Rapamycin

Perifosine Inhibits Multiple Signaling Pathways in Glial Progenitors and Cooperates With Temozolomide to Arrest Cell Proliferation in Gliomas  Abstract Perifosine is an oral Akt inhibitor which exerts a marked cytotoxic effect on human tumor cell lines, and is currently being tested in several phase II trials for treatment of major human cancers. However, the efficacy of perifosine in human gliomas has not been established. As Akt is activated in ∼70% of human glioblastomas, we investigated the impact of perifosine on glia in culture and on a mouse glioma model  in vivo . Here we show that perifosine strongly reduces phosphorylation levels of Akt and extracellular signal-regulated kinase (Erk) 1/2, induces cell cycle arrest in G 1  and G 2 , and causes dose-dependent growth inhibition of mouse glial progenitors in which Akt and/or Ras-Erk 1/2 pathways are activated. Furthermore, because temozolomide is a common oral alkylating agent used in the treatment of gliomas, we in...

Novel Fusion Protein Approach for Efficient High-Throughput Screening of Small Molecule–Mediating Protein-Protein Interactions in Cells and Living Animals Abstract Networks of protein interactions execute many different intracellular pathways. Small molecules either synthesized within the cell or obtained from the external environment mediate many of these protein-protein interactions. The study of these small molecule–mediated protein-protein interactions is important in understanding abnormal signal transduction pathways in a variety of disorders, as well as in optimizing the process of drug development and validation. In this study, we evaluated the rapamycin-mediated interaction of the human proteins FK506-binding protein (FKBP12) rapamycin-binding domain (FRB) and FKBP12 by constructing a fusion of these proteins with a split- Renilla  luciferase or a split enhanced green fluorescent protein (split-EGFP) such that complementation of the reporter fragments occurs in the presenc...

Signaling through IFN Regulatory Factor-5 Sensitizes p53-Deficient Tumors to DNA Damage–Induced Apoptosis and Cell Death Abstract Human IFN regulatory factor-5 (IRF-5) is a candidate tumor suppressor gene that mediates cell arrest, apoptosis, and immune activation. Here we show that ectopic IRF-5 sensitizes p53-proficient and p53-deficient colon cancer cells to DNA damage–induced apoptosis. The combination IFN-β and irinotecan (CPT-11) cooperatively inhibits cell growth and IRF-5 synergizes with it to further promote apoptosis. The synergism is due to IRF-5 signaling since a striking defect in apoptosis and cell death was observed in IRF-5-deficient cells, which correlated well with a reduction in DNA damage–induced cellular events. Components of this IRF-5 signaling pathway are investigated including a mechanism for DNA damage–induced IRF-5 activation. Thus, IRF-5–regulated pathways may serve as a target for cancer therapeutics.  https://cancerres.aacrjournals.org/content/65/16/74...

Why human lifespan is rapidly increasing: solving "longevity riddle" with "revealed-slow-aging" hypothesis.  Mikhail V. Blagosklonny Abstract Healthy life span is rapidly increasing and human aging seems to be postponed. As recently exclaimed in Nature, these findings are so perplexing that they can be dubbed the 'longevity riddle'. To explain current increase in longevity, I discuss that certain genetic variants such as hyper-active mTOR (mTarget of Rapamycin) may increase survival early in life at the expense of accelerated aging. In other words, robustness and fast aging may be associated and slow-aging individuals died prematurely in the past. Therefore, until recently, mostly fast-aging individuals managed to survive into old age. The progress of civilization (especially 60 years ago) allowed slow-aging individuals to survive until old age, emerging as healthy centenarians now. I discuss why slow aging is manifested as postponed (healthy) aging, why the...