A novel semisynthetic inhibitor of the FRB domain of mammalian target of rapamycin blocks proliferation and triggers apoptosis in chemoresistant prostate cancer cells.

Content Provider	Semantic Scholar
Author	Morad, Samy A. F. Schmid, Maximilian Buechele, Berthold Siehl, Hans-Ullrich Gafaary, Menna El Lunov, Oleg Syrovets, Tatiana Simmet, Thomas
Copyright Year	2013
Abstract	The mammalian target of rapamycin (mTOR) is a key regulator of cell growth and its uncontrolled activation is a hallmark of cancer. Moreover, mTOR activation has been implicated in the resistance of cancer cells to many anticancer drugs, rendering this pathway a promising pharmacotherapeutic target. Here we explored the capability of a semisynthetic compound to intercept mTOR signaling. We synthesized and chemically characterized a novel, semisynthetic triterpenoid derivative, 3-cinnamoyl-11-keto-β-boswellic acid (C-KβBA). Its pharmacodynamic effects on mTOR and several other signaling pathways were assessed in a number of prostate and breast cancer cell lines as well as in normal prostate epithelial cells. C-KβBA exhibits specific antiproliferative and proapoptotic effects in cancer cell lines in vitro as well as in PC-3 prostate cancer xenografts in vivo. Mechanistically, the compound significantly inhibits the cap-dependent transition machinery, decreases expression of eukaryotic translation initiation factor 4E and cyclin D1, and induces G(1) cell-cycle arrest. In contrast to conventional mTOR inhibitors, C-KβBA downregulates the phosphorylation of p70 ribosomal S6 kinase, the major downstream target of mTOR complex 1, without concomitant activation of mTOR complex 2/Akt and extracellular signal-regulated kinase pathways, and independently of protein phosphatase 2A, liver kinase B1/AMP-activated protein kinase/tuberous sclerosis complex, and F12-protein binding. At the molecular level, the compound binds to the FKBP12-rapamycin-binding domain of mTOR with high affinity, thereby competing with the endogenous mTOR activator phosphatidic acid. C-KβBA represents a new type of proapoptotic mTOR inhibitor that, due to its special mechanistic profile, might overcome the therapeutic drawbacks of conventional mTOR inhibitors.
Starting Page	2330
Ending Page	2331
Page Count	2
File Format	PDF HTM / HTML
Alternate Webpage(s)	http://molpharm.aspetjournals.org/content/molpharm/83/2/531.full.pdf?with-ds=yes
PubMed reference number	23208958v1
Alternate Webpage(s)	https://doi.org/10.1124/mol.112.081349
DOI	10.1124/mol.112.081349
Journal	Molecular pharmacology
Volume Number	83
Issue Number	2
Language	English
Access Restriction	Open
Subject Keyword	Affinity Apoptosis Cultured Cell Line Exhibits as Topic FRAP1 protein, human Mammals Mammary Neoplasms New type Peptide Initiation Factors Pharmacodynamics Phosphatidic Acid Point of Interception Precipitating Factors Prostatic Neoplasms Protein Kinases Protein phosphatase Ribosomal Protein S6 Kinase Sirolimus Thioctic Acid Transcription Initiation Translation Initiation Tuberous Sclerosis Xenograft procedure cancer cell cell growth mTOR Inhibitor pentacyclic triterpenoid biosynthetic process
Content Type	Text
Resource Type	Article