Control of proliferation in astrocytoma cells by the receptor tyrosine kinase/PI3K/AKT signaling axis and the use of PI-103 and TCN as potential anti-astrocytoma therapies

Abstract

A growing body of work suggests that astrocytomas and glioblastoma multiforme will require carefully tailored, molecularly targeted therapy for successful treatment. Recent efforts to comprehensively identify mutations and gene expression changes in glioblastoma have shown that mutation of NF1 is a common alteration in human glioblastoma. We have developed and characterized a panel of 14 tumor lines from grades II through IV astrocytomas developed from our Nf1-/+;Trp53-/+cis mouse model and have used this panel to characterize signal transduction pathways and inhibitors that are candidate therapeutic targets for astrocytoma and glioblastoma. We show that these tumors express platelet-derived growth factor receptor-α, epidermal growth factor receptor, and their respective ligands to varying degrees. We find that both the MEK and PI3K signaling pathways downstream of epidermal growth factor receptor and platelet-derived growth factor receptor-α are necessary for full proliferation of astrocytoma cells; however, inhibition of the PI3K pathway is more effective than inhibition of MEK at blocking cell growth. We have examined inhibitors of the PI3K/Akt/mTOR signaling pathway and find that PI-103 and TCN show particular promise for inhibiting growth in Nf1 and Trp53 mutant astrocytoma cells.

TCN, an AKT inhibitor, exhibits potent antitumor activity and enhances radiosensitivity in hypoxic esophageal squamous cell carcinoma in vitro and in vivo

“…In addition, TCN downregulated p-AKT, HIF-1α and VEGF in ESCC cells, and suppressed the growth of ESCC xenografts. These results may complement those from previous studies on TCN, which suggested that TCN may be an antitumor agent in different cancers, and may expand our understanding of the mechanisms of TCN activity (18).…”

“…HIF-1α is an oxygen-sensitive subunit (14), which, under hypoxic conditions, is an important factor for tumor cells to resist IR (15). TCN, which was initially described as a DNA synthesis inhibitor, has recently been shown to function as an inhibitor of AKT (18). Previous studies demonstrated that TCN inhibits AKT phosphorylation at Thr308 and Ser473 and AKT activity in the human prostate cancer cell line PC-3 (18).…”

“…TCN, which was initially described as a DNA synthesis inhibitor, has recently been shown to function as an inhibitor of AKT (18). Previous studies demonstrated that TCN inhibits AKT phosphorylation at Thr308 and Ser473 and AKT activity in the human prostate cancer cell line PC-3 (18). In addition, TCN sensitized PC-3 cells to tumor necrosis factor-related apoptosis-inducing ligand-and anti-cluster of differentiation 95-induced apoptosis, whereas the cells remained resistant to DNA damaging chemotherapeutics (16).…”

“…Triciribine (TCN), as an effective AKT inhibitor, has been demonstrated to effectively inhibit p-AKT (18). It has been reported that TCN potently and selectively inhibits the activation, TCN, an AKT inhibitor, exhibits potent antitumor activity and enhances radiosensitivity in hypoxic esophageal squamous cell carcinoma in vitro and in vivo dimerization and nuclear translocation of AKT, resulting in an increase in the apoptosis of prostate carcinoma cells (19).…”

Resveratrol inhibits glioma cell growth via targeting oncogenic microRNAs and multiple signaling pathways

“…A number of studies have demonstrated that EGFR is overexpressed in 60-90% of glioblastomas (36), as well as in C6 glioma cells (25). hyperactivated EGFR signaling promotes cell growth and inhibits apoptosis via its major downstream and crosstalk signaling pathways, such as PI3K/AKT/mTOR and RAS/MAPK, which can regulate cell survival, proliferation, invasion and angiogenesis (37)(38)(39). Our previous studies have demonstrated that antisense and dominantnegative EGFR cDNA or siRNA targeting EGFR effectively inhibit glioma cell growth (25,40).…”