부산대학교 도서관

To purchase or authenticate to the full-text of this article, please visit this link: http://dx.doi.org/10.1111/j.1471-4159.2008.05625.x Byline: Richa Tewari, Vivek Sharma, Nitin Koul, Ellora Sen Keywords: apoptosis; Fas; glioblastoma; lipid rafts; miltefosine; Ras Abstract: Abstract The anti-neoplastic property of alkyl phospholipids has been tested for the treatment of several malignancies. In this study, we evaluated the efficacy of miltefosine (Hexadecylphosphocholine - an alkyl phospholipids analogue) on glioblastoma multiforme. In this study, we demonstrate that miltefosine-induced apoptosis is accompanied by elevated Fas, Fas-associated death domain (FADD) expression, caspase-8 activity and the increased distribution of Fas and FADD towards lipid raft microdomain to form death inducing signaling complex. Treatment with miltefosine resulted in increase in Ras, extracellular signal-regulated kinase (ERK) and p38MAPK activity. Expression of dominant-negative Ras (Ras N17) attenuated miltefosine-mediated apoptosis. Although inhibition of both ERK and p38MAPK decreased the pro-apoptotic effects of miltefosine, it was the inhibition of ERK and not p38MAPK activation that decreased Fas and FADD expression. An ERK-dependent increase in the expression of [gamma]H2AX-involved in response to DNA double-stranded breaks was also observed. Taken together, our findings suggest the involvement of ERK activation in miltefosine-induced glioma cell apoptosis. Article History: Received June 6, 2008; revised manuscript received July 29, 2008; accepted August 4, 2008. Article note: Address correspondence and reprint requests to Ellora Sen, National Brain Research Centre, Nainwal Mode, NH-8, Manesar, Gurgaon, Haryana-122050, India. E-mail: ellora@nbrc.res.in