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GSK1838705A, an IGF-1R inhibitor, inhibits glioma cell proliferation and suppresses tumor growth in vivo.

Zhou X, Shen F, Ma P, Hui H, Pei S, Chen M, Wang Z, Zhou W, Jin B - Mol Med Rep (2015)

Bottom Line: Its anti-proliferative activity has been demonstrated in various tumor cell lines.The GSK1838705A‑treated cells exhibited reduced migratory activity in response to chemoattractants.The present study further demonstrated the antitumor activity of GSK1838705A in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453100, P.R. China.

ABSTRACT
Glioma is a type of primary malignant tumor of the central nervous system in humans. At present, standard treatment involves surgical resection, followed by radiation therapy and chemotherapy. However, the prognosis is poor and the long‑term survival rate remains low. An improved understanding of the molecular basis for glioma tumorigenesis is in urgently required. The pro‑survival effect of the insulin‑like growth factor (IGF) signaling pathway has been implicated in progression of the glioma disease state. GSK1838705A is a novel, small molecule kinase inhibitor of IGF‑IR, which inhibits IGF signal transduction and downstream target activation. Its anti-proliferative activity has been demonstrated in various tumor cell lines. The present study investigated the potential use of GSK1838705A for the treatment of glioma. Human U87MG glioma cells were used to examine the inhibitory activity of GSK1838705A in cell proliferation, migration and apoptosis. The antitumor activity of GSK1838705A was assessed in a xenograft mouse model. GSK1838705A inhibited the growth and induced the apoptosis of the U87MG glioma cells in a dose‑dependent manner. The GSK1838705A‑treated cells exhibited reduced migratory activity in response to chemoattractants. The present study further demonstrated the antitumor activity of GSK1838705A in vivo. The administration of GSK1838705A significantly inhibited the growth of glioma tumors by inducing the apoptosis of tumor cells. These results suggested that targeting IGF signaling with GSK1838705A may be a promising therapeutic strategy for the treatment of patients with glioma.

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GSK1838705A induces the apoptosis of glioma cells. (A) U87MG cells were treated with DMSO or GSK1838705A at the indicated concentrations for 48 h, followed by the analysis of sub-G1 DNA content. (B) U87MG cells were incubated with DMSO or 100 µM GSK1838705A for 48 h. The nuclei were stained with Hoechst and analyzed using fluorescent microscopy (magnification, ×100). Representative images are shown. (C) Number of cells with condensed/fragmented nuclei, quantified by counting in seven randomly-selected fields, from which the average percentage was calculated. P<0.05, 25, 50 and 100 vs. 0 µM. The data are expressed as the mean ± standard deviation DMSO, dimethyl sulfoxide.
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f2-mmr-12-04-5641: GSK1838705A induces the apoptosis of glioma cells. (A) U87MG cells were treated with DMSO or GSK1838705A at the indicated concentrations for 48 h, followed by the analysis of sub-G1 DNA content. (B) U87MG cells were incubated with DMSO or 100 µM GSK1838705A for 48 h. The nuclei were stained with Hoechst and analyzed using fluorescent microscopy (magnification, ×100). Representative images are shown. (C) Number of cells with condensed/fragmented nuclei, quantified by counting in seven randomly-selected fields, from which the average percentage was calculated. P<0.05, 25, 50 and 100 vs. 0 µM. The data are expressed as the mean ± standard deviation DMSO, dimethyl sulfoxide.

Mentions: Tumor cells often evolve mechanisms to evade or antagonize programmed cell death, and IGF is a potent pro-survival factor, which increases cell proliferation, therefore activation of IGF signaling provides cells with a growth advantage (8). The present study investigated whether inhibiting IGF signaling via treatment of glioma cells with GSK1838705A induced apoptosis in the glioma cell. The sub-G1 DNA content in cells was measured as an indicator of late stage apoptosis (21). Consistent with the results obtained in the measurement of cell viability, GSK1838705A caused an increase in sub-G1 DNA content in a dose-dependent manner, which confirmed that the inhibition of IGF signaling promoted apoptosis in the affected cells (Fig. 2A). Apoptosis-induced condensation and fragmentation of DNA was visualized following nuclear staining. Compared with the untreated cells, the cells treated with GSK1838705A exhibited marked apoptosis, as shown in Fig. 2B. Similar to the results shown in Fig. 2A, the percentage of cells with condensed/fragmented DNA increased proportionally with increasing concentrations of GSK1838705A (Fig. 2C).


GSK1838705A, an IGF-1R inhibitor, inhibits glioma cell proliferation and suppresses tumor growth in vivo.

Zhou X, Shen F, Ma P, Hui H, Pei S, Chen M, Wang Z, Zhou W, Jin B - Mol Med Rep (2015)

GSK1838705A induces the apoptosis of glioma cells. (A) U87MG cells were treated with DMSO or GSK1838705A at the indicated concentrations for 48 h, followed by the analysis of sub-G1 DNA content. (B) U87MG cells were incubated with DMSO or 100 µM GSK1838705A for 48 h. The nuclei were stained with Hoechst and analyzed using fluorescent microscopy (magnification, ×100). Representative images are shown. (C) Number of cells with condensed/fragmented nuclei, quantified by counting in seven randomly-selected fields, from which the average percentage was calculated. P<0.05, 25, 50 and 100 vs. 0 µM. The data are expressed as the mean ± standard deviation DMSO, dimethyl sulfoxide.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581800&req=5

f2-mmr-12-04-5641: GSK1838705A induces the apoptosis of glioma cells. (A) U87MG cells were treated with DMSO or GSK1838705A at the indicated concentrations for 48 h, followed by the analysis of sub-G1 DNA content. (B) U87MG cells were incubated with DMSO or 100 µM GSK1838705A for 48 h. The nuclei were stained with Hoechst and analyzed using fluorescent microscopy (magnification, ×100). Representative images are shown. (C) Number of cells with condensed/fragmented nuclei, quantified by counting in seven randomly-selected fields, from which the average percentage was calculated. P<0.05, 25, 50 and 100 vs. 0 µM. The data are expressed as the mean ± standard deviation DMSO, dimethyl sulfoxide.
Mentions: Tumor cells often evolve mechanisms to evade or antagonize programmed cell death, and IGF is a potent pro-survival factor, which increases cell proliferation, therefore activation of IGF signaling provides cells with a growth advantage (8). The present study investigated whether inhibiting IGF signaling via treatment of glioma cells with GSK1838705A induced apoptosis in the glioma cell. The sub-G1 DNA content in cells was measured as an indicator of late stage apoptosis (21). Consistent with the results obtained in the measurement of cell viability, GSK1838705A caused an increase in sub-G1 DNA content in a dose-dependent manner, which confirmed that the inhibition of IGF signaling promoted apoptosis in the affected cells (Fig. 2A). Apoptosis-induced condensation and fragmentation of DNA was visualized following nuclear staining. Compared with the untreated cells, the cells treated with GSK1838705A exhibited marked apoptosis, as shown in Fig. 2B. Similar to the results shown in Fig. 2A, the percentage of cells with condensed/fragmented DNA increased proportionally with increasing concentrations of GSK1838705A (Fig. 2C).

Bottom Line: Its anti-proliferative activity has been demonstrated in various tumor cell lines.The GSK1838705A‑treated cells exhibited reduced migratory activity in response to chemoattractants.The present study further demonstrated the antitumor activity of GSK1838705A in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453100, P.R. China.

ABSTRACT
Glioma is a type of primary malignant tumor of the central nervous system in humans. At present, standard treatment involves surgical resection, followed by radiation therapy and chemotherapy. However, the prognosis is poor and the long‑term survival rate remains low. An improved understanding of the molecular basis for glioma tumorigenesis is in urgently required. The pro‑survival effect of the insulin‑like growth factor (IGF) signaling pathway has been implicated in progression of the glioma disease state. GSK1838705A is a novel, small molecule kinase inhibitor of IGF‑IR, which inhibits IGF signal transduction and downstream target activation. Its anti-proliferative activity has been demonstrated in various tumor cell lines. The present study investigated the potential use of GSK1838705A for the treatment of glioma. Human U87MG glioma cells were used to examine the inhibitory activity of GSK1838705A in cell proliferation, migration and apoptosis. The antitumor activity of GSK1838705A was assessed in a xenograft mouse model. GSK1838705A inhibited the growth and induced the apoptosis of the U87MG glioma cells in a dose‑dependent manner. The GSK1838705A‑treated cells exhibited reduced migratory activity in response to chemoattractants. The present study further demonstrated the antitumor activity of GSK1838705A in vivo. The administration of GSK1838705A significantly inhibited the growth of glioma tumors by inducing the apoptosis of tumor cells. These results suggested that targeting IGF signaling with GSK1838705A may be a promising therapeutic strategy for the treatment of patients with glioma.

Show MeSH
Related in: MedlinePlus