Focal adhesion kinase autophosphorylation inhibition decreases colon cancer cell growth and enhances the efficacy of chemotherapy

• Published in: Cancer biology & therapy 2013-08, Vol.14 (8), p.761-772
• Main Authors: Heffler, Melissa, Golubovskaya, Vita M, Dunn, Kelli M Bullard, Cance, William
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Cell Proliferation - drug effects; colon carcinoma; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Female; focal adhesion kinase; Focal Adhesion Protein-Tyrosine Kinases - antagonists & inhibitors; Focal Adhesion Protein-Tyrosine Kinases - metabolism; HT29 Cells; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Phenylenediamines - pharmacology; Phosphorylation - drug effects; Protein Kinase Inhibitors - pharmacology; Research Paper; small molecule inhibitors; SW480 cells; SW620; Xenograft Model Antitumor Assays
• ISSN: 1538-4047; 1555-8576
• DOI: 10.4161/cbt.25185

Focal adhesion kinase (FAK) increasingly has been implicated in cancer growth and progression. 1,2,4,5-Benzenetetraamine tetrahydrochloride (Y15) is a small molecule FAK inhibitor that blocks the Y397 autophosphorylation site. FAK inhibitor, Y15 decreased Y397 FAK in different colon cancer cells lines in a dose-dependent manner. In addition, Y15 decreased phosphorylated Src in SW480 and SW620 cells. Y15 decreased cell viability, increased detachment, and increased apoptosis in SW480 and SW620 cells in vitro. Combination of FAK inhibitor Y15 and Src inhibitor PP2 decreased colon cancer cell viability more effectively than each agent alone. In addition, when combined with 5-FU, oxaliplatin or 5-FU and oxaliplatin, colon cancer viability was decreased further, demonstrating that dual and triple therapy synergistically inhibits cell viability. In vivo, Y15 decreased subcutaneous SW620 tumor growth by 28%. Combination of oral Y15 with 5-FU/or oxaliplatin decreased tumor growth by 48% more effectively than each inhibitor alone. Finally, tumors treated with Y15 expressed less Y397 phosphorylation, Src phosphorylation and had greater apoptosis than controls. Thus, the small molecule FAK inhibitor, Y15, inhibits cell growth in vitro and in vivo and enhances the efficacy of chemotherapy, demonstrating that it can be an effective therapeutic inhibitor for treating colon cancer.