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Foretinib inhibits angiogenesis, lymphangiogenesis and tumor growth of pancreatic cancer in vivo by decreasing VEGFR-2/3 and TIE-2 signaling.

Chen HM, Tsai CH, Hung WC - Oncotarget (2015)

Bottom Line: We found Foretinib decreased basal- and HGF-induced c-MET activity at low concentrations.Foretinib inhibited VEGF-A, VEGF-C and Angiopoetin-2 (ANG-2)-stimulated tube formation and sprouting of LECs by reducing VEGFR-2, VEGFR-3 and TIE-2 activation and increased apoptosis of LECs.Additionally, Foretinib inhibited angiogenesis and lymphangiogenesis more significantly and exhibited low detrimental effect in orthotopic animal study.

View Article: PubMed Central - PubMed

Affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan, Republic of China.

ABSTRACT
Foretinib, a multiple kinase inhibitor undergoing clinical trials, could suppress the activity of hepatocyte growth factor (HGF) receptor c-MET and vascular endothelial growth factor receptor-2 (VEGFR-2). In addition, Foretinib may inhibit two critical lymphangiogenic signaling receptors VEGFR-3 and TIE-2. However, the effect of Foretinib on lymphatic endothelial cells (LECs) in vitro and lymphangiogenesis in vivo is still unknown. We found Foretinib decreased basal- and HGF-induced c-MET activity at low concentrations. However, Foretinib only reduced the proliferation of pancreatic cancer cells at high concentration reflecting the intrinsic chemoresistance of pancreatic cancer cells. Foretinib inhibited VEGF-A, VEGF-C and Angiopoetin-2 (ANG-2)-stimulated tube formation and sprouting of LECs by reducing VEGFR-2, VEGFR-3 and TIE-2 activation and increased apoptosis of LECs. In xenograft animal study, Foretinib suppressed tumor growth by inhibiting proliferation, angiogenesis and lymphangiogenesis. Additionally, Foretinib inhibited angiogenesis and lymphangiogenesis more significantly and exhibited low detrimental effect in orthotopic animal study. Collectively, we suggested that Foretinib simultaneously inhibits cancer cells and LECs to reduce pancreatic tumor growth in vivo and demonstrated for the first time that Foretinib suppresses angiogenesis and lymphangiogenesis by blocking VEGFR-2/3 and TIE-2 signaling.

No MeSH data available.


Related in: MedlinePlus

Effect of Foretinib on viability of pancreatic cancer cell lines and the activity of c-Met, AKT and ERKHuman pancreatic cancer cell lines Panc-1 A. Capan-2 B. and Mia-PaCa C. were treated with indicated concentrations of Foretinib in growth medium containing 10% FBS for 24 or 48 h and the cell viability was measured. Values were Mean ± SEM of three separate experiments. D. Panc-1 cells were pre-treated with indicated concentrations of Foretinib for 1 h and then co-incubated with or without HGF (50 ng/ml) for 15 min. Cellular proteins were separated by SDS-PAGE and the blots were probed with different antibodies to detect the total or phosphorylated form of c-MET, AKT, ERK. β-actin was used as the sample loading control.
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Figure 1: Effect of Foretinib on viability of pancreatic cancer cell lines and the activity of c-Met, AKT and ERKHuman pancreatic cancer cell lines Panc-1 A. Capan-2 B. and Mia-PaCa C. were treated with indicated concentrations of Foretinib in growth medium containing 10% FBS for 24 or 48 h and the cell viability was measured. Values were Mean ± SEM of three separate experiments. D. Panc-1 cells were pre-treated with indicated concentrations of Foretinib for 1 h and then co-incubated with or without HGF (50 ng/ml) for 15 min. Cellular proteins were separated by SDS-PAGE and the blots were probed with different antibodies to detect the total or phosphorylated form of c-MET, AKT, ERK. β-actin was used as the sample loading control.

Mentions: To investigate anti-cancer activity of Foretinib, the viability of three different pancreatic cancer cell lines after Foretinib treatment was studied. Viability was only slightly reduced by 1 μM of Foretinib in Panc-1, Capan-2 and Mia-Paca cells (Fig. 1A–1C). Foretinib at 5 μM showed significant cytotoxic effect on Capan-2 cells (Fig. 1B) while less effect was found in Panc-1 and Mia-Paca cells. Next, we used non-cytotoxic concentrations (0.1 and 1 μM) of Foretininb to treat Panc-1 cells and studied its effect on the activation of c-MET and downstream signaling pathways. Hepatocyte growth factor (HGF) increased phosphorylation of c-MET and its downstream AKT and ERK which could be significantly inhibited by Foretinib (Fig. 1D). These data indicated that Foretinib is a potent inhibitor of c-MET in pancreatic cancer as found in other cancers. However, Foretinib only showed significant anti-cancer activity at high concentration reflecting the intrinsic chemoresistance of pancreatic cancer cells and additional RTKs beside c-MET are important for the proliferation and survival of these cancer cells.


Foretinib inhibits angiogenesis, lymphangiogenesis and tumor growth of pancreatic cancer in vivo by decreasing VEGFR-2/3 and TIE-2 signaling.

Chen HM, Tsai CH, Hung WC - Oncotarget (2015)

Effect of Foretinib on viability of pancreatic cancer cell lines and the activity of c-Met, AKT and ERKHuman pancreatic cancer cell lines Panc-1 A. Capan-2 B. and Mia-PaCa C. were treated with indicated concentrations of Foretinib in growth medium containing 10% FBS for 24 or 48 h and the cell viability was measured. Values were Mean ± SEM of three separate experiments. D. Panc-1 cells were pre-treated with indicated concentrations of Foretinib for 1 h and then co-incubated with or without HGF (50 ng/ml) for 15 min. Cellular proteins were separated by SDS-PAGE and the blots were probed with different antibodies to detect the total or phosphorylated form of c-MET, AKT, ERK. β-actin was used as the sample loading control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4558127&req=5

Figure 1: Effect of Foretinib on viability of pancreatic cancer cell lines and the activity of c-Met, AKT and ERKHuman pancreatic cancer cell lines Panc-1 A. Capan-2 B. and Mia-PaCa C. were treated with indicated concentrations of Foretinib in growth medium containing 10% FBS for 24 or 48 h and the cell viability was measured. Values were Mean ± SEM of three separate experiments. D. Panc-1 cells were pre-treated with indicated concentrations of Foretinib for 1 h and then co-incubated with or without HGF (50 ng/ml) for 15 min. Cellular proteins were separated by SDS-PAGE and the blots were probed with different antibodies to detect the total or phosphorylated form of c-MET, AKT, ERK. β-actin was used as the sample loading control.
Mentions: To investigate anti-cancer activity of Foretinib, the viability of three different pancreatic cancer cell lines after Foretinib treatment was studied. Viability was only slightly reduced by 1 μM of Foretinib in Panc-1, Capan-2 and Mia-Paca cells (Fig. 1A–1C). Foretinib at 5 μM showed significant cytotoxic effect on Capan-2 cells (Fig. 1B) while less effect was found in Panc-1 and Mia-Paca cells. Next, we used non-cytotoxic concentrations (0.1 and 1 μM) of Foretininb to treat Panc-1 cells and studied its effect on the activation of c-MET and downstream signaling pathways. Hepatocyte growth factor (HGF) increased phosphorylation of c-MET and its downstream AKT and ERK which could be significantly inhibited by Foretinib (Fig. 1D). These data indicated that Foretinib is a potent inhibitor of c-MET in pancreatic cancer as found in other cancers. However, Foretinib only showed significant anti-cancer activity at high concentration reflecting the intrinsic chemoresistance of pancreatic cancer cells and additional RTKs beside c-MET are important for the proliferation and survival of these cancer cells.

Bottom Line: We found Foretinib decreased basal- and HGF-induced c-MET activity at low concentrations.Foretinib inhibited VEGF-A, VEGF-C and Angiopoetin-2 (ANG-2)-stimulated tube formation and sprouting of LECs by reducing VEGFR-2, VEGFR-3 and TIE-2 activation and increased apoptosis of LECs.Additionally, Foretinib inhibited angiogenesis and lymphangiogenesis more significantly and exhibited low detrimental effect in orthotopic animal study.

View Article: PubMed Central - PubMed

Affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan, Republic of China.

ABSTRACT
Foretinib, a multiple kinase inhibitor undergoing clinical trials, could suppress the activity of hepatocyte growth factor (HGF) receptor c-MET and vascular endothelial growth factor receptor-2 (VEGFR-2). In addition, Foretinib may inhibit two critical lymphangiogenic signaling receptors VEGFR-3 and TIE-2. However, the effect of Foretinib on lymphatic endothelial cells (LECs) in vitro and lymphangiogenesis in vivo is still unknown. We found Foretinib decreased basal- and HGF-induced c-MET activity at low concentrations. However, Foretinib only reduced the proliferation of pancreatic cancer cells at high concentration reflecting the intrinsic chemoresistance of pancreatic cancer cells. Foretinib inhibited VEGF-A, VEGF-C and Angiopoetin-2 (ANG-2)-stimulated tube formation and sprouting of LECs by reducing VEGFR-2, VEGFR-3 and TIE-2 activation and increased apoptosis of LECs. In xenograft animal study, Foretinib suppressed tumor growth by inhibiting proliferation, angiogenesis and lymphangiogenesis. Additionally, Foretinib inhibited angiogenesis and lymphangiogenesis more significantly and exhibited low detrimental effect in orthotopic animal study. Collectively, we suggested that Foretinib simultaneously inhibits cancer cells and LECs to reduce pancreatic tumor growth in vivo and demonstrated for the first time that Foretinib suppresses angiogenesis and lymphangiogenesis by blocking VEGFR-2/3 and TIE-2 signaling.

No MeSH data available.


Related in: MedlinePlus