PI3K inhibitors block an intraceullar pathway called PTEN-PI3K-AKT-mTOR. Blocking PI3K seems promising for many types of cancers, not just GIST. The trial for Gleevec plus a PI3K inhibitor is available at a few locations, notably Dana Farber in Boston, but others. The combination at least has a good theoretical rationale. THere isn't any publicly available data to know how GIST pts are doing in the trial. If this is a trial that interests you, then you would have to make an appt at one of the trial sites. You can find the trial at www.clinicaltrials.gov if you search for Gleevec BKM120.

Epigallocatechin gallate (EGCG), a major component of green tea, is a dual phosphoinositide-3-kinase/mTOR inhibitor.

Van Aller GS, Carson JD, Tang W, Peng H, Zhao L, Copeland RA, Tummino PJ, Luo L.

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Department of Cancer Research, GlaxoSmithKline, Collegeville, PA 19426, USA. glenn.s.van.aller@gsk.com

Abstract

The PI3K signaling pathway is activated in a broad spectrum of human cancers, either directly by genetic mutation or indirectly via activation of receptor tyrosine kinases or inactivation of the PTEN tumor suppressor. The key nodes of this pathway have emerged as important therapeutic targets for the treatment of cancer. In this study, we show that (-)-epigallocatechin-3-gallate (EGCG), a major component of green tea, is an ATP-competitive inhibitor of both phosphoinositide-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) with K(i) values of 380 and 320nM respectively. The potency of EGCG against PI3K and mTOR is within physiologically relevant concentrations. In addition, EGCG inhibits cell proliferation and AKT phosphorylation at Ser473 in MDA-MB-231 and A549 cells. Molecular docking studies show that EGCG binds well to the PI3K kinase domain active site, agreeing with the finding that EGCG competes for ATP binding. Our results suggest another important molecular mechanism for the anticancer activities of EGCG.

Curcumin inhibits Akt/mTOR signaling through protein phosphatase-dependent mechanism^*

Siwang Yu, Guoxiang Shen, Tin Oo Khor, Jung-Hwan Kim, and Ah-Ng Kong^#

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Abstract

Akt/mTOR signaling plays an important role in tumorigenesis and is dysregulated in many tumors, especially metastatic prostate cancers. Curcumin has been shown to effectively prevent or inhibit prostate cancer in vivo and inhibit Akt/mTOR signaling in vitro, but the mechanism(s) remains unclear. Here we show that curcumin concentration- and time-dependently inhibited the phosphorylation of Akt, mTOR, and their downstream substrates in human prostate cancer PC-3 cells, and this inhibitory effect acts downstream of PI3K and PDK1. Overexpression of constitutively activated Akt or disruption of TSC1-TSC2 complex by siRNA or gene knockout only partially restored curcumin-mediated inhibition of mTOR and downstream signaling, indicating they are not the primary effectors of curcumin-mediated inhibition of Akt/mTOR signaling. Curcumin also activated AMPK and MAP kinases, however, inhibition of these kinases failed to rescue the inhibition by curcumin. Finally, it was demonstrated that the inhibition of Akt/mTOR signaling by curcumin is resulted from calyculin A-sensitive protein phosphatase-dependent dephosphorylation. Our study reveals the profound effects of curcumin on the Akt/mTOR signaling network in PC-3 cells, and provides new mechanisms for the anti-cancer effects of curcumin.

Keywords: Curcumin, Akt, mTOR, AMPK, TSC1/TSC2, Protein phosphatase