricultural product safety.

Caspofungin Treatment of Aspergillus fumigatus Results in ChsG-Dependent Upregulation of Chitin Synthesis and the Formation of Chitin-Rich Microcolonies.

Treatment of Aspergillus fumigatus with echinocandins such as caspofungin inhibits the synthesis of cell wall ß-1,3-glucan, which triggers a compensatory stimulation of chitin synthesis. Activation of chitin synthesis can occur in response to sub-MICs of caspofungin and to CaCl2 and calcofluor white (CFW), agonists of the protein kinase C (PKC), and Ca(2+)-calcineurin signaling pathways. A. fumigatus mutants with the chs gene (encoding chitin synthase) deleted (ΔAfchs) were tested for their response to these agonists to determine the chitin synthase enzymes that were required for the compensatory upregulation of chitin synthesis. Only the ΔAfchsG mutant was hypersensitive to caspofungin, and all other ΔAfchs mutants tested remained capable of increasing their chitin content in response to treatment with CaCl2 and CFW and caspofungin. The resulting increase in cell wall chitin content correlated with reduced susceptibility to caspofungin in the wild type and all ΔAfchs mutants tested, with the exception of the ΔAfchsG mutant, which remained sensitive to caspofungin. In vitro exposure to the chitin synthase inhibitor, nikkomycin Z, along with caspofungin demonstrated synergistic efficacy that was again AfChsG dependent. Dynamic imaging using microfluidic perfusion chambers demonstrated that treatment with sub-MIC caspofungin resulted initially in hyphal tip lysis. However, thickened hyphae emerged that formed aberrant microcolonies in the continued presence of caspofungin. In addition, intrahyphal hyphae were formed in response to echinocandin treatment. These in vitro data demonstrate that A. fumigatus has the potential to survive echinocandin treatment in vivo by AfChsG-dependent upregulation of chitin synthesis. Chitin-rich cells may, therefore, persist in human tissues and act as the focus for breakthrough infections.

Layered double hydroxides intercalated with anionic surfactants/benzophenone as potential materials for sunscreens.

Layered double hydroxides intercalated with dodecylsulfate or dodecylbenzenesulfonate were synthesized by co-precipitation under alkaline conditions. After characterization by PXRD, FTIR, and TGA/DTA, the ZnxAl/SUR compounds were reacted with neutral benzophenone, using different procedures. The products obtained from benzophenone adsolubilization were investigated by PXRD, FTIR, and DRUV-Vis spectroscopy before and after exposure to UV radiation. In general, the content of adsolubilized benzophenone was small and depended on the synthetic procedure. The best results were achieved under microwave irradiation, which furnished 9.09 wt% adsolubilized benzophenone. The products presented good adsorption in the full UV region, from UVC to UVA, and good stability to UV radiation. They did not cause skin irritation in tests conducted on rabbits, which makes them good candidates for the development of a new generation of sunscreens.

Targeted agents and systemic therapy in hepatocellular carcinoma.

Cytotoxic chemotherapy, hormonal agents, and immunotherapy have been tested in hepatocellular cancer (HCC) with marginal efficacy to date. Recent insights into the molecular pathogenesis of HCC have identified several aberrant signaling pathways that have served as targets for novel therapeutic agents. These discoveries have been translated into the clinical realm with the use of the antiangiogenic and the Raf kinase inhibitor, sorafenib, and have revealed the potential of targeted agents to produce clinically meaningful survival benefits in patients with advanced HCC. Efforts continue in the quest to improve the outcome of HCC patients through the development and evaluation of other targeted agents, and to better understand the interactions between the underlying disease biology and response to therapy. Several pathways are now implicated in hepatocarcinogenesis and agents that target these pathways continue to be developed.

Evaluation of the relationship between MR estimates of blood oxygen saturation and hypoxia: effect of an antiangiogenic treatment on a gliosarcoma model.

PURPOSE: To assess the reproducibility of the magnetic resonance (MR) estimate of blood oxygen saturation (sO(2)) in the rat brain, to evaluate the relationship between low MR estimate of sO(2) values and tissue hypoxia in a hypoxic and necrotic glioscarcoma model (9L gliosarcoma cells), and to evaluate the capability of the MR estimate of sO(2) parameter to help identify modifications induced by an antiangiogenic treatment (sorafenib) in 9L gliosarcoma tumors. MATERIALS AND METHODS: Experiments were performed with permits from the French Ministry of Agriculture. Forty-eight male rats bearing a 9L gliosarcoma were randomized in untreated and treated (sorafenib) groups. MR blood volume fraction and MR estimate of sO(2) parameters were estimated 1 day before and 1, 3, 5, and 8 days after the start of the treatment. The in vivo MR estimate of sO(2) measurement was correlated with the ex vivo hypoxia assessment by using pimonidazole staining. Paired and unpaired t tests, as well as parametric Pearson tests, were used for the statistical analyses. RESULTS: In healthy tissues, MR estimate of sO(2) measurements were comparable to literature values and were reproducible (mean across all animals, 68.0% ± 6.5 [standard deviation]). In untreated tumors, MR estimate of sO(2) and immunohistochemical analysis yielded correlated fractional hypoxic-necrotic areas (R(2) = 0.81). In tumors treated with antiangiogenic therapy, tumor MR estimate of sO(2) was decreased with respect to the healthy tissue (P< .001). CONCLUSION: Results of this study suggest that the MR estimate of sO(2) is a reproducible estimate that could be used as an in vivo probe of hypoxia in brain tumors and as a sensitive reporter of the hypoxic effects of antiangiogenic therapies.

MCM7 expression predicts post-operative prognosis for hepatocellular carcinoma.

BACKGROUND: Dysregulation of minichromosome maintenance protein 7 (MCM7) was previously identified in multiple human malignancies. The clinical significance of MCM7 expression is yet to be delineated in patients with hepatocellular carcinoma (HCC). METHODS: Paired cancerous and non-cancerous specimens from 87 patients with HCC who underwent resection were used for the immunohistochemical evaluation of MCM7 expression. Effect of sorafenib on the expression of MCM7 was tested in two human HCC cell lines SMMC-7721 and PLC/PRF/5. RESULTS: Non-cancerous tissues were negative for immunohistochemical staining for MCM7 expression. Nuclear MCM7 was expressed in 42 of 87 HCC (48.2%) and was correlated with hepatitis B virus infection (P = 0.020), intrahepatic metastasis (P = 0.022) and vascular invasion (P = 0.013). Moreover, its expression was correlated with shorter overall survival (P = 0.033). Multivariate analysis showed that MCM7 expression was an independent prognostic factor for overall survival(P = 0.041). Sorafenib inhibited the expression of MCM7 in a concentration-dependent manner in vitro. CONCLUSIONS: The current findings suggested that MCM7 expression may be a useful predictor of prognosis in patients with HCC after resection. Adjuvant therapy with sorafenib might be a valuable therapeutic strategy for MCM7-positive HCC patients.

Chemical genetic discovery of targets and anti-targets for cancer polypharmacology.

The complexity of cancer has led to recent interest in polypharmacological approaches for developing kinase-inhibitor drugs; however, optimal kinase-inhibition profiles remain difficult to predict. Using a Ret-kinase-driven Drosophila model of multiple endocrine neoplasia type 2 and kinome-wide drug profiling, here we identify that AD57 rescues oncogenic Ret-induced lethality, whereas related Ret inhibitors imparted reduced efficacy and enhanced toxicity. Drosophila genetics and compound profiling defined three pathways accounting for the mechanistic basis of efficacy and dose-limiting toxicity. Inhibition of Ret plus Raf, Src and S6K was required for optimal animal survival, whereas inhibition of the 'anti-target' Tor led to toxicity owing to release of negative feedback. Rational synthetic tailoring to eliminate Tor binding afforded AD80 and AD81, compounds featuring balanced pathway inhibition, improved efficacy and low toxicity in Drosophila and mammalian multiple endocrine neoplasia type 2 models. Combining kinase-focused chemistry, kinome-wide profiling and Drosophila genetics provides a powerful systems pharmacology approach towards developing compounds with a maximal therapeutic index.

Sorafenib in non-small cell lung cancer.

INTRODUCTION: Conventional chemotherapy has reached a plateau of effectiveness for the treatment of non-small cell lung cancer (NSCLC). Patients with EGFR mutation or ALK translocations will benefit significantly from agents targeting these pathways, however, only 20% of western NSCLC patients have these mutations. Anti-VEGF antibody bevacizumab was approved for advanced NSCLC, but the clinical benefits are modest and all patients eventually develop resistance. Multi-targeted tyrosine kinase inhibitors (TKI) may offer more efficient inhibition of angiogenesis by blocking overlapping pathways and they may also have direct anti-tumor effects. Sorafenib is approved in the treatment of renal cell carcinoma and hepatocellular carcinoma and is now under investigation in the treatment of NSCLC. AREAS COVERED: This review summarizes recent studies evaluating sorafenib in the treatment of NSCLC. EXPERT OPINION: Sorafenib has shown anti-tumor activity in NSCLC. However, because NSCLC is complex and molecularly heterogeneous, it is very likely that only a subset of NSCLC patients will benefit from sorafenib, and so it is imperative to discover biomarkers to select patients who will probably benefit from sorafenib. Combination with other agents targeting parallel and compensatory pathways, such as EGFR inhibitors, may offer broader coverage and better disease control.

Erlotinib and sorafenib in an orthotopic rat model of hepatocellular carcinoma.

BACKGROUND & AIMS: The combination of erlotinib with sorafenib is currently being investigated in a phase III RCT. We studied the effect of erlotinib and sorafenib on HCC in a preclinical model. METHODS: The Morris Hepatoma (MH) and HepG2 cells were treated in vitro with sorafenib (1-10 µM) and erlotinib (1-5 µM) and evaluated for tumor cell viability, apoptosis, and target regulation. Antiangiogenic effects were studied by measuring VEGF levels, endothelial cell viability, apoptosis, migration, and the aortic ring assay. In vivo, MH cells were implanted into the liver of syngeneic rats and treated with vehicle, sorafenib 5-10mg/kg, erlotinib 10mg/kg, and respective combinations. RESULTS: In vitro, erlotinib downregulated p-ERK but showed no significant effect on tumor cell viability in MH and HEPG2 cells. Despite a similar target regulation, sorafenib significantly reduced cell viability of HCC cells by induction of apoptosis, in a dose-dependent manner (11 ± 5%; 20 ± 10%; 51 ± 5% for sorafenib 1, 5, 10 µM). No additional effect was observed upon combination with erlotinib. Of note, erlotinib treatment resulted in endothelial cell migration and vascular sprouting of aortic rings through induction of VEGF mRNA and protein levels in endothelial and tumor cells, which was blocked by sorafenib. In vivo, erlotinib had no single agent antitumor activity, raised serum-VEGF levels, and lacked a synergistic effect in combination with sorafenib. CONCLUSIONS: Erlotinib had no antitumor effect on HCC in vitro nor in vivo, but induced VEGF, which may reflect a resistance mechanism to erlotinib monotherapy. No improvement of sorafenib efficacy was observed upon combination with erlotinib.

A phase II trial of intrapatient dose-escalated sorafenib in patients with metastatic renal cell carcinoma.

PURPOSE: Sorafenib has been demonstrated as second-line therapy, with limited significant adverse events at a dose of 400 mg twice a day (b.i.d.) in patients with metastatic renal cell carcinoma. This study evaluated the ability of patients to dose-escalate, response rate, progression-free survival (PFS), and overall survival. METHODS: The initial dose of sorafenib was 400 mg b.i.d.. Dose escalation of sorafenib to 600 mg b.i.d. occurred from days 29-56 and increased to 800 mg b.i.d. on day 57 and beyond as tolerated. Dose modifications were performed for toxicity per the National Cancer Institute Common Toxicity Criteria version 3.0. The patients were evaluated every 2 cycles (8 weeks) by using Response Evaluation Criteria in Solid Tumors version 1.0. RESULTS: Forty-four patients were evaluable for response. Median age was 62.5 years, 39 patients had a Karnofsky Perfomance Status of 100%. Twenty-two patients received no prior therapy. Of the evaluable patients, 42 were dose escalated to 600 mg b.i.d., and 74% (31) of these were further dose escalated to 800 mg b.i.d.. Eight patients had a complete response (CR), 13 patients demonstrated a partial response (PR), and 21 patients had stable disease. Common treatment-related adverse events included hypertension, hand-foot syndrome, skin rash, diarrhea, dry skin, alopecia, and facial redness. DISCUSSION: The majority of patients were escalated to 600 mg b.i.d. or 800 mg b.i.d.. Intrapatient dose-escalated sorafenib has promising antitumor activity as demonstrated by a 48% CR-PR rate (21 patients). Antitumor activity is further suggested by a prolonged PFS ≥6 months in 64% (28) of patients. Significant antitumor activity and reversible adverse events has been demonstrated in escalated doses of sorafenib.

[Sorafenib and octreotide combination therapy can inhibit proliferation of and induce apoptosis in human hepatoma cells].

To investigate the effects of sorafenib and octreotide combination treatment on cellular proliferation and explore the underlying molecular mechanisms by using an in vitro cell culture system with the human hepatoma cell line, HepG2. HepG2 cells were treated with different concentrations of sorafenib and octreotide alone or in combination. Untreated HepG2 cells were used as controls. Treatment-induced cytotoxicity was determined with the cell counting kit-8 by Sigma-Aldrich, and rate of apoptosis was detected by flow cytometry. Fluorescent microscopy was used to observe rates of cell growth under the various treatments. Treatment-induced changes in protein expressions were detected by enzyme-linked immunosorbent assay (for vascular endothelial growth factor (VEGF)) and Western blotting (for the Mcl-1 apoptosis mediator and the ERK1/2 and PERK1/2 kinases). Sorafenib and octreotide, used alone or in combination, inhibited proliferation and induced apoptosis in HepG2 cells. Combination treatment was more effective than either mono-treatment (F = 200.398, P less than 0.05). Fluorescent microscopy showed that combination treatment stimulated phosphatidylserine, the marker of early apoptosis, better than either mono-treatment. VEGF expression in cultures exposed to combination treatment was also significantly lower than in mono-treatment or untreated control cultures (F = 1019.725, P less than 0.05). Western blotting showed that octreotide mono-treatment had no effect on Mcl-1 expression (vs. control group; P more than 0.05) and that combination treatment significantly lowered Mcl-1 expression (vs. mono-treatment and control groups; P less than 0.05). None of the treatments affected ERK1/2 expression (all, P more than 0.05), while all treatments significantly lowered PERK1/2 expression (vs. control group; F = 2.401, P less than 0.05) and the combination treatment lowered PERK1/2 significantly more than either mono-treatment (P less than 0.05). Sorafenib and octreotide can inhibit proliferation and induce apoptosis in the human hepatoma cell line, HepG2. Combination treatment is significantly more efficacious (P less than 0.05) and produced synergistic effects. The mechanism underlying this phenomenon may depend on synergistic inhibition of VEGF, the anti-apoptotic protein Mcl-1, and the proliferation-inducing PERK1/2.

The effects of sorafenib on liver regeneration in a model of partial hepatectomy.

BACKGROUND: Sorafenib is currently approved for advanced hepatocellular carcinoma (HCC) and is presently being studied as an adjuvant treatment for HCC following resection. The effects of sorafenib on liver regeneration have not been clearly defined. Our objective was to identify the effects of sorafenib on liver regeneration in a murine partial hepatectomy (PH) model. MATERIALS AND METHODS: We performed PH in C57Bl/6 mice treated with a range of sorafenib doses with assessments at several time points. Liver sinusoidal endothelial cells (LSEC) and hepatocyte DNA synthesis and proliferation were assessed with 5-bromo-2'-deoxyuridine (BrdU) and Ki67 by flow cytometry and immunohistochemistry. RESULTS: Treatment with sorafenib did not result in any deaths following PH. When we measured BrdU uptake to assess DNA synthesis, there was a statistically significant increase at 48 h post-PH for nonfibrotic LSEC following treatment with 60 mg/kg of sorafenib. However, BrdU and Ki67 staining among LSEC and hepatocytes was not significantly affected by sorafenib at any of the other doses or time points. BrdU and Ki67 flow cytometry data correlated with immunohistochemistry findings and postoperative liver weights. CONCLUSION: In a murine PH model, sorafenib did not alter the repair response of normal or fibrotic livers following PH as measured by changes in liver weight, DNA synthesis, and cellular proliferation. These findings suggest sorafenib administered following hepatic resection does not impair liver regeneration.

Sorafenib in liver cancer.

INTRODUCTION: With growing knowledge of the molecular pathway of carcinogenesis, targeted therapies have become the 'blue ocean' of cancer treatment. sorafenib is an oral multikinase inhibitor that targets Raf/mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK) (Raf/MEK/ERK) and several tyrosine kinases (VEGFR-2, VEGFR-3, PDGFR-ß) that has shown efficacy in hepatocellular carcinoma (HCC). AREAS COVERED: An updated summary of the preclinical and clinical experience with sorafenib in HCC is presented in this paper. Data are based on abstracts from international conferences and journal articles found in a PubMed search of literature published up to December 2011. EXPERT OPINION: Based on favorable data from preclinical and clinical trials, sorafenib has been approved as a standard therapy in advanced HCC. However, further efforts to understand the additional roles of sorafenib in the treatment of HCC are still necessary. Data for sorafenib will guide the development of new drugs for the treatment of HCC.