pd-0325901 and Carcinoma--Hepatocellular

To provide support for combined usage of phosphoinositide 3-kinase (PI3K) inhibitors or mitogen-activated protein kinase pathway inhibitors together with sorafenib in treatment of sorafenib-resistant hepatocellular carcinoma.. The sorafenib-resistant cell lines were established to evaluate the effects of MK-2206 2HCL, a dual PI3K/mammalian target of rapamycin (mTOR) inhibitor, and PD0325901, an rat sarcoma (RAS) and/or extracellular signal-regulated kinase (ERK) inhibitor, on cell proliferation and apoptosis, as both single and combined treatments with sorafenib. In addition, multidrug resistance 1 gene expression, mutation status of key members in PI3K/mTOR, and RAS/ERK pathways and pathway activation were analyzed to identify predictors of drug response.. Molecular studies reveal that combining MK-2206 2HCL or PD0325901 with sorafenib not only has a synergistic effect, in suppressing PI3K/protein kinase B/mTOR and RAS/MEK/ERK signaling more effectively than either treatment alone, but also prevents the cross activation of the other pathway that occurs with single treatments in both sorafenib sensitive and resistant lines. PD0325901 exhibited a stronger synergic effect with sorafenib than MK-2206 2HCL. Sorafenib-resistant cell lines were characterized by activation of both of the two pathways, as indicated by multidrug resistance 1 gene expression profiles and pathway activity analysis.. Our studies have showed that both inhibitors of PI3K/mTOR and RAS/ERK signaling are potentially effective antihepatocellular carcinoma drugs especially in treating sorafenib-resistant hepatocellular carcinoma.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Biomarkers, Tumor; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Cell Survival; Diphenylamine; Drug Resistance, Neoplasm; Heterocyclic Compounds, 3-Ring; Humans; Liver Neoplasms; Niacinamide; Phenylurea Compounds; Sorafenib

Hepatocellular carcinoma (HCC) causes 600,000 mortalities per year worldwide. Previous studies from our lab provide evidence for altered mitogen-activated protein kinase and extracellular signal-regulated kinase kinase (MEK) signaling in HCC pathogenesis. We hypothesized that pharmacologic targeting of MEK may prevent HCC. Transforming growth factor-alpha-transgenic mice (CD1-MT42) exposed to diethylnitrosamine were randomized to 20 (trial I) or 35 (trial II) weeks of MEK inhibitor PD0325901 (1, 10 mg/kg) or control via orogastric gavage. Ten HCC (44%) formed in trial I controls versus 0 in treatment arms (p<0.05). Fourteen HCC (50%) formed in trial II controls versus 1 (9%) in treatment arms (p<0.05). Mean HCC volume was 578 mm3 in control versus 46 mm3 in the single tumor formed in trial II. In trial I, foci of altered hepatocytes (FAH) formed in 78% of control versus 40% and 0% (1 and 10 mg/kg PD0325901) in treatment arms (p<0.05). In trial II, incidence of FAH was 80% in control versus 20% and 50% (1 and 10 mg/kg PD0325901) in treatment arms (p<0.05). Hepatocyte expression of phosphorylated extracellular signal-regulated kinase dose-dependently decreased in trial I but remained the same in trial II. Control and treated HCC demonstrated similar proliferation rates, but apoptosis appeared increased with treatment. MEK targeting is effective HCC chemoprevention, perhaps by lowering the apoptotic threshold.

Topics: Alkylating Agents; Animals; Apoptosis; Benzamides; Carcinoma, Hepatocellular; Cell Proliferation; Chemoprevention; Diethylnitrosamine; Diphenylamine; Dose-Response Relationship, Drug; Extracellular Signal-Regulated MAP Kinases; Follow-Up Studies; Hepatocytes; Immunohistochemistry; Ki-67 Antigen; Liver Neoplasms, Experimental; Mice; Mice, Transgenic; Transforming Growth Factor alpha