In vitro: PS-1145 blocks TNFalpha-induced NF-kappaB activation through inhibition of IkappaBalpha phosphorylation, and blocks the protective effect of IL-6 against Dex-induced apotosis. PS-1145 also inhibits paracrine MM cell growth and IL-6 secretion in BMSCs triggered by MM cell adherence. In human primary CD4(+) T cells, PS-1145 abrogates cell proliferation and impairs the activation of NF-κB and AP-1 transcription factors by engagement of CD3 and CD28 coreceptor. In vivo: In male Wistar rats with DMBA-induced skin tumor, PS-1145 (50 mg/kg, i.v.) enhances tumor cell apoptosis by up-regulating p53, activating caspases and down regulating NF-κB and VEGF factor, and thus induces the tumor progression.
|Cell lines||MM.1S, U266, and RPMI8226 cell lines|
|Preparation method||The inhibitory effect of PS-1145 on MM growth is assessed by measuring MTT dye absorbance of the cells. Cells from 48-h cultures are pulsed with 10 μL of 5 mg/ml MTT to each well for the last 4 h of 48-h cultures, followed by 100 μl of isopropanol containing 0.04N HCl. Absorbance is measured at 570 nm using a spectrophotometer.|
|Incubation time||48 h|
|Animal models||Male Wistar rats with DMBA-induced skin tumor|
|Formulation||Dissolved at 0.4 mg/mL in DMSO and diluted with 0.9% NaCl|
|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||64 mg/mL in DMSO|
Interleukin 6, a nuclear factor-kappaB target, predicts resistance to docetaxel in hormone-independent prostate cancer and nuclear factor-kappaB inhibition by PS-1145 enhances docetaxel antitumor activity.
Domingo-Domenech J, et al. Clin Cancer Res. 2006 Sep 15;12(18):5578-86. PMID: 17000695.
NF-kappaB as a target for the prevention of graft-versus-host disease: comparative efficacy of bortezomib and PS-1145.
Vodanovic-Jankovic S, et al. Blood. 2006 Jan 15;107(2):827-34. PMID: 16174760.
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