The piperidine nitroxide Tempol potentiates the cytotoxic effects of temozolomide in human glioblastoma cells.

Temozolomide (TMZ) is a methylating agent with promising antitumor efficacy for the treatment of melanomas and intermediate-grade gliomas. Unfortunately, its use in the management of high-grade gliomas (glioblastomas) is limited by multifaceted resistance mechanisms. The aim of this study was to evaluate the possibility to improve the cytotoxic response of two human glioblastoma cell lines, U87MG and U373MG, to TMZ by the use of Tempol (TPL), a low molecular weight piperidine nitroxide that has been shown to inhibit in vitro and in vivo growth of murine glioma cells. To this purpose, we used two different schedules for the combined exposure to the two agents. Our data indicate that TPL synergizes with TMZ in both U87MG and U373MG cells for both schedules tested. This effect is accompanied by an increase in apoptotic cell death and by changes in the expression of genes involved in control of the apoptotic process. TPL was also observed to induce a cell-type specific decrease in GSH levels and in GSH-related enzyme activities that could contribute to its sensitizing effect.

Angiotensin II type 1 receptor expression in polymorphonuclear leukocytes from high-risk subjects: changes after treatment with simvastatin.

Statins may directly interfere with the effects of angiotensin (Ang) II, which is a key player in the pathogenesis of atherosclerosis (ATH). Ang II promotes a wide array of detrimental processes including a prominent proinflammatory effect, increasingly regarded as a target for therapeutic intervention. Because the proinflammatory effects of Ang II are exerted mainly through the activation of Ang II type 1 receptors (AT1Rs) the present study was devised to investigate by means of real-time polymerase chain reaction (PCR) and flow cytometry techniques the expression of such receptors on circulating polymorphonuclear leukocytes (PMNs) from subjects at high risk for vascular events before and during treatment with simvastatin and in sex- and age-matched healthy controls. In vitro experiments were also performed to assess the ability of simvastatin to interfere with Ang II signaling in human PMNs. In comparison to controls, high-risk subjects had similar AT1R expression on the cell membranes but significantly higher AT1R messenger ribonucleic acid (mRNA) levels. Treatment of high-risk subjects with simvastatin for 30 days resulted in a reduction of AT1R mRNA down to the levels of cells from healthy subjects. In vitro, Ang II-induced activation of the guanosine triphosphate (GTP)-binding protein Rac 1 in human PMNs was inhibited by simvastatin. In conclusion, simvastatin induces downregulation of AT1R expression, interferes with Ang II activity in PMNs, and contributes to the antiinflammatory profile of statins that can explain the therapeutic effects of these drugs.