ABSTRACT
The tyrosine and phosphoinositide kinases play crucial roles in the regulation of many cancer cell processes including cell survival and cell motility. Anaplastic thyroid carcinoma (ATC) is a rare and deadly type of thyroid cancer, and so far, there are no effective therapeutic compounds for ATC. Herein, we investigate the anticancer activities of PP121, a dual inhibitor of tyrosine and phosphoinositide kinases, in ATC therapy. We found that PP121 is effective at suppressing cell viability, inducing cell apoptosis, and inhibiting cell migration and invasion. The potential anticancer mechanism for PP121 might be its inhibitory effects on phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways in ATC cells. Furthermore, PP121 is effective at suppressing ATC tumor growth in vivo. In summary, our studies suggest that PP121 might be a promising therapeutic compound for ATC treatment, which might shed new light on ATC therapy.
Subject(s)
Cell Movement/drug effects , Cell Proliferation/drug effects , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Thyroid Carcinoma, Anaplastic/drug therapy , Thyroid Neoplasms/drug therapy , 1-Phosphatidylinositol 4-Kinase/antagonists & inhibitors , 1-Phosphatidylinositol 4-Kinase/metabolism , Animals , Apoptosis/drug effects , Blotting, Western , Cell Line, Tumor , Cell Survival/drug effects , Dose-Response Relationship, Drug , Humans , Immunohistochemistry , Mice, Nude , Microscopy, Fluorescence , Phosphatidylinositol 3-Kinases/metabolism , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , Thyroid Carcinoma, Anaplastic/metabolism , Thyroid Carcinoma, Anaplastic/pathology , Thyroid Neoplasms/metabolism , Thyroid Neoplasms/pathology , Time Factors , Tumor Burden/drug effects , Xenograft Model Antitumor AssaysABSTRACT
The phosphatidylinositol-3-kinase/Akt pathway and receptor tyrosine kinases regulate many tumorigenesis related cellular processes including cell metabolism, cell survival, cell motility, and angiogenesis. Anaplastic thyroid carcinoma (ATC) is a rare type of thyroid cancer with no effective systemic therapy. It has been shown that Akt activation is associated with tumor progression in ATC. Here we observed the additive effect between an Akt inhibitor (MK-2206) and a novel platelet-derived growth factor receptor inhibitor (tyrphostin AG 1296) in ATC therapy. We found an additive effect between MK-2206 and tyrphostin AG 1296 in suppressing ATC cell viability. The combination of MK-2206 and tyrphostin AG 1296 induces additive apoptosis, additive suppression of the Akt signaling pathway, as well as additive inhibition of cell migration and invasion of ATC cells. Furthermore, the combination of MK-2206 and tyrphostin AG 1296 induced additive suppression of ATC tumor growth in vivo. In summary, our studies suggest that the combination of Akt and receptor tyrosine kinase inhibitors may be an efficient therapeutic strategy for ATC treatment, which might shed new light on ATC therapy.
