OSU-03012 is a novel and potent inhibitor of PDK-1. OSU-03012 exhibits anti-cancer activity in a COX-2-independent manner via inhibition of the phosphatidyl inositol-3-kinase (PI3K)/Akt pathway. It has an IC50 of 5 µM for inhibition of 3-phosphoinositide-dependent kinase-1 (PDK-1), and therefore Akt activation, with no measurable COX-2 inhibition up to 50 µM. OSU-03012 induces apoptosis of chronic lymphocytic leukemia (CLL) cells independent of bcl-2 overexpression using both caspase-dependent and independent pathways. A recent study shows that OSU-03012 could enhance the susceptibility of (Bcr)-Abl mutant cell lines to imatinib-induced apoptosis. OSU-03012 may lead to cell swelling and shortening of AP via reduced ATP production in mouse ventricular cells.
|Source||Mol Med Rep (2015). Figure 2.OSU‑03012|
|Cell Lines||LX2 cells|
|Incubation Time||48 or 72 h|
|Results||Aapoptosis was not induced in LX2 cells treated with OSU‑03012, compared with those treated with DMSO. These results indicated that OSU‑03012 did not inhibit the growth of LX2 cells via the induction of apoptosis.|
|Cell lines||VS and HMS-97 cells|
|Preparation method||Cell proliferation assay VS and HMS-97 cells were grown in polylysine/laminin-coated 96-well plates (5 × 103 to 1 × 104 per well). After incubation at 37°C for 24 hrs, cells were treated with various concentrations of OSU-03012 or DMSO as a vehicle control at 37°C for another 48 hrs. To assess cell proliferation, the CellTiter 96®AQueous One Solution Cell Proliferation Assay (Promega) was used according to the manufacturer’s instructions. Briefly, 20μl of CellTiter 96® AQueous One Solution Reagent were added to each well and incubated at 37°C for 1 to 4 hrs. The amount of colored formazan produced in the cells was measured at 490nm using a Victor3 1420 Multilabel Counter (Perkin Elmer). The percentage of cell proliferation was plotted against the concentrations of OSU-03012, and the IC50 (defined as the drug concentration at which the population of viable cells was reduced by 50%) was determined using CalcuSyn software (Biosoft). The experiments were replicated six times, and the mean IC50 was calculated.|
|Animal models||Schwannoma xenografts in severe combined immunodeficiency mice (SCID)|
|Formulation||methylcellulose (0.5%, w/v) and Tween 80 (0.1%, w/v) in sterile water|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO ≥90 mg/mL|
OSU-03012 suppresses GRP78/BiP expression that causes PERK-dependent increases in tumor cell killing.
Booth et al. Cancer Biol Ther. 2012 Feb 15;13(4):224-36. PMID: 22354011.
Endogenous adenosine contributes to renal sympathetic neurotransmission via postjunctional A1 receptor-mediated coincident signaling.
Jackson et al. Am J Physiol Renal Physiol. 2012 Feb;302(4):F466-76. PMID: 22114202.
The phosphoinositide-3-kinase-Akt signaling pathway is important for Staphylococcus aureus internalization by endothelial cells.
Oviedo-Boyso et al. Infect Immun. 2011 Nov;79(11):4569-77. PMID: 21844240.
OSU-03012, a novel celecoxib derivative, induces cell swelling and shortens action potential duration in mouse ventricular cells.
Yamamoto et al. Biomed Res. 2010 Dec;31(6):413-7. PMID: 21187652.
OSU-03012 enhances Ad.7-induced GBM cell killing via ER stress and autophagy and by decreasing expression of mitochondrial protective proteins.
Hamed et al. Cancer Biol Ther. 2010 Apr;9(7):526-36. PMID: 20107314.
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