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The lack of primary liver tumor cells has hampered testing of potential chemotherapeutic agents in vitro. To overcome this issue we developed a primary mouse liver tumor cell line K07074. The K07074 cells were immortal, exhibited a biliary phenotype, formed colonies in soft agar and displayed an increase in Hedgehog, Notch and Akt signaling. To study the effect of single and combined inhibition of the liver tumor-related pathways on the growth of K07074 cells we treated these with small-molecule antitumor agents. While the inhibition of Akt and Notch pathways strongly inhibited the growth of K07074 cells the inhibition of Wnt and Hedgehog pathways was less efficient in cell growth suppression. Interestingly, the inhibition of Akt pathway at the level of Akt-Pdpk1 interaction was sufficient to suppress the growth of tumor cells and no significant additive effect could be detected when co-treated with the inhibitors of Wnt, Hedgehog or Notch pathways. Only when suboptimal doses of Akt-Pdpk1 interaction inhibitor NSC156529 were used an additive effect with Notch inhibition was seen. We conclude that the Akt pathway inhibitor NSC156529 is potentially useful as single treatment for liver tumors with hyperactivated Akt signaling., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The serine/threonine kinase AKT/PKB has a critical role in the regulation of cell proliferation. Because AKT signaling is deregulated in numerous human malignancies, it has become an attractive anticancer drug target. A number of small molecule AKT kinase inhibitors have been developed; however, severe side effects have prevented their use in clinical trials. To find inhibitors of AKT1 signaling with principally novel mechanism of action, we carried out a live cell-based screen for small molecule inhibitors of physical interaction between AKT1 and its primary activator PDPK1. The screen revealed one molecule-NSC156529, which downregulated AKT1 signaling, efficiently decreased the proliferation of human cancer cells in vitro, and substantially inhibited the growth of prostate tumor xenografts in vivo. Interestingly, the treated tumor xenografts exhibited higher expression level of normal prostate differentiation markers but did not show augmented cell death, suggesting that the identified compound primarily enhances the differentiation of malignant cells toward normal prostate epithelium and thus poses as an attractive lead compound for developing novel antitumor agents with less cytotoxic side effects., (©2015 American Association for Cancer Research.)