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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 inhibits the migration of glioma cells. (A) U87MG cells were treated with dimethyl sulfoxide or GSK1838705A (3.75, 7.5 or 15 µM) for 8 h. Non-migrating cells on the upper surface of the filter were removed and migrated cells on the lower side were stained, following which images were captured (magnification, ×40). Ten fields from each group were randomly selected, and migrated cells appeared to be dark and spindle-shaped after crystal violet staining. Representative images are shown. (B) Migrating cells were lysed and colorimetric determination was assessed at 595 nm. Quantification of the inhibition is shown. The data are expressed as the mean ± standard deviation. P<0.05, 15 and 7.5 vs. 3.75 µM.
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f3-mmr-12-04-5641: GSK1838705A inhibits the migration of glioma cells. (A) U87MG cells were treated with dimethyl sulfoxide or GSK1838705A (3.75, 7.5 or 15 µM) for 8 h. Non-migrating cells on the upper surface of the filter were removed and migrated cells on the lower side were stained, following which images were captured (magnification, ×40). Ten fields from each group were randomly selected, and migrated cells appeared to be dark and spindle-shaped after crystal violet staining. Representative images are shown. (B) Migrating cells were lysed and colorimetric determination was assessed at 595 nm. Quantification of the inhibition is shown. The data are expressed as the mean ± standard deviation. P<0.05, 15 and 7.5 vs. 3.75 µM.

Mentions: Malignant tumor cells, including gliomas, are capable of migrating and invading to a secondary site through the processes of angiogenesis and metastasis, in which IGF signaling is important (8,13). Therefore, IGF/IGF-IR is an attractive target in cancer therapeutics. The present study further investigated the effect of IGF inhibition on glioma cell migration. U87MG cells, in the presence or absence of GSK1838705A, were induced to migrate in a Transwell assay. As shown in Fig. 3A and B, an inhibitory effect of GSK1838705A on cellular migration was observed after 8 h of treatment at concentrations as low as 3.75 µM and reached its peak effect at 15 µM. The reduced number of migrating cells was not a result of apoptosis due to GSK1838705A treatment itself, as the duration of treatment was significantly shorter and the concentrations of GSK1838705A were significantly lower compared with those used to examine the cell viability and apoptosis (Figs. 1 and 2).


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 inhibits the migration of glioma cells. (A) U87MG cells were treated with dimethyl sulfoxide or GSK1838705A (3.75, 7.5 or 15 µM) for 8 h. Non-migrating cells on the upper surface of the filter were removed and migrated cells on the lower side were stained, following which images were captured (magnification, ×40). Ten fields from each group were randomly selected, and migrated cells appeared to be dark and spindle-shaped after crystal violet staining. Representative images are shown. (B) Migrating cells were lysed and colorimetric determination was assessed at 595 nm. Quantification of the inhibition is shown. The data are expressed as the mean ± standard deviation. P<0.05, 15 and 7.5 vs. 3.75 µM.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3-mmr-12-04-5641: GSK1838705A inhibits the migration of glioma cells. (A) U87MG cells were treated with dimethyl sulfoxide or GSK1838705A (3.75, 7.5 or 15 µM) for 8 h. Non-migrating cells on the upper surface of the filter were removed and migrated cells on the lower side were stained, following which images were captured (magnification, ×40). Ten fields from each group were randomly selected, and migrated cells appeared to be dark and spindle-shaped after crystal violet staining. Representative images are shown. (B) Migrating cells were lysed and colorimetric determination was assessed at 595 nm. Quantification of the inhibition is shown. The data are expressed as the mean ± standard deviation. P<0.05, 15 and 7.5 vs. 3.75 µM.
Mentions: Malignant tumor cells, including gliomas, are capable of migrating and invading to a secondary site through the processes of angiogenesis and metastasis, in which IGF signaling is important (8,13). Therefore, IGF/IGF-IR is an attractive target in cancer therapeutics. The present study further investigated the effect of IGF inhibition on glioma cell migration. U87MG cells, in the presence or absence of GSK1838705A, were induced to migrate in a Transwell assay. As shown in Fig. 3A and B, an inhibitory effect of GSK1838705A on cellular migration was observed after 8 h of treatment at concentrations as low as 3.75 µM and reached its peak effect at 15 µM. The reduced number of migrating cells was not a result of apoptosis due to GSK1838705A treatment itself, as the duration of treatment was significantly shorter and the concentrations of GSK1838705A were significantly lower compared with those used to examine the cell viability and apoptosis (Figs. 1 and 2).

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