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 eIF4E, cyclin D1, and induces G1 cell cycle arrest. In contrast to conventional mTOR inhibitors, C-KβBA downregulates the phosphorylation of S6K1, the major downstream target of mTORC1, without concomitant activation of mTORC2/Akt and ERK pathways, and independently of protein phosphatase 2A, LKB1/AMPK/TSC, and F12-protein binding. At the molecular level, the compound binds to the FRB 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.
- AKT / PKB
- ERK p38 Jun
- Mammalian target of rapamycin (mTOR)
- PI-3 kinase / PTEN
- Homology modeling
- Apoptosis
- Received July 18, 2012.
- Revision received December 2, 2012.
- Accepted December 3, 2012.
- The American Society for Pharmacology and Experimental Therapeutics