title: An α-acetoxy-tirucallic acid isomer inhibits Akt/mTOR signaling and induces oxidative stress in prostate cancer cells.
abstract: Here we provide evidence that αATA(8,24) (3α-acetyloxy-tir-8,24-dien-21-oic acid) inhibits Akt/mammalian target of rapamycin (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 with 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) exerted no overt toxic effects on peripheral blood mononuclear cells or 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 cyclin D1, cyclin E, and cyclin B1, as well as cyclin-dependent kinases CDK4 and CDK2 and phosphoretinoblastoma protein, which led to inhibition of the cell-cycle progression. In agreement with the 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 reactive oxygen species 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.
authors.affiliation: Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany (M.E.G., B.B., Ta.S., C.Q.S., Th.S.); and Max Planck Institute for Chemical Ecology, Research Group Biosynthesis/NMR, Jena, Germany (S.A., B.S.).
authors.forename: Menna
authors.initials: M
authors.lastname: El Gaafary
authors.affiliation: Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany (M.E.G., B.B., Ta.S., C.Q.S., Th.S.); and Max Planck Institute for Chemical Ecology, Research Group Biosynthesis/NMR, Jena, Germany (S.A., B.S.).
authors.forename: Berthold
authors.initials: B
authors.lastname: Büchele
authors.affiliation: Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany (M.E.G., B.B., Ta.S., C.Q.S., Th.S.); and Max Planck Institute for Chemical Ecology, Research Group Biosynthesis/NMR, Jena, Germany (S.A., B.S.).
authors.forename: Tatiana
authors.initials: T
authors.lastname: Syrovets
authors.affiliation: Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany (M.E.G., B.B., Ta.S., C.Q.S., Th.S.); and Max Planck Institute for Chemical Ecology, Research Group Biosynthesis/NMR, Jena, Germany (S.A., B.S.).
authors.forename: Sara
authors.initials: S
authors.lastname: Agnolet
authors.affiliation: Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany (M.E.G., B.B., Ta.S., C.Q.S., Th.S.); and Max Planck Institute for Chemical Ecology, Research Group Biosynthesis/NMR, Jena, Germany (S.A., B.S.).
authors.forename: Bernd
authors.initials: B
authors.lastname: Schneider
authors.affiliation: Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany (M.E.G., B.B., Ta.S., C.Q.S., Th.S.); and Max Planck Institute for Chemical Ecology, Research Group Biosynthesis/NMR, Jena, Germany (S.A., B.S.).
authors.forename: Christoph Q
authors.initials: CQ
authors.lastname: Schmidt
authors.affiliation: Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany (M.E.G., B.B., Ta.S., C.Q.S., Th.S.); and Max Planck Institute for Chemical Ecology, Research Group Biosynthesis/NMR, Jena, Germany (S.A., B.S.) thomas.simmet@uni-ulm.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Simmet
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D029743:Boswellia / Q000737:chemistry; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007536:Isomerism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008958:Models, Molecular; D008968:Molecular Conformation; D015388:Organelles / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D011471:Prostatic Neoplasms / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014315:Triterpenes / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*
chemical_list: C000594606:3-acetyloxytir-8,24-dien-21-oic acid; D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D014315:Triterpenes; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases