Inhibition of angiogenesis and tumor progression of MK-0429, an integrin αvβ3 antagonist, on oral squamous cell carcinoma

Takayuki Nakagawa; Kouji Ohta; Takako Naruse; Miyuki Sakuma; Syohei Fukada; Nao Yamakado; Misaki Akagi; Kazuki Sasaki; Chieko Niwata; Shigehiro Ono; Tomonao Aikawa

doi:10.1007/s00432-022-04100-3

Inhibition of angiogenesis and tumor progression of MK-0429, an integrin αvβ₃ antagonist, on oral squamous cell carcinoma

J Cancer Res Clin Oncol. 2022 Dec;148(12):3281-3292. doi: 10.1007/s00432-022-04100-3. Epub 2022 Jun 17.

Authors

Affiliations

¹ Department of Oral and Maxillofacial Surgery, Program of Dentistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-Ward, Hiroshima, 734-8553, Japan. tnakaga@hiroshima-u.ac.jp.
² Department of Public Oral Health, Program of Oral Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-Ward, Hiroshima, 734-8553, Japan.
³ Department of Oral and Maxillofacial Surgery, Program of Dentistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-Ward, Hiroshima, 734-8553, Japan.

Abstract

Purpose: Integrin αvβ₃ is an essential molecule for tumor angiogenesis. This study aimed to investigate the anti-tumor effect of MK-0429, an integrin αvβ₃ antagonist, on oral squamous cell carcinoma (OSCC) through its inhibitory effect on angiogenesis.

Methods: In this study, we investigated the effect of MK-0429 on cellular function and angiogenesis in vitro with the use of an immortalized human umbilical vein endothelial cell, HUEhT-1, which is immortalized by the electroporatic transfection of hTERT. The effect of MK-0429 on the integrin αvβ₃ signaling pathway was examined by FAK, MEK1/2 and ERK 1/2 phosphorylation. The anti-angiogenic effect of MK-0429 was evaluated by in vitro tube formation assay. The anti-tumor effect on OSCC was assessed by administrating MK-0429 to mouse oral cancer xenografts.

Results: MK-0429 inhibited cell proliferation, migration, and adhesion of HUEhT-1 in a dose-dependent manner. FAK, MEK and ERK phosphorylation were significantly blocked by MK-0429 treatment. Tube formation was suppressed by MK-0429 in dose-dependent manner. Tumor progression was significantly suppressed by MK-0429 administration in mouse oral cancer xenografts. Histological study revealed that MK-0429 decreased tumor vascularization.

Conclusion: These results indicated integrin αvβ₃ as a therapeutic target for OSCC and suggested that MK-0429 might be clinically applicable as an anti-tumor agent with potent anti-angiogenic activity.

Keywords: Anti-angiogenesis; Integrin αvβ3; MK-0429; Oral squamous cell carcinoma.

MeSH terms

Animals
Carcinoma, Squamous Cell* / drug therapy
Cell Movement
Head and Neck Neoplasms*
Humans
Integrin alphaVbeta3 / metabolism
Mice
Mitogen-Activated Protein Kinase Kinases / pharmacology
Mouth Neoplasms* / drug therapy
Neovascularization, Pathologic / drug therapy
Neovascularization, Pathologic / metabolism
Squamous Cell Carcinoma of Head and Neck

Substances

Integrin alphaVbeta3
3-(6-methoxypyridin-3-yl)-3-(2-oxo-3-(3-(5,6,7,8-tetrahydro(1,8)naphthyridin-2-yl)propyl)imidazolidin-1-yl)propionic acid
Mitogen-Activated Protein Kinase Kinases