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Aberrant Signaling in Astrocytomas and Glioblastoma Multiforme (GBM): Utilizing Inhibitors of Proliferation as Potential Therapies

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dc.contributor.advisor Baranova, Ancha Connell-Albert, Yvette
dc.creator Connell-Albert, Yvette en_US 2013-08-09T15:39:28Z 2013-08-09T15:39:28Z 2013 en_US
dc.description.abstract Glioblastomas (GBMs), the most aggressive malignant astrocytomas, are recurrent, infiltrative, and fatal. In GBMs, receptor tyrosine kinases (RTKs) are often activated by mutations, leading to the dysregulation of cell signaling pathways. The PI3K/Akt1/mTOR pathway, which plays a role in many biological processes such as proliferation, survival, invasion, migration and angiogenesis, is often deregulated in malignant cancers, often by the simultaneous loss of tumor suppressor PTEN, and the hyperactivation of the kinase Akt. Therefore, pharmacological inhibition of the PI3K/Akt1/mTOR pathway may prove beneficial in arresting the growth of astrocytomas and glioblastomas. In order to determine if the candidate molecules Choloroquine, Nelfinivir, PIA-6, OSU03012, Rapamycin, Tricribine (TCN), and PI-103 inhibit the PI3K/Akt-1/mTOR pathway, we used the Alamar blue assay as a measure of cell viability and cytotoxicity in mouse astrocytoma cell lines K1861-10 Grade II; KR158 Grade III; K130G#3 Grade IV; human astrocytoma cell lines, U87MG and SF295, both Grades IV; and normal proliferating mouse primary astrocytes treated with candidate molecules described above. Inhibitors with low IC50 values in tumor cells as compared to normal primary astrocytes were selected. From the select panel of inhibitors, only the AKT inhibitor Tricirbine and dual PI3K/Akt-1 inhibitor PI-103 showed low IC50 values in the nM or pM range, suggesting strong inhibition of cell viability in the astrocytoma cell lines tested. Rapamycin, an mTOR inhibitor, showed inconsistent inhibition of cell viability on the cell lines tested, suggesting that rapamycin may be acting through more than one pathway. The results of our study suggest that the PI3K/Akt1/mTOR pathway has potential as a druggable target in astrocytomas and glioblastomas.
dc.format.extent 200 pages en_US
dc.language.iso en en_US
dc.rights Copyright 2013 Yvette Connell-Albert en_US
dc.subject Biology en_US
dc.subject Oncology en_US
dc.subject Gliomas en_US
dc.subject Astrocytomas en_US
dc.subject GBMS en_US
dc.subject Nelfinivir en_US
dc.subject PIA-6 en_US
dc.subject OSU-03012 en_US
dc.subject Chloroquine en_US
dc.subject Perifosine en_US
dc.subject Pannexin 2 en_US
dc.subject PI-103 en_US
dc.subject Tricirbine en_US
dc.subject Rapamycin en_US
dc.subject PI3K/AKT/mTOR en_US
dc.subject Schweinfurthin A en_US
dc.subject 3DSB en_US
dc.subject NSC#746620 en_US
dc.title Aberrant Signaling in Astrocytomas and Glioblastoma Multiforme (GBM): Utilizing Inhibitors of Proliferation as Potential Therapies en_US
dc.type Dissertation en Doctoral en Biosciences en George Mason University en

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