title: EDL-360: A Potential Novel Antiglioma Agent.
abstract: Glioma is a brain tumor that arises from glial cells or glial progenitor cells, and represents 80% of malignant brain tumor incidence in the United States. Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor malignancy with fewer than 8% of patients with GBM surviving for more than 3 years. Over the past 10 years, despite improvement in diagnosis and therapies for cancer, the survival rate for high-grade glioma patients remains dismal. The main focus of our research is to identify potent novel antiglioma small molecules. We previously showed that EDL-360, a tetrahydroisoquinoline (THIQ) analog, as being highly cytotoxic to human glioma cell cultures. Here we show that EDL-360 significantly induced apoptosis in human glioma cell lines (U87 and LN18). However, in normal astrocytic cells, EDL-360 induced a modest G0/G1 cell cycle arrest but did not induce apoptosis. In an attempt to enhance EDL-360 induced cell death, we tested simultaneous treatment with EDL-360 and embelin (an inhibitor of the anti-apoptotic protein, XIAP). We found that, glioma cells had significant lower viability when EDL-360 and embelin were used in combination when compared to EDL-360 alone. We also used combination treatment of EDL-360 with decylubiquinone (dUb), a caspase-9 inhibitor, and found that the combination treatment induced a significant cell death when compared to treatment with EDL-360 alone. This is the first report that suggests that dUb has anticancer activity, and perhaps acts as a XIAP inhibitor. Finally, ourin vivodata showed that EDL-360 treatment induced a partial regression in glioma tumorigenesis and induced cell death in the treated tumors as shown by H&E staining. Taken together these data suggests that EDL-360 has a potential therapeutic application for treating glioma, especially when combined with XIAP inhibitors.
authors.affiliation: Departments of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, USA ; The Center for Cancer Research, University of Tennessee Health Science Center, USA ; Department of Chemistry, College of Science, Fayoum University, Fayoum, Egypt.
authors.forename: Amira
authors.initials: A
authors.lastname: Hosni-Ahmed
authors.affiliation: Departments of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, USA ; The Center for Cancer Research, University of Tennessee Health Science Center, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Sims
authors.affiliation: Scientific Affairs, Amgen, Thousand oaks, CA, USA.
authors.forename: Terreia S
authors.initials: TS
authors.lastname: Jones
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, USA.
authors.forename: Renukadevi
authors.initials: R
authors.lastname: Patil
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, USA.
authors.forename: Shivaputra
authors.initials: S
authors.lastname: Patil
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA ; Department of Chemistry, College of Science, Fayoum University, Fayoum, Egypt.
authors.forename: Hossam
authors.initials: H
authors.lastname: Abdelsamed
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, USA.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Yates
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, USA.
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
authors.affiliation: Departments of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, USA ; The Center for Cancer Research, University of Tennessee Health Science Center, USA.
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Pfeffer
keywords: Angiogenesis; Ovarian cancer; PARP inhibitors