RETRACTED ARTICLE: The Akt inhibitor KP372-1 suppresses Akt activity and cell proliferation and induces apoptosis in thyroid cancer cells

Abstract

The phosphatidylinositol 3 0 kinase (PI3K)/phosphatase and tensin homologue deleted on chromosome ten/Akt pathway, which is a critical regulator of cell proliferation and survival, is mutated or activated in a wide variety of cancers. Akt appears to be a key central node in this pathway and thus is an attractive target for targeted molecular therapy. We demonstrated that Akt is highly phosphorylated in thyroid cancer cell lines and human thyroid cancer specimens, and hypothesised that KP372-1, an Akt inhibitor, would block signalling through the PI3K pathway and inhibit cell proliferation while inducing apoptosis of thyroid cancer cells. KP372-1 blocked signalling downstream of Akt in thyroid tumour cells, leading to inhibition of cell proliferation and increased apoptosis. As thyroid cancer consistently expresses phosphorylated Akt and KP372-1 effectively blocks Akt signalling, further preclinical evaluation of this compound for treatment of thyroid cancer is warranted.

Antivascular Therapy of Human Follicular Thyroid Cancer Experimental Bone Metastasis by Blockade of Epidermal Growth Factor Receptor and Vascular Growth Factor Receptor Phosphorylation

“…FTC cells invading the thyroid capsule or blood vessels, or metastasizing to other areas, have been characterized by activation of Akt in a nuclear pattern, suggesting an association between Akt activity and progression of tumors (54). Our laboratory has shown that the inhibition of Akt phosphorylation by a novel Akt inhibitor successfully suppressed cellular growth and induced apoptosis in thyroid cancer cells (56).…”

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

“…However, depending upon Akt phosphorylation status, the mode of apoptosis induction is different [144,145] . KP372-1, a triazinones derivative (Figure 3), inhibits proliferation and induces apoptosis in thyroid cancer, glioblastoma, squamous cell cancer, and acute myelogenous leukemia cell lines [146][147][148][149] . It is also a PDK1 and FLT3 inhibitor that causes the inhibition of PKB activation through Ser473 phosphorylation, as well as downstream target phosphorylation, which reflects the non-selective mode of action.…”

Quantitative Analysis of Anti-apoptotic Function of Akt in Akt1 and Akt2 Double Knock-out Mouse Embryonic Fibroblast Cells under Normal and Stressed Conditions

“…Moreover, Akt1 and Akt2 are dispensable for cell survival in isolated osteoclast precursors (24), possibly because of the redundant function from Akt3. Although several Akt inhibitors have been reported to induce apoptosis in cancer cells, these inhibitors may have additional targets other than Akt (25)(26)(27)). In the current study, we used an Akt3 siRNA to analyze apoptosis induction in Akt1 and Akt2 double knock-out MEF cells (MEF-Akt1,2-DKO).…”