The PI3K/AKT/mTOR signaling pathway is involved in various cellular processes such as cell proliferation, migration, survival and angiogenesis. The phosphatidylinositol-3,4,5-triphosphate (PIP3) binding function of pleckstrin homology (PH) domain is essential for the activation of oncogenic Akt/PKB kinase[3]. SC66 is an allosteric Akt inhibitor that affects AKT/mTOR signaling by a decrease in AKT phosphorylation levels and in total protein levels[4]. After treatment with increasing concentrations of SC-66, activating PIK3CA (E545K, E542K) and inactivating PTEN (R233*) mutations were identified in human cervical cancer. SC-66 effectively inhibited AKT, mTOR and mTOR substrates in C33A cells. SC-66 inhibited glucose uptake via reduced delivery of Glut1 and Glut4 to the cell membrane. SC-66 (1 µg/ml-56%) treatment decreased cell viability through a non-apoptotic mechanism. Decreases in cell viability were enhanced when AKT inhibitors were combined with 2-DG. The scratch assay showed a substantial reduction in cell migration upon SC-66 treatment[5]. A mouse xenograft tumor model of Hep3B cells was used to demonstrate the effectiveness in vivo of SC66 on HCC. Treatment with 25 mg/Kg SC66 via i.p. injection twice a week significantly reduced tumor volume to 37%. SC66 inhibit HCC cell viability with IC50 values of approximately 0.85 and 0.75 μg/ml at 48 and 72 hours, respectively for HepG2, HA22T/VGH and PLC/PRF/5 cells[4].
作用机制
SC66 manifests a dual inhibitory activity that directly interferes with the PH domain binding to PIP3 and facilitates Akt ubiquitination[3].
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