Delayed activation of insulin-like growth factor-1 receptor/Src/MAPK/Egr-1 signaling regulates clusterin expression, a pro-survival factor.

Secretory clusterin protein (sCLU) is a general genotoxic stress-induced, pro-survival gene product implicated in aging, obesity, heart disease, and cancer. However, the regulatory signal transduction processes that control sCLU expression remain undefined. Here, we report that induction of sCLU is delayed, peaking 72 h after low doses of ionizing radiation, and is dependent on the up-regulation of insulin-like growth factor-1 as well as phosphorylation-dependent activation of its receptor (IGF-1 and IGF-1R, respectively).

Enhancement of solubility and bioavailability of beta-lapachone using cyclodextrin inclusion complexes.

Purpose: To explore the use of cyclodextrins (CD) to form inclusion complexes with beta-lapachone (beta-lap) to overcome solubility and bioavailability problems previously noted with this drug.

Methods: Inclusion complexes between beta-lap and four cyclodextrins (alpha-, beta-, gamma-, and HPbeta-CD) in aqueous solution were investigated by phase solubility studies, fluorescence, and 1H-NMR spectroscopy. Biologic activity and bioavailability of beta-lap inclusion complexes were investigated by in vitro cytotoxicity studies with MCF-7 cells and by in vivo lethality studies with C57Blk/6 mice (18-20 g).

Repression of IR-inducible clusterin expression by the p53 tumor suppressor protein.

The clusterin (CLU) protein has been reported to have both cytoprotective and cytotoxic activities. Previous data from our lab suggest that the secretory form of CLU (sCLU) is cytoprotective and induced after very low, nontoxic doses of ionizing radiation (IR: >0.02 Gy), while a nuclear form is cytotoxic.