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




Connell-Albert, Yvette

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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.



Biology, Oncology, Gliomas, Astrocytomas, GBMS, Nelfinivir, PIA-6, OSU-03012, Chloroquine, Perifosine, Pannexin 2, PI-103, Tricirbine, Rapamycin, PI3K/AKT/mTOR, Schweinfurthin A, 3DSB, NSC#746620