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Lenvatinib in combination with golvatinib overcomes hepatocyte growth factor pathway-induced resistance to vascular endothelial growth factor receptor inhibitor.

Nakagawa T, Matsushima T, Kawano S, Nakazawa Y, Kato Y, Adachi Y, Abe T, Semba T, Yokoi A, Matsui J, Tsuruoka A, Funahashi Y - Cancer Sci. (2014)

Bottom Line: Here, we explored the effect of the HGF/Met signaling pathway and its inhibitors on resistance to lenvatinib, a VEGFR inhibitor.Lenvatinib potently inhibited the growth of HUVECs induced by VEGF alone, but cells induced by VEGF plus HGF showed lenvatinib resistance.This HGF-induced resistance was cancelled when the Met inhibitor, golvatinib, was added with lenvatinib.

View Article: PubMed Central - PubMed

Affiliation: Tsukuba Research Laboratory, Eisai Co., Ltd., Tsukuba, Japan.

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Effects of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) on cell proliferation and tube formation of endothelial cells in vitro. (a) Chemical structure of lenvatinib (left panel), golvatinib (middle panel), and the inhibitory activity of compounds against vascular endothelial growth factor receptor 2 (VEGFR2) and Met (right panel). (b) HUVECs were incubated for 3 days in the presence of VEGF (20 ng/mL), HGF (30 ng/mL), or both. Cell numbers were quantified using the sulforhodamine B method. Data represent means ± SD. *P < 0.05 versus control; ** P < 0.05 versus the indicated group. (c) Quantification of HUVEC tube formation induced with VEGF, HGF, or both. The relative length of network was calculated relative to the control. Data represent means ± SD. *P < 0.05 versus control. (d) Representative images of tube formation induced by VEGF, HGF, or both.
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fig01: Effects of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) on cell proliferation and tube formation of endothelial cells in vitro. (a) Chemical structure of lenvatinib (left panel), golvatinib (middle panel), and the inhibitory activity of compounds against vascular endothelial growth factor receptor 2 (VEGFR2) and Met (right panel). (b) HUVECs were incubated for 3 days in the presence of VEGF (20 ng/mL), HGF (30 ng/mL), or both. Cell numbers were quantified using the sulforhodamine B method. Data represent means ± SD. *P < 0.05 versus control; ** P < 0.05 versus the indicated group. (c) Quantification of HUVEC tube formation induced with VEGF, HGF, or both. The relative length of network was calculated relative to the control. Data represent means ± SD. *P < 0.05 versus control. (d) Representative images of tube formation induced by VEGF, HGF, or both.

Mentions: Lenvatinib mesylate (E7080 mesylate; 4-[3-chloro-4-(N′-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide methanesulfonate mesylate), and golvatinib tartrate (E7050 tartrate; N-[2-fluoro-4-({2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonylaminopyridin-4-yl} oxy) phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (2R,3R)-tartrate) were synthesized at Eisai Co., Ltd (Tsukuba, Japan) (Fig.1a). Recombinant human HGF, recombinant human VEGF, and anti-human HGF neutralizing antibody were purchased from R&D Systems (Minneapolis, MN, USA). Antibodies against phospho-Met (Y1234/Y1235) (D26), phospho-VEGFR2 (Y996), phospho-Akt (S473), phospho-Erk1/2 (T202/Y204), Erk1/2 (Cell Signaling Technology, Beverly, MA, USA), Met (C-28), VEGFR2 (C-1158), and Akt (H-136) (Santa Cruz Biotechnology, Santa Cruz, CA, USA), and GAPDH (Sigma, St. Louis, MO, USA) were used for Western blot analyses.


Lenvatinib in combination with golvatinib overcomes hepatocyte growth factor pathway-induced resistance to vascular endothelial growth factor receptor inhibitor.

Nakagawa T, Matsushima T, Kawano S, Nakazawa Y, Kato Y, Adachi Y, Abe T, Semba T, Yokoi A, Matsui J, Tsuruoka A, Funahashi Y - Cancer Sci. (2014)

Effects of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) on cell proliferation and tube formation of endothelial cells in vitro. (a) Chemical structure of lenvatinib (left panel), golvatinib (middle panel), and the inhibitory activity of compounds against vascular endothelial growth factor receptor 2 (VEGFR2) and Met (right panel). (b) HUVECs were incubated for 3 days in the presence of VEGF (20 ng/mL), HGF (30 ng/mL), or both. Cell numbers were quantified using the sulforhodamine B method. Data represent means ± SD. *P < 0.05 versus control; ** P < 0.05 versus the indicated group. (c) Quantification of HUVEC tube formation induced with VEGF, HGF, or both. The relative length of network was calculated relative to the control. Data represent means ± SD. *P < 0.05 versus control. (d) Representative images of tube formation induced by VEGF, HGF, or both.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4317894&req=5

fig01: Effects of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) on cell proliferation and tube formation of endothelial cells in vitro. (a) Chemical structure of lenvatinib (left panel), golvatinib (middle panel), and the inhibitory activity of compounds against vascular endothelial growth factor receptor 2 (VEGFR2) and Met (right panel). (b) HUVECs were incubated for 3 days in the presence of VEGF (20 ng/mL), HGF (30 ng/mL), or both. Cell numbers were quantified using the sulforhodamine B method. Data represent means ± SD. *P < 0.05 versus control; ** P < 0.05 versus the indicated group. (c) Quantification of HUVEC tube formation induced with VEGF, HGF, or both. The relative length of network was calculated relative to the control. Data represent means ± SD. *P < 0.05 versus control. (d) Representative images of tube formation induced by VEGF, HGF, or both.
Mentions: Lenvatinib mesylate (E7080 mesylate; 4-[3-chloro-4-(N′-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide methanesulfonate mesylate), and golvatinib tartrate (E7050 tartrate; N-[2-fluoro-4-({2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonylaminopyridin-4-yl} oxy) phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (2R,3R)-tartrate) were synthesized at Eisai Co., Ltd (Tsukuba, Japan) (Fig.1a). Recombinant human HGF, recombinant human VEGF, and anti-human HGF neutralizing antibody were purchased from R&D Systems (Minneapolis, MN, USA). Antibodies against phospho-Met (Y1234/Y1235) (D26), phospho-VEGFR2 (Y996), phospho-Akt (S473), phospho-Erk1/2 (T202/Y204), Erk1/2 (Cell Signaling Technology, Beverly, MA, USA), Met (C-28), VEGFR2 (C-1158), and Akt (H-136) (Santa Cruz Biotechnology, Santa Cruz, CA, USA), and GAPDH (Sigma, St. Louis, MO, USA) were used for Western blot analyses.

Bottom Line: Here, we explored the effect of the HGF/Met signaling pathway and its inhibitors on resistance to lenvatinib, a VEGFR inhibitor.Lenvatinib potently inhibited the growth of HUVECs induced by VEGF alone, but cells induced by VEGF plus HGF showed lenvatinib resistance.This HGF-induced resistance was cancelled when the Met inhibitor, golvatinib, was added with lenvatinib.

View Article: PubMed Central - PubMed

Affiliation: Tsukuba Research Laboratory, Eisai Co., Ltd., Tsukuba, Japan.

Show MeSH
Related in: MedlinePlus