%0 Journal Article
%T Inhibition of NF-百B by Dehydroxymethylepoxyquinomicin Suppresses Invasion and Synergistically Potentiates Temozolomide and 污-Radiation Cytotoxicity in Glioblastoma Cells
%A M. S. Brassesco
%A G. M. Roberto
%A A. G. Morales
%A J. C. Oliveira
%A L. E. A. Delsin
%A J. A. Pezuk
%A E. T. Valera
%A C. G. Carlotti Jr.
%A E. M. Rego
%A H. F. de Oliveira
%A C. A. Scrideli
%A K. Umezawa
%A L. G. Tone
%J Chemotherapy Research and Practice
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/593020
%X Despite advances in neurosurgery and aggressive treatment with temozolomide (TMZ) and radiation, the overall survival of patients with glioblastoma (GBM) remains poor. Vast evidence has indicated that the nuclear factor NF-百B is constitutively activated in cancer cells, playing key roles in growth and survival. Recently, Dehydroxymethylepoxyquinomicin (DHMEQ) has shown to be a selective NF-百B inhibitor with antiproliferative properties in GBM. In the present study, the ability of DHMEQ to surmount tumor's invasive nature and therapy resistance were further explored. Corroborating results showed that DHMEQ impaired cell growth in dose- and time-dependent manners with G2/M arrest when compared with control. Clonogenicity was also significantly diminished with increased apoptosis, though necrotic cell death was also observed at comparable levels. Notably, migration and invasion were inhibited accordingly with lowered expression of invasion-related genes. Moreover, concurrent combination with TMZ synergistically inhibited cell growth in all cell lines, as determined by proliferation and caspase-3 activation assays, though in those that express O6-methylguanine-DNA methyltransferase, the synergistic effects were schedule dependent. Pretreatment with DHMEQ equally sensitized cells to ionizing radiation. Taken together, our results strengthen the potential usefulness of DHMEQ in future therapeutic strategies for tumors that do not respond to conventional approaches. 1. Introduction Glioblastoma (GBM) is the most aggressive primary brain tumor [1]. Despite improvements in neurosurgery, radiation management, and the advent of temozolomide (TMZ), the outcome of patients remains extremely poor, with a mean life expectancy of approximately one year [2], owing to its ability to infiltrate/invade surrounding tissues and inherent radio- and chemoresistance. Over the past decade, compelling evidence demonstrated that constitutive activation of NF-百B and aberrant regulation of the signaling pathways that control its activity are involved in cancer development and progression, as well as in resistance to therapy in many types of malignancies including GBM [3每6]. Thus, inhibition of the NF-百B pathway seems to be a promising option to improve the efficacy of conventional anticancer therapies. A plethora of NF-百B inhibitors has shown to be effective against various carcinomas and lymphomas (including proteasome inhibitors, IKK inhibitors, and inhibitors of IkB phosphorylation) [7], though, most of them barely discriminate between malignant and normal cells and result in
%U http://www.hindawi.com/journals/cherp/2013/593020/