An α‐Acetoxy‐Tirucallic Acid Isomer Inhibits Akt/mTOR Signaling and Induces Oxidative Stress in Prostate Cancer Cells

Here we provide evidence that 3α‐acetyloxy‐tir‐8,24‐dien‐21‐oic acid (αATA(8,24)) inhibits the Akt/mTOR signaling. αATA(8,24) and other tirucallic acids were isolated from the acetylated extract of the oleo gum resin of Boswellia serrata to chemical homogeneity. Compared to related tirucallic acids, αATA(8,24) was the most potent inhibitor of the proliferation of androgen‐insensitive prostate cancer cells in vitro and in vivo , in prostate cancer xenografted onto chick chorioallantoic membranes. αATA(8,24) induced loss of cell membrane asymmetry, caspase 3 activation, and DNA fragmentation in vitro and in vivo . These effects were selective for cancer cells, because αATA(8,24) did not exert overt toxic effects either on peripheral blood mononuclear cells or on the chick embryo. At the molecular level, αATA(8,24) inhibited the Akt1 kinase activity. Prior to all biochemical signs of cellular dysfunction, αATA(8,24) induced inhibition of the Akt downstream target mTOR as indicated by dephosphorylation of S6K1. This event was followed by decreased expression of cell cycle regulators, such as cyclins, cyclin‐dependent kinases, and phospho retinoblastoma protein, which led to inhibition of the cell cycle progression. In agreement with mTOR inhibition, αATA(8,24) and rapamycin increased the volume of acidic vesicular organelles. In contrast to rapamycin, αATA(8,24) destabilized lysosomal and mitochondrial membranes, and induced ROS production in cancer cells. The ability of αATA(8,24) to inhibit Akt/mTOR signaling and to induce simultaneously oxidative stress could be exploited for the development of novel antitumor therapeutics with a lower profile of toxic side effects.