Propofol induces apoptosis of non-small cell lung cancer cells via ERK1/2-dependent upregulation of PUMA.

OBJECTIVE: Propofol is one of the most commonly used intravenous anesthetic agents used in cancer resections, but the effect of propofol on non-small cell lung cancer (NSCLC) remains unclear. Previous researches have reported that propofol can inhibit extracellular signal-regulated kinase (ERK) 1/2 phosphorylation or activate p53-upregulated modulator of apoptosis (PUMA) signaling, resulting in apoptosis. In addition, PUMA is negatively regulated by ERK1/2 activation. In the present work, we determined the effect of propofol on NSCLC A549 cells and explored its signaling pathway. MATERIALS AND METHODS: A549 cells were treated with different concentrations of propofol (1-10 µg/mL) for 6 h. After washing, cells were cultured in Dulbecco's Modified Eagle Medium supplemented with 10% fetal bovine serum and antibiotics for another 72 h. Cell survival and apoptosis were determined by MTT, flow cytometry, and TUNEL analyses. To assess whether propofol functions via ERK1/2 and PUMA signaling pathways, A549 cells were transfected with small interfering RNA (siRNA) to target PUMA, or treated with human recombinant ERK1/2 (hrERK1/2) to activate ERK1/2. RESULTS: Propofol treatment inhibited viability and induced apoptosis of A549 cells in a dose-dependent manner in vitro. Propofol inhibited phosphorylation of ERK1/2 (pERK1/2) and increased ERK1/2-dependent PUMA expression. Knockdown of PUMA by siRNA or treatment with hrERK1/2 to activate ERK1/2 blocked propofol-induced apoptosis and cell viability. Upregulation of PUMA expression by propofol requires pERK1/2 inactivation. CONCLUSIONS: Propofol inhibits viability and induces apoptosis of A549 cells via an ERK1/2-dependent PUMA signaling.

Management of difficult intra-articular fractures or fracture dislocations of the proximal interphalangeal joint.

Intra-articular fractures or fracture dislocations of the proximal interphalangeal joint are difficult clinically because the bone and soft tissue structures are small and intricate. Suboptimal treatment of intra-articular fractures typically leads to functional impairment of the hand. This article reviews the current methods of treatment, together with the senior author's experience in treating difficult proximal interphalangeal joint fractures and dislocations. Besides conservative treatments, surgical treatments include open or closed reduction with traditional Osteosynthesis, such as K-wires, screws or plates. Among recent developments are the percutaneous application of thin cannulated compression screws and novel dynamic external fixators. After a preferred minimally invasive treatment with stable reconstruction of the articular surface, sufficient aftercare is necessary to improve surgical outcomes.

Transplacental genotoxicity of triethylenemelamine, benzene, and vinblastine in mice.

Transplacental cytogenetic effects of triethylenemelamine (TEM), benzene, and vinblastine on maternal mice and their fetuses have been investigated using micronucleus and sister chromatid exchange (SCE) as genetic endpoints. CD-1 mice were treated on day 14 and 15 of gestation with TEM (0.125, 0.25, and 0.5 mg/kg), benzene (439,878, and 1,318 mg/kg), and vinblastine (0.5, 1, and 2 mg/kg) by intraperitoneal injection at 24 hr intervals, and sacrificed 40 hr after the first injection. Erythrocytic precursor cells in maternal bone marrow and fetal livers (2-4) from each pregnant mouse were used for the micronucleus and/or the SCE analyses. Significant dose-related increases in both micronuclei and SCE were found in maternal bone marrow and fetal liver following TEM treatment. Benzene at the highest dose (1,318 mg/kg) also caused a significant increase in micronuclei and SCE in both maternal bone marrow and fetal liver cells. The embryonic genotoxic effect of TEM was much higher than that of benzene for both genetic endpoints, and the frequency of micronuclei induced by benzene was higher in fetal liver than in maternal bone marrow cells. Vinblastine, a spindle poison, induced micronuclei but not SCE. Micronuclei induction by vinblastine was 7 fold greater in maternal bone marrow than in fetal liver cells. All three chemicals were cytotoxic in maternal bone marrow cells, but not in fetal liver cells except for TEM, which showed a weak cytotoxicity in fetal liver cells in the micronucleus assay. These results indicate that TEM, benzene, and vinblastine are transplacental genotoxicants in mice.

Genotoxicity of diesel-exhaust particles dispersed in simulated pulmonary surfactant.

Diesel-exhaust particles from two sources were dispersed in aqueous mixtures of dipalmitoyl phosphatidyl choline, a major component of pulmonary surfactant, and were tested for genotoxicity. Diesel samples from the same sources were extracted with dichloromethane and transferred into dimethyl sulfoxide and subjected to the same assays. Both types of extractions yielded similar results in both the Salmonella mutagenicity assay and the sister-chromatid exchange assay using V79 cells. After separation of the samples into supernatant and sediment fractions, the activity of both diesel samples was shown to reside exclusively in the supernatant fraction for the solvent-extracted samples, and exclusively in the sedimented fraction for surfactant dispersed samples. These findings indicate that genotoxic activity associated with diesel particles inhaled into the lung may be made bioavailable by virtue of the solubilization/dispersion properties of pulmonary surfactant components.

Effect of tetrandrine on micronucleus formation and sister-chromatid exchange in both in vitro and in vivo assays.

The genotoxicity of tetrandrine, a drug potentially useful for the treatment of silicosis, was studied using the micronucleus and the sister-chromatid exchange (SCE) assay systems. Cultured Chinese hamster lung (V79) cells were used for the in vitro micronucleus and sister-chromatid exchange studies. Mouse bone marrow was used for the in vivo micronucleus assay and mouse spleen cells for the in vivo/in vitro sister-chromatid exchange analysis. The results show that SCE levels in V79 and in spleen cells were significantly elevated by treatment with tetrandrine at doses above 0.08 mg/ml and 100 mg/kg bw, respectively. Increased tetradrine-induced SCE in vitro was metabolic activation dependent. Tetrandrine failed to induce micronuclei at any of the doses tested. A decrease of replicative index with an increase in the concentration of tetrandrine was found both in vitro and in vivo. These results indicate that tetrandrine is a weak indirect-acting genotoxicant.

Enhancing effect of tetrandrine on sister-chromatid exchanges induced by mitomycin C and cigarette-smoke condensate in mammalian cells.

The enhancing effect of tetrandrine, an antisilicosis, antitumor and antiinflammatory drug, on the genotoxic activity of two known mutagens, mitomycin C (MMC) and cigarette-smoke condensate (CSC), has been studied using cultured Chinese hamster lung (V79) cells. The sister-chromatid exchange (SCE) was used as genetic endpoint to measure genotoxicity. One-day cultured cells were exposed to the test chemicals for 3 h with or without metabolic activation. The results show that the frequencies of SCE induced by MMC or CSC were enhanced by tetrandrine. The percent of enhancement was dependent on the concentration of tetrandrine.