The orally bioavailable met inhibitor PF-2341066 inhibits osteosarcoma growth and osteolysis/matrix production in a xenograft model.

Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents. Ninety percent of patients who present with metastatic and 30% to 40% of patients with nonmetastatic disease experience relapse, creating an urgent need for novel therapeutic strategies. The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are important for mitosis, motility, and cell survival. Upregulation of Met/HGF signaling via receptor overexpression, amplification, or mutation drives the proliferation, invasiveness, and metastasis of a variety of cancer cells, including OS, prompting the development of Met/HGF inhibitors. OS cells depend on Met overexpression because introduction of dominant-negative Met inhibits in vivo tumorigenicity. Despite the importance of Met/HGF signaling in the development and maintenance of OS, the potential efficacy of pharmacologic Met inhibition in OS has been addressed only in in vitro studies. PF-2341066 is an orally bioavailable, selective ATP-competitive Met inhibitor that showed promising results recently in a phase I clinical trial in non-small cell lung cancer (NSCLC) patients. We tested the ability of PF-2341066 to inhibit malignant properties of osteosarcoma cells in vitro and orthotopic xenograft growth in vivo. In vitro, PF-2341066 inhibited osteosarcoma behavior associated with primary tumor growth (eg, proliferation and survival) as well as metastasis (eg, invasion and clonogenicity). In nude mice treated with PF-2341066 via oral gavage, the growth and associated osteolysis and extracortical bone matrix formation of osteosarcoma xenografts were inhibited by PF-2341066. PF-2341066 may represent an effective new systemic therapy for localized and potentially disseminated osteosarcoma.

The impact of HMG-CoA reductase therapy on serum PSA.

BACKGROUND: 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors, otherwise known as statins, inhibit the enzyme that controls the conversion of HMG-CoA to mevalonate, a precursor for cholesterol. Statins may be important to prostate cancer biology by inhibiting cell growth, inflammation, and oxidative stress. The purpose of this study was to assess the influence of statin therapy on serum prostate-specific antigen (PSA) levels. METHODS: The computerized medical records at the University of Rochester Medical Center were used to identify men who filled statin prescriptions between May 31st, 2008 and September 30th, 2008. Men with at least one PSA assay performed within 2 years before and at least one PSA assay performed within 1 year after starting a statin medication were included. The primary endpoint was the change in PSA concentration computed as the difference between PSA levels before and after starting a statin medication. Paired t-tests were used to analyze the mean differences in PSA values. RESULTS: A total of 962 patients were identified. The mean difference in serum PSA level after statin administration was -0.29 ng/ml (-8.04%). Subgroup analyses for mean PSA concentration change before and after statin administration by age group revealed: 50-59 years old (-0.1609, 95% CI: -0.2444, -0.0775, P < 0.0002), 60-69 years old (-0.3393, 95% CI: -0.4641, -0.2145, P < 0.0001), and >70 years old (-0.351, 95% CI: -0.490, -0.212, P < 0.0001). CONCLUSIONS: These observations suggest a statistically significant reduction in serum PSA level that is associated with the onset of statin therapy.

Propofol activates and allosterically modulates recombinant protein kinase C epsilon.

BACKGROUND: Myocardial protection by anesthetics is known to involve activation of protein kinase C epsilon (PKC epsilon). A key step in the activation process is autophosphorylation of the enzyme at serine 729. This study's objectives were to identify the extent to which propofol interacts with PKC epsilon and to identify the molecular mechanism(s) of interaction. METHODS: Immunoblot analysis of recombinant PKC epsilon was used to assess autophosphorylation of PKC epsilon at serine 729 before and after exposure to propofol. An enzyme-linked immunosorbant assay kit was used for measuring PKC epsilon activity. Spectral shifts in fluorescence emission maxima of the C1B subdomain of PKC epsilon in combination with the fluorescent phorbol ester, sapintoxin D, was used to identify molecular interactions between propofol and the phorbol ester/diacylglycerol binding site on the enzyme. RESULTS: Propofol (1 microM) caused a sixfold increase in immunodetectable serine 729 phosphorylated PKC epsilon and increased catalytic activity of the enzyme in a dose-dependent manner. Dioctanoylglycerol-induced or phorbol myristic acetate-induced activation of recombinant PKC epsilon activity was enhanced by preincubation with propofol. Both propofol and phorbol myristic acetate quenched the intrinsic fluorescence spectra of the PKC epsilon C1B subdomain in a dose-dependent manner, and propofol caused a further leftward-shift in the fluorescence emission maxima of sapintoxin D after addition of the C1B subdomain. CONCLUSIONS: These results demonstrate that propofol interacts with recombinant PKC epsilon causing autophosphorylation and activation of the enzyme. Moreover, propofol enhances phorbol ester-induced catalytic activity, suggesting that propofol binds to a region near the phorbol ester binding site allowing for allosteric modulation of PKC epsilon catalytic activity.