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, our in vivo data 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.

Glioblastomas with copy number gains in EGFR and RNF139 show increased expressions of carbonic anhydrase genes transformed by ENO1

“…Accordingly, the negative correlation and significant association for lack of XIAP gains with expression of CA12 in our study suggests that it may regulate expression of CA12 to control acidity in tumors. However, this relationship is complex in that there are also reports of several types of tumors, including gliomas, where targeting XIAP has been suggested for treatment purposes [73] , [74] , [75] , [76] .…”

Coenzyme Q10 Analogues: Benefits and Challenges for Therapeutics

“…Although DUb is known for being a CoQ 10 analogue and presumably keeps its beneficial effects, it also shows new effects as a mitochondrial PTP modulator [96]. In cancer research, the combination treatment of DUb, an X-linked inhibitor of the antiapoptotic protein (XIAP) and EDL-360 significantly inhibited glioma growth by inducing apoptosis, which shows that DUb has anticancer activity [103]. Furthermore, combination treatment of DUb with thialysine significantly suppressed the viability of human acute leukemia Jurkat T cells [104].…”

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