3-(Hydroxymethyl)-Bearing Phosphatidylinositol Ether Lipid Analogues and Carbonate Surrogates Block PI3-K, Akt, and Cancer Cell Growth

Abstract

Phosphatidylinositol 3-kinase (PI3-K) phosphorylates the 3-position of phosphatidylinositol to give rise to three signaling phospholipids. Binding of the pleckstrin homology (PH) domain of Akt to membrane PI(3)P's causes the translocation of Akt to the plasma membrane bringing it into contact with membrane-bound Akt kinase (PDK1 and 2), which phosphorylates and activates Akt. Akt inhibits apoptosis by phosphorylating Bad, thus promoting its binding to and blockade of the activity of the cell survival factor Bcl-x. Herein we present the synthesis and biological activity of several novel phosphatidylinositol analogues and demonstrate the ability of the carbonate group to function as a surrogate for the phosphate moiety. Due to a combination of their PI3-K and Akt inhibitory activities, the PI analogues 2, 3, and 5 proved to be good inhibitors of the growth of various cancer cell lines with IC(50) values in the 1-10 microM range. The enhanced Akt inhibitory activity of the axial hydroxymethyl-bearing analogue 5 compared to its equatorial counterpart 6 is rationalized based upon postulated differences in the H-bonding patterns of these compounds in complex with a homology modeling generated structure of the PH domain of Akt. This work represents the first attempt to examine the effects of 3-modified PI analogues on these two crucial cell signaling proteins, PI3-K and Akt, in an effort to better understand their cell growth inhibitory properties.

M-CSF, TNFα and RANK ligand promote osteoclast survival by signaling through mTOR/S6 kinase

“…This inhibitor did not interfere with phosphorylation of Akt itself (Figure 5d). The concentration of Akt inhibitor used (10 mM) was two-fold above its IC 50 for suppression of Akt and eightfold below its IC 50 for PI3K, 45 suggesting that this response was relatively Akt specific. pp60 c-src activity may also play a role in this part of the pathway, since it is required for signaling from PI3K to S6K and from RANKL to Akt.…”

IL-4 protects the B-cell lymphoma cell line CH31 from anti-IgM-induced growth arrest and apoptosis: contribution of the PI-3 kinase/AKT pathway

“…These results suggest that PI-3K and molecules downstream of it are involved in the IL-4-mediated protection. To test whether Akt function is directly involved with the IL-4-mediated protection from apoptosis, we cultured CH31 cells in the presence of the Akt inhibitor AktI, which prevents binding of Akt to D3 phosphatidylinositol (PIP3) [53]. We observed that this inhibitor also abrogated the ability of IL-4 to protect cells from anti-IgM-induced apoptosis ( Figure 7C), suggesting that Akt activity and its downstream sequelae contribute to the anti-apoptotic activity of IL-4 in this model.…”

A new selective AKT pharmacological inhibitor reduces resistance to chemotherapeutic drugs, TRAIL, all-trans-retinoic acid, and ionizing radiation of human leukemia cells

“…21,22 Recently, a selective Akt pharmacological inhibitor, 1L-6-hydroxymethyl-chiro-inositol 2(R)-2-O-methyl-3-O-octadecylcarbonate (Akt inhibitor), has been synthesized. 23 HL60 cells derived from a human acute promyelocytic leukemia and are usually sensitive to chemotherapeutic drugs and TRAIL. We have described an HL60 leukemia human cell clone (named HL60AR) with a constitutively activated PI3K/Akt axis.…”