Tyrosine Kinase Inhibitor AG490 Inhibits the Proliferation and Migration and Disrupts Actin Organization of Cancer Cells

Abstract

Metastasis, a multistep process, is a major cause of mortality in cancer patients. Thus, it is hoped that inhibition of metastasis at any step, such as proliferation, migration, or invasion, using small-molecule inhibitors will reduce this mortality. Recent study suggests that the Janus kinase/signal transducer and activator of transcription 3 signal transduction pathway is a central pathway that regulates tumor progression and metastasis and can be blocked using tyrosine kinase inhibitors. In this study we used a synthetic tyrosine kinase inhibitor, AG490, to block the constitutive activation of the Janus kinase/signal transducer and activator of transcription 3 pathway in A549 lung carcinoma and A375 melanoma cell lines. Our results show that AG490 at subtoxic doses can effectively suppress tumor cell proliferation by limiting the expression of cyclin D1. Furthermore, AG490 is seen to induce apoptosis, inhibit cellular migration by disrupting actin organization, and suppress matrix metalloproteinase 2 activity. Taken together, these data demonstrate that AG490 can exert antimetastatic activity by inhibiting cellular proliferation, invasion, and migration.