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Until now, there is not yet antitumor drug with dramatically improved efficacy on non-small cell lung cancer (NSCLC). Marine organisms are rich source of novel compounds with various activities. We isolated stellettin B (Stel B) from marine sponge Jaspis stellifera, and demonstrated that it induced G1 arrest, apoptosis and autophagy at low concentrations in human NSCLC A549 cells. G1 arrest by Stel B might be attributed to the reduction of cyclin D1 and enhancement of p27 expression. The apoptosis induction might be related to the cleavage of PARP and increase of ROS generation. Moreover, we demonstrated that Stel B induced autophagy in A549 cells by use of various assays including monodansylcadaverine (MDC) staining, transmission electron microscopy (TEM), tandem mRFP-GFP-LC3 fluorescence microscopy, and western blot detection of the autophagy markers of LC3B, p62 and Atg5. Meanwhile, Stel B inhibited the expression of PI3K-p110, and the phosphorylation of PDK1, Akt, mTOR, p70S6K as well as GSK-3β, suggesting the correlation of blocking PI3K/Akt/mTOR pathway with the above antitumor activities. Together, our findings indicate the antitumor potential of Stel B for NSCLC by targeting PI3K/Akt/mTOR pathway.

Class I phosphatidylinositol 3 kinases (PI3K) phosphorylate phosphatidylinositol 4,5-bisphosphate to generate phosphatidylinositol 3,4,5-trisphosphate. These molecules play an important role in fundamental cellular responses. Four isoforms of class I PI3K are known to have different functions, and abnormalities in their activities have been related to various diseases such as cancer and inflammation. We previously identified a novel PI3K inhibitor, ZSTK474, which showed potent antitumor activity in vivo against a human cancer xenograft without observable toxicity. However, the mode of its molecular action was not investigated in detail. Our previous study only suggested that ZSTK474 possibly competes with ATP for the ATP-binding pocket of PI3Kγ γ γ γ. In the present study, we have used an in vitro homogenous time-resolved fluorescence kinase assay to examine whether ZSTK474 is indeed an ATPcompeting inhibitor of PI3K, and also to determine whether the inhibitory activity of ZSTK474 was isoform-specific. LineweaverBurk plot analysis revealed that ZSTK474 inhibits all four PI3K isoforms in an ATP-competitive manner. Among all of the PI3K isoforms, PI3Kδ δ δ δ was inhibited most potently by ZSTK474 with a K i of 1.8 nM, and the other isoforms were inhibited at higher doses. We have also used a kinase activity ELISA to determine whether ZSTK474 inhibits mammalian target of rapamycin, a key kinase acting downstream of PI3K to promote protein synthesis and cell proliferation. Even at a concentration of 100 µ µ µ µM, ZSTK474 inhibited mammalian target of rapamycin activity rather weakly. These results indicate that ZSTK474 is an ATP-competitive pan-class I PI3K inhibitor. (Cancer Sci 2007; 98: 1638-1642) P hosphatidylinositol 3-kinases (PI3K) are ubiquitously expressed lipid kinases that phosphorylate phosphoinositides at the 3-hydroxyl of the inositol ring.(1) The products of these enzymes serve as second messengers with key roles in fundamental cellular responses such as proliferation, survival, motility and metabolism.(2,3) The PI3K were classified into three types based on their primary structure and substrate specificity. The class I PI3K phosphorylate phosphatidylinositol 4,5-bisphosphate (PIP2) to generate phosphatidylinositol 3,4, 5-trisphosphate (PIP3). This class was further divided into subclasses IA and IB based on the regulatory subunit. The class IA kinases are heterodimers composed of a regulatory subunit p85 and a catalytic subunit p110. The p85 binds to various tyrosine kinases to activate p110 and downstream molecules such as Akt. The catalytic subunit of class IA consists of the three isoforms p110α, -β and -δ. Class IB PI3K contains the catalytic subunit p110γ and the regulatory subunit p101, which is mainly activated by G-protein-coupled receptors. (4,5) Previous studies showed that the four class I PI3K isoforms possess specialized functions. PI3Kα, which is known to play an important role in tumorigenesis because a high frequency of mutations was detected in the PIK3CA gene encoding the catalytic...

The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in human cancers. Class I PI3Ks are lipid kinases that phosphorylate phosphatidylinositol 4,5-bisphosphate (PIP2) at the 3-OH of the inositol ring to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3), which in turn activates Akt and the downstream effectors like mammalian target of rapamycin (mTOR) to play key roles in carcinogenesis. Therefore, PI3K has become an important anticancer drug target, and currently there is very high interest in the pharmaceutical development of PI3K inhibitors. Idelalisib has been approved in USA and Europe as the first-in-class PI3K inhibitor for cancer therapy. Dozens of other PI3K inhibitors including BKM120 and ZSTK474 are being evaluated in clinical trials. Multifaceted studies on these PI3K inhibitors are being performed, such as single and combinational efficacy, resistance, biomarkers, etc. This review provides an introduction to PI3K and summarizes key advances in the development of PI3K inhibitors.

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