Anticancer Agents Med Chem. 2010 Aug 10. [Epub ahead of print]
Updates of mTOR inhibitors.
Zhou H, Luo Y, Huang S.
Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932, USA.
Abstract
Mammalian target of rapamycin (mTOR) is a central controller of cell growth, proliferation, metabolism and angiogenesis. mTOR signaling is often dysregulated in various human diseases and thus attracts great interest in developing drugs that target mTOR. Currently it is known that mTOR functions as two complexes, mTOR complex 1/2 (mTORC1/2). Rapamycin and its analogs (all termed rapalogs) first form a complex with the intracellular receptor FK506 binding protein 12 (FKBP12) and then bind a domain separated from the catalytic site of mTOR, blocking mTOR function. Rapalogs are selective for mTORC1 and effective as anticancer agents in various preclinical models. In clinical trials, rapalogs have demonstrated efficacy against certain types of cancer. Recently, a new generation of mTOR inhibitors, which compete with ATP in the catalytic site of mTOR and inhibit both mTORC1 and mTORC2 with a high degree of selectivity, have been developed. Besides, some natural products, such as epigallocatechin gallate (EGCG), caffeine, curcumin and resveratrol, have been found to inhibit mTOR as well. Here, we summarize the current findings regarding mTOR signaling pathway and review the updated data about mTOR inhibitors as anticancer agents.
PMID: 20812900
PLoS One. 2010 Feb 15;5(2):e9199.
SIRT1 negatively regulates the mammalian target of rapamycin.
Ghosh HS, McBurney M, Robbins PD.
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Abstract
The IGF/mTOR pathway, which is modulated by nutrients, growth factors, energy status and cellular stress regulates aging in various organisms. SIRT1 is a NAD+ dependent deacetylase that is known to regulate caloric restriction mediated longevity in model organisms, and has also been linked to the insulin/IGF signaling pathway. Here we investigated the potential regulation of mTOR signaling by SIRT1 in response to nutrients and cellular stress. We demonstrate that SIRT1 deficiency results in elevated mTOR signaling, which is not abolished by stress conditions. The SIRT1 activator resveratrol reduces, whereas SIRT1 inhibitor nicotinamide enhances mTOR activity in a SIRT1 dependent manner. Furthermore, we demonstrate that SIRT1 interacts with TSC2, a component of the mTOR inhibitory-complex upstream to mTORC1, and regulates mTOR signaling in a TSC2 dependent manner. These results demonstrate that SIRT1 negatively regulates mTOR signaling potentially through the TSC1/2 complex.
PMID: 20169165 [PubMed - in process]PMCID: PMC2821410 Free PMC Article
If rapamycin extends lifespan by inhibiting mTOR, one might expect the same from resveratol. Sinclair's study on normal diet mice did not find this to be the case, though they found resveratrol plus caloric restriction to extend mouse lifespan by more than CR alone did. They did use a genetically messed up mouse; I am awaiting the results of the NIA study on genetically heterologous mice.