Inhibition of NADPH oxidase 4 induces apoptosis in malignant mesothelioma: Role of reactive oxygen species.

Malignant pleural mesothelioma (MPM) is an aggressive tumor that is characterized by dysregulated growth and resistance to apoptosis. Reactive oxygen species (ROS)-generating NADPH oxidase (Nox) family enzymes have been suggested to be involved in neoplastic proliferation. Both the antioxidant N-acetylcysteine (NAC) and the inhibitor of flavoprotein-dependent oxidase, diphenylene iodonium (DPI), inhibited the cell viability of MPM cells in a dose-dependent manner. To examine whether Nox-mediated ROS generation confers antiapoptotic activity and thus a growth advantage to MPM cells, we analyzed the mRNA expression of Nox family members using quantitative RT-PCR in 7 MPM cell lines and a normal mesothelial cell line. Nox4 mRNA was expressed in all of the examined MPM cell lines, whereas little or no Nox2, Nox3 and Nox5 mRNA expression was detected. In 2 MPM cell lines, Nox4 mRNA expression was significantly higher than that in a normal mesothelial cell line. siRNAs targeting Nox4 suppressed ROS generation and cell viability in the MPM cell lines. In addition, DPI treatment and knockdown of Nox4 attenuated phosphorylation of AKT and ERK. Taken together, our results indicate that Nox4-mediated ROS, at least in part, transmit cell survival signals and their depletion leads to apoptosis, thus highlighting the Nox4-ROS-AKT signaling pathway as a potential therapeutic target for MPM treatment.

Comparison of the histological and immunohistochemical features of the thymus in young- and elderly-onset myasthenia gravis without thymoma.

We performed histological and immunohistochemical analyses of the removed thymuses from 20 elderly (onset age > 60 years) and 23 young (onset age < 40 years) patients with myasthenia gravis (MG) who tested positive for serum anti-acetylcholine receptor (AChR) antibodies, but who did not have associated thymoma. In the elderly group, nine (45%) patients had accumulations of lymphocytes, indicating an atrophied thymus with loss of the basic structure. The elderly MG patients with atrophied thymic tissues had higher titres of anti-AChR antibody (59.6+/-81.0 nmol/L) than those with adipose infiltration of the thymus alone (20.1+/-20.9 nmol/L). In immunohistochemical studies using image analysis, both young patients and elderly patients with atrophied thymic tissues were found to have significantly higher levels of CD20 than age-matched controls (p < 0.005). Atrophied thymic tissues, often seen immunohistochemically in young MG patients, may also be found in elderly patients, particularly in those with high titres of the anti-AChR antibody, even though adipose infiltration is marked in these patients.