title: (3-Chloroacetyl)-indole, a novel allosteric AKT inhibitor, suppresses colon cancer growth in vitro and in vivo.
abstract: Indole-3-carbinol (I3C) is produced in Brassica vegetables such as broccoli and cabbage and has been shown to inhibit proliferation and induce apoptosis in various cancer cells, including breast, prostate, colon, and leukemia. However, only high doses of I3C were shown to inhibit cell proliferation (IC(50) = 200-300 μmol/L). Our goal here was to develop a more potent antitumor agent by modifying the structure of I3C. We created I3C derivatives and found that (3-chloroacetyl)-indole (3CAI) more strongly inhibited colon cancer cell growth than I3C. In addition, by screening 85 kinases in a competitive kinase assay, we found that 3CAI was a specific AKT inhibitor. AKT is a serine/threonine kinase that plays a pivotal role in promoting transformation and chemoresistance by inducing proliferation and inhibiting apoptosis. Therefore, AKT is regarded as a critical target for cancer therapy. 3ICA, a derivative of I3C, is a potent and specific AKT inhibitor. This compound showed significant inhibition of AKT in an in vitro kinase assay and suppressed expression of AKT direct downstream targets such as mTOR and GSK3β as well as induced growth inhibition and apoptosis in colon cancer cells. In addition, oral administration of this potent AKT inhibitor suppressed cancer cell growth in an in vivo xenograft mouse model.
authors: The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912, USA.
authors: Dong Joon
authors: DJ
authors: Kim
authors: Kanamata
authors: K
authors: Reddy
authors: Myoung Ok
authors: MO
authors: Kim
authors: Yan
authors: Y
authors: Li
authors: Janos
authors: J
authors: Nadas
authors: Yong-Yeon
authors: YY
authors: Cho
authors: Jong-Eun
authors: JE
authors: Kim
authors: Jung-Hyun
authors: JH
authors: Shim
authors: Nu Ry
authors: NR
authors: Song
authors: Andria
authors: A
authors: Carper
authors: Ronald A
authors: RA
authors: Lubet
authors: Ann M
authors: AM
authors: Bode
authors: Zigang
authors: Z
authors: Dong
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D011487:Protein Conformation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D007211:Indoles; C056007:3-chloroacetylindole; D051057:Proto-Oncogene Proteins c-akt