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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 suppresses glioma tumor growth and induces apoptosis in vivo. (A) Following inoculation of U87MG cells, formulated vehicle control or GSK1838705A (4 and 8 mg/kg) was injected into the corresponding group of nude mice (n=6/group) once daily. The tumors were measured every other day for 11 days and the tumor volumes were calculated. Starting on day 7, the differences between the treatment groups (4 and 8 mg/kg) and the vehicle control group were significant (P<0.05). (B) Body weights of the mice during the course of treatment were measured as an indication of significant cytotoxic effects. The data are expressed as the mean ± standard deviation. No significant differences are observed between any two of the groups during the course of treatment. (C) At the end of treatment, the tumors were harvested. GSK1838705A (8 mg/kg) induced the apoptosis of tumor cells in vivo, determined using a TUNEL assay (green) and nuclear staining with Hoechst (blue). Representative images are shown (magnification, ×40). TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling.
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f4-mmr-12-04-5641: GSK1838705A suppresses glioma tumor growth and induces apoptosis in vivo. (A) Following inoculation of U87MG cells, formulated vehicle control or GSK1838705A (4 and 8 mg/kg) was injected into the corresponding group of nude mice (n=6/group) once daily. The tumors were measured every other day for 11 days and the tumor volumes were calculated. Starting on day 7, the differences between the treatment groups (4 and 8 mg/kg) and the vehicle control group were significant (P<0.05). (B) Body weights of the mice during the course of treatment were measured as an indication of significant cytotoxic effects. The data are expressed as the mean ± standard deviation. No significant differences are observed between any two of the groups during the course of treatment. (C) At the end of treatment, the tumors were harvested. GSK1838705A (8 mg/kg) induced the apoptosis of tumor cells in vivo, determined using a TUNEL assay (green) and nuclear staining with Hoechst (blue). Representative images are shown (magnification, ×40). TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling.

Mentions: Subsequent to the results obtained from the in vitro investigations, the present study investigated the antitumor efficacy of GSK1838705A in vivo, in which U87MG cells were injected into athymic nude mice. Following successful inoculation, GSK1838705A (4 or 8 mg/kg) was administered once daily and the tumor volumes were measured every other day. GSK1838705A significantly inhibited the growth of the tumor mass. Treatment with GSK1838705A at 4 or 8 mg/kg resulted in reductions of ~45 and 85% in tumor volume, respectively, 11 days after the first administration (Fig. 4A). The antitumor efficacy of GSK1838705A was consistent with the concentration used. No significant weight loss was observed in either treatment group during the course of treatment, indicating that the concentrations of GSK1838705A used were well tolerated by the recipient mice, and no significant cytotoxicity accompanied the GSK1838705A treatment (Fig. 4B). Consistent with the results of the in vitro investigations, GSK1838705A induced significant apoptosis in the tumor cells. Following treatment of tumors with 8 mg/kg GSK1838705A, significant DNA fragmentation was detected using a TUNEL assay and nuclear staining (Fig. 4C). Taken together, these results provided clear evidence indicating that GSK1838705A effectively suppressed the growth of the tumor in vivo by inducing apoptosis of the tumor cells.


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 suppresses glioma tumor growth and induces apoptosis in vivo. (A) Following inoculation of U87MG cells, formulated vehicle control or GSK1838705A (4 and 8 mg/kg) was injected into the corresponding group of nude mice (n=6/group) once daily. The tumors were measured every other day for 11 days and the tumor volumes were calculated. Starting on day 7, the differences between the treatment groups (4 and 8 mg/kg) and the vehicle control group were significant (P<0.05). (B) Body weights of the mice during the course of treatment were measured as an indication of significant cytotoxic effects. The data are expressed as the mean ± standard deviation. No significant differences are observed between any two of the groups during the course of treatment. (C) At the end of treatment, the tumors were harvested. GSK1838705A (8 mg/kg) induced the apoptosis of tumor cells in vivo, determined using a TUNEL assay (green) and nuclear staining with Hoechst (blue). Representative images are shown (magnification, ×40). TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4-mmr-12-04-5641: GSK1838705A suppresses glioma tumor growth and induces apoptosis in vivo. (A) Following inoculation of U87MG cells, formulated vehicle control or GSK1838705A (4 and 8 mg/kg) was injected into the corresponding group of nude mice (n=6/group) once daily. The tumors were measured every other day for 11 days and the tumor volumes were calculated. Starting on day 7, the differences between the treatment groups (4 and 8 mg/kg) and the vehicle control group were significant (P<0.05). (B) Body weights of the mice during the course of treatment were measured as an indication of significant cytotoxic effects. The data are expressed as the mean ± standard deviation. No significant differences are observed between any two of the groups during the course of treatment. (C) At the end of treatment, the tumors were harvested. GSK1838705A (8 mg/kg) induced the apoptosis of tumor cells in vivo, determined using a TUNEL assay (green) and nuclear staining with Hoechst (blue). Representative images are shown (magnification, ×40). TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling.
Mentions: Subsequent to the results obtained from the in vitro investigations, the present study investigated the antitumor efficacy of GSK1838705A in vivo, in which U87MG cells were injected into athymic nude mice. Following successful inoculation, GSK1838705A (4 or 8 mg/kg) was administered once daily and the tumor volumes were measured every other day. GSK1838705A significantly inhibited the growth of the tumor mass. Treatment with GSK1838705A at 4 or 8 mg/kg resulted in reductions of ~45 and 85% in tumor volume, respectively, 11 days after the first administration (Fig. 4A). The antitumor efficacy of GSK1838705A was consistent with the concentration used. No significant weight loss was observed in either treatment group during the course of treatment, indicating that the concentrations of GSK1838705A used were well tolerated by the recipient mice, and no significant cytotoxicity accompanied the GSK1838705A treatment (Fig. 4B). Consistent with the results of the in vitro investigations, GSK1838705A induced significant apoptosis in the tumor cells. Following treatment of tumors with 8 mg/kg GSK1838705A, significant DNA fragmentation was detected using a TUNEL assay and nuclear staining (Fig. 4C). Taken together, these results provided clear evidence indicating that GSK1838705A effectively suppressed the growth of the tumor in vivo by inducing apoptosis of the tumor cells.

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