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GSK1838705A, an insulin-like growth factor-1 receptor/insulin receptor inhibitor, induces apoptosis and reduces viability of docetaxel-resistant prostate cancer cells both in vitro and in vivo.

Zhou F, Chen X, Fan S, Tai S, Jiang C, Zhang Y, Hao Z, Zhou J, Shi H, Zhang L, Liang C - Onco Targets Ther (2015)

Bottom Line: We found that GSK1838705A could effectively reduce the viability of both docetaxel-sensitive and docetaxel-resistant prostate cancer cells.Further, GSK1838705A significantly inhibited phosphorylation of IGF1R/IR.Importantly, GSK1838705A significantly suppressed docetaxel-resistant PC-3R tumor growth in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, First Affiliated Hospital of Anhui Medical University, Hefei, People's Republic of China ; Department of Urology, Traditional Chinese Medical Hospital of Wuhu City, WuHu, People's Republic of China.

ABSTRACT
Prostate cancer is the leading malignancy and the second most common cause of cancer-related death in men. Despite high cure rates with surgery and/or radiation, 30%-40% of patients eventually develop advanced cancer. Docetaxel is one of the most effective and well established chemotherapeutic agents for prostate cancer. However, docetaxel resistance often develops within months. Combination therapies have been proposed to improve the therapeutic efficacy of docetaxel in prostate cancer, and there is an urgent need to identify agents that are effective for treatment of the disease, especially docetaxel-resistant prostate cancer. In this work, we investigated the activity of GSK1838705A, a potent insulin-like growth factor-1 receptor (IGF1R)/insulin receptor (IR) inhibitor, in prostate cancer, especially docetaxel-resistant prostate cancer. We found that GSK1838705A could effectively reduce the viability of both docetaxel-sensitive and docetaxel-resistant prostate cancer cells. GSK1838705A induced marked apoptosis in docetaxel-resistant cells, and also dramatically inhibited migration of these cells. Further, GSK1838705A significantly inhibited phosphorylation of IGF1R/IR. Importantly, GSK1838705A significantly suppressed docetaxel-resistant PC-3R tumor growth in vivo. This is the first study of GSK1838705A in prostate cancer. Our results indicate that GSK1838705A is a promising compound for the treatment of prostate cancer, especially for those who develop resistance to docetaxel, and might shed new light on treatment for prostate cancer.

No MeSH data available.


Related in: MedlinePlus

GSK1838705A induces apoptosis in docetaxel-resistant cells.Notes: (A) PC-3R cells were treated with GSK1838705A (0.25–2 μM) for 48 hours, followed by propidium iodide staining and flow cytometry analysis. (B) Analysis of results of flow cytometry data. (C) PC-3R cells were incubated with GSK1838705A (0.25–2 μM) for 48 hours. The nuclei were stained with Hoechst or a TUNEL staining kit, and analyzed by fluorescent microscopy. Representative images are shown. (D) The number of cells with condensed/fragmented nuclei was quantitated by counting in five random fields and inhibition was calculated. (E) Western blot analysis of cleaved caspase-3 after treatment with GSK1838705A (0.25 and 1 μM) for 48 hours.Abbreviations: GADPH, glyceraldehyde-3-phosphate dehydrogenase; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling.
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f2-ott-8-753: GSK1838705A induces apoptosis in docetaxel-resistant cells.Notes: (A) PC-3R cells were treated with GSK1838705A (0.25–2 μM) for 48 hours, followed by propidium iodide staining and flow cytometry analysis. (B) Analysis of results of flow cytometry data. (C) PC-3R cells were incubated with GSK1838705A (0.25–2 μM) for 48 hours. The nuclei were stained with Hoechst or a TUNEL staining kit, and analyzed by fluorescent microscopy. Representative images are shown. (D) The number of cells with condensed/fragmented nuclei was quantitated by counting in five random fields and inhibition was calculated. (E) Western blot analysis of cleaved caspase-3 after treatment with GSK1838705A (0.25 and 1 μM) for 48 hours.Abbreviations: GADPH, glyceraldehyde-3-phosphate dehydrogenase; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling.

Mentions: IGF1R/IR-mediated signaling pathways play a crucial role in inhibiting apoptosis and increasing cell viability,10–15 so we next examined GSK1838705A-induced apoptosis in PC-3R cells. As shown in Figure 2A and B, the subG1 DNA content in PC-3R cells significantly increased after treatment with GSK1838705A when compared with the control group (P<0.01). We also observed the nuclear morphology in PC-3R cells after treatment with GSK1838705A. After treatment with GSK1838705A, the PC-3R cell nuclei showed consistent morphological changes, including chromatin condensation and nuclear fragmentation, both of which are indicators of cell apoptosis (Figure 2C and D). GSK1838705A-induced cell apoptosis was also confirmed by TUNEL staining assay (Figure 2C). These structural alterations indicate that treatment with GSK1838705A generated apoptosis in docetaxel-resistant PC-3R cells. Further, Western blot analysis showed that treatment with GSK1838705A significantly increased levels of cleaved caspase-3 in resistant cells (Figure 2E), further confirming GSK1838705A-induced apoptosis in resistant cells. These data are consistent with the viability suppression results reported above.


GSK1838705A, an insulin-like growth factor-1 receptor/insulin receptor inhibitor, induces apoptosis and reduces viability of docetaxel-resistant prostate cancer cells both in vitro and in vivo.

Zhou F, Chen X, Fan S, Tai S, Jiang C, Zhang Y, Hao Z, Zhou J, Shi H, Zhang L, Liang C - Onco Targets Ther (2015)

GSK1838705A induces apoptosis in docetaxel-resistant cells.Notes: (A) PC-3R cells were treated with GSK1838705A (0.25–2 μM) for 48 hours, followed by propidium iodide staining and flow cytometry analysis. (B) Analysis of results of flow cytometry data. (C) PC-3R cells were incubated with GSK1838705A (0.25–2 μM) for 48 hours. The nuclei were stained with Hoechst or a TUNEL staining kit, and analyzed by fluorescent microscopy. Representative images are shown. (D) The number of cells with condensed/fragmented nuclei was quantitated by counting in five random fields and inhibition was calculated. (E) Western blot analysis of cleaved caspase-3 after treatment with GSK1838705A (0.25 and 1 μM) for 48 hours.Abbreviations: GADPH, glyceraldehyde-3-phosphate dehydrogenase; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4403692&req=5

f2-ott-8-753: GSK1838705A induces apoptosis in docetaxel-resistant cells.Notes: (A) PC-3R cells were treated with GSK1838705A (0.25–2 μM) for 48 hours, followed by propidium iodide staining and flow cytometry analysis. (B) Analysis of results of flow cytometry data. (C) PC-3R cells were incubated with GSK1838705A (0.25–2 μM) for 48 hours. The nuclei were stained with Hoechst or a TUNEL staining kit, and analyzed by fluorescent microscopy. Representative images are shown. (D) The number of cells with condensed/fragmented nuclei was quantitated by counting in five random fields and inhibition was calculated. (E) Western blot analysis of cleaved caspase-3 after treatment with GSK1838705A (0.25 and 1 μM) for 48 hours.Abbreviations: GADPH, glyceraldehyde-3-phosphate dehydrogenase; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling.
Mentions: IGF1R/IR-mediated signaling pathways play a crucial role in inhibiting apoptosis and increasing cell viability,10–15 so we next examined GSK1838705A-induced apoptosis in PC-3R cells. As shown in Figure 2A and B, the subG1 DNA content in PC-3R cells significantly increased after treatment with GSK1838705A when compared with the control group (P<0.01). We also observed the nuclear morphology in PC-3R cells after treatment with GSK1838705A. After treatment with GSK1838705A, the PC-3R cell nuclei showed consistent morphological changes, including chromatin condensation and nuclear fragmentation, both of which are indicators of cell apoptosis (Figure 2C and D). GSK1838705A-induced cell apoptosis was also confirmed by TUNEL staining assay (Figure 2C). These structural alterations indicate that treatment with GSK1838705A generated apoptosis in docetaxel-resistant PC-3R cells. Further, Western blot analysis showed that treatment with GSK1838705A significantly increased levels of cleaved caspase-3 in resistant cells (Figure 2E), further confirming GSK1838705A-induced apoptosis in resistant cells. These data are consistent with the viability suppression results reported above.

Bottom Line: We found that GSK1838705A could effectively reduce the viability of both docetaxel-sensitive and docetaxel-resistant prostate cancer cells.Further, GSK1838705A significantly inhibited phosphorylation of IGF1R/IR.Importantly, GSK1838705A significantly suppressed docetaxel-resistant PC-3R tumor growth in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, First Affiliated Hospital of Anhui Medical University, Hefei, People's Republic of China ; Department of Urology, Traditional Chinese Medical Hospital of Wuhu City, WuHu, People's Republic of China.

ABSTRACT
Prostate cancer is the leading malignancy and the second most common cause of cancer-related death in men. Despite high cure rates with surgery and/or radiation, 30%-40% of patients eventually develop advanced cancer. Docetaxel is one of the most effective and well established chemotherapeutic agents for prostate cancer. However, docetaxel resistance often develops within months. Combination therapies have been proposed to improve the therapeutic efficacy of docetaxel in prostate cancer, and there is an urgent need to identify agents that are effective for treatment of the disease, especially docetaxel-resistant prostate cancer. In this work, we investigated the activity of GSK1838705A, a potent insulin-like growth factor-1 receptor (IGF1R)/insulin receptor (IR) inhibitor, in prostate cancer, especially docetaxel-resistant prostate cancer. We found that GSK1838705A could effectively reduce the viability of both docetaxel-sensitive and docetaxel-resistant prostate cancer cells. GSK1838705A induced marked apoptosis in docetaxel-resistant cells, and also dramatically inhibited migration of these cells. Further, GSK1838705A significantly inhibited phosphorylation of IGF1R/IR. Importantly, GSK1838705A significantly suppressed docetaxel-resistant PC-3R tumor growth in vivo. This is the first study of GSK1838705A in prostate cancer. Our results indicate that GSK1838705A is a promising compound for the treatment of prostate cancer, especially for those who develop resistance to docetaxel, and might shed new light on treatment for prostate cancer.

No MeSH data available.


Related in: MedlinePlus