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

• DOI: 10.1007/s00432-022-04100-3
• Publication Date: 2022-06-17T12:05:54Z
• Authors: Takayuki Nakagawa; Kouji Ohta; Takako Naruse; Miyuki Sakuma; Syohei Fukada; Nao Yamakado; Misaki Akagi; Kazuki Sasaki; Chieko Niwata; Shigehiro Ono; Tomonao Aikawa
• Keywords: Mitogen-Activated Protein Kinase Kinases; Neovascularization, Pathologic; Squamous Cell Carcinoma of Head and Neck; Integrin alphaVbeta3; 3. Good health; Mice; 03 medical and health sciences; 0302 clinical medicine; Cell Movement; Head and Neck Neoplasms; Carcinoma, Squamous Cell; Humans; Animals; Mouth Neoplasms; Original Article – Cancer Research

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.