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 Experiment | |
|---|---|
| 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. |
| Concentrations | ~50 μM |
| Incubation time | 48 h |
| Animal Experiment | |
|---|---|
| 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 |
| Dosages | ~50 mg/kg |
| Administration | i.v. |
| Molecular Weight | 322.75 |
| Formula | C17H11ClN4O |
| CAS Number | 431898-65-6 |
| Solubility (25°C) | 60 mg/mL in DMSO |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
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