(3-Chloroacetyl)-indole, a novel allosteric AKT inhibitor, suppresses colon cancer growth in vitro and in vivo

Dong Joon Kim, Srinivasa Reddy Kanamata Reddy, Myoung Ok Kim, Yan Li, Janos Nadas, Yong Yeon Cho, Jong Eun Kim, Jung Hyun Shim, Nu Ry Song, Andria Carper, Ronald A. Lubet, Ann M. Bode, Zigang Dong

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1842-1851
Number of pages10
JournalCancer Prevention Research
Volume4
Issue number11
DOIs
StatePublished - Nov 2011

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