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EDL-360: A Potential Novel Antiglioma Agent.

Hosni-Ahmed A, Sims M, Jones TS, Patil R, Patil S, Abdelsamed H, Yates CR, Miller DD, Pfeffer LM - J Cancer Sci Ther (2014)

Bottom Line: However, in normal astrocytic cells, EDL-360 induced a modest G0/G1 cell cycle arrest but did not induce apoptosis.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus

EDL-360 reduces tumor growth in human glioma xenograft mouse modelU87Luc cells were injected into the right flank of the mice. Once the tumor became palpable in the mice, treatment was initiated. A, Weight of the mice was obtained twice a week. There was no sign of toxicity or weight lose in EDL-360 treated group compared to the control mice. B, Tumor dimensions were obtained using digital caliper to determine tumor volume. C, Bioluminescence signal from control and treated mice showed an obvious decrease in tumor viable cells after 17 days of treatment. D, Quantification of bioluminescence signal showed a continuous tumor growth in the control mice. Bars represent the means; whiskers represent the standard deviation (±); * p<0.05.
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Figure 4: EDL-360 reduces tumor growth in human glioma xenograft mouse modelU87Luc cells were injected into the right flank of the mice. Once the tumor became palpable in the mice, treatment was initiated. A, Weight of the mice was obtained twice a week. There was no sign of toxicity or weight lose in EDL-360 treated group compared to the control mice. B, Tumor dimensions were obtained using digital caliper to determine tumor volume. C, Bioluminescence signal from control and treated mice showed an obvious decrease in tumor viable cells after 17 days of treatment. D, Quantification of bioluminescence signal showed a continuous tumor growth in the control mice. Bars represent the means; whiskers represent the standard deviation (±); * p<0.05.

Mentions: To assess the antiglioma activity of EDL-360 in vivo, mice bearing U87 glioma xenografts were treated with a daily single dose of the compound, and tumor growth examined by caliper and Xenogen animal imaging. For bioluminescence imaging, the U87 glioma cell line was transduced with the pLenti-Luc-mKate-pgk-puro viral vector, and the cells were grown in puromycin to select stably transfected cells. To generate the glioma mouse model, U87Luc cells were injected subcutaneously into the right flank of 4–6 week old BALBc (NSG) mice. Once the tumor became palpable, the mice were randomly assigned into groups of 5 mice. The treated group received 5 μM of EDL-360 daily, whereas the control group did not receive any treatment. Mice were monitored daily for any signs or symptoms of drug related toxicity. In addition, mice were weighed twice a week. There was no sign of toxicity or weight loss in the EDL-360 treated group compared to the control mice (Figure 4A).


EDL-360: A Potential Novel Antiglioma Agent.

Hosni-Ahmed A, Sims M, Jones TS, Patil R, Patil S, Abdelsamed H, Yates CR, Miller DD, Pfeffer LM - J Cancer Sci Ther (2014)

EDL-360 reduces tumor growth in human glioma xenograft mouse modelU87Luc cells were injected into the right flank of the mice. Once the tumor became palpable in the mice, treatment was initiated. A, Weight of the mice was obtained twice a week. There was no sign of toxicity or weight lose in EDL-360 treated group compared to the control mice. B, Tumor dimensions were obtained using digital caliper to determine tumor volume. C, Bioluminescence signal from control and treated mice showed an obvious decrease in tumor viable cells after 17 days of treatment. D, Quantification of bioluminescence signal showed a continuous tumor growth in the control mice. Bars represent the means; whiskers represent the standard deviation (±); * p<0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4285352&req=5

Figure 4: EDL-360 reduces tumor growth in human glioma xenograft mouse modelU87Luc cells were injected into the right flank of the mice. Once the tumor became palpable in the mice, treatment was initiated. A, Weight of the mice was obtained twice a week. There was no sign of toxicity or weight lose in EDL-360 treated group compared to the control mice. B, Tumor dimensions were obtained using digital caliper to determine tumor volume. C, Bioluminescence signal from control and treated mice showed an obvious decrease in tumor viable cells after 17 days of treatment. D, Quantification of bioluminescence signal showed a continuous tumor growth in the control mice. Bars represent the means; whiskers represent the standard deviation (±); * p<0.05.
Mentions: To assess the antiglioma activity of EDL-360 in vivo, mice bearing U87 glioma xenografts were treated with a daily single dose of the compound, and tumor growth examined by caliper and Xenogen animal imaging. For bioluminescence imaging, the U87 glioma cell line was transduced with the pLenti-Luc-mKate-pgk-puro viral vector, and the cells were grown in puromycin to select stably transfected cells. To generate the glioma mouse model, U87Luc cells were injected subcutaneously into the right flank of 4–6 week old BALBc (NSG) mice. Once the tumor became palpable, the mice were randomly assigned into groups of 5 mice. The treated group received 5 μM of EDL-360 daily, whereas the control group did not receive any treatment. Mice were monitored daily for any signs or symptoms of drug related toxicity. In addition, mice were weighed twice a week. There was no sign of toxicity or weight loss in the EDL-360 treated group compared to the control mice (Figure 4A).

Bottom Line: However, in normal astrocytic cells, EDL-360 induced a modest G0/G1 cell cycle arrest but did not induce apoptosis.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus