Droxinostat is originally identified as a sensitizer of PPC-1 cells to FAS and TRAIL by down-regulating the expression of c-Fas-associated death domain-like interleukin-1-converting enzyme-like inhibitory protein (c-FLIP). Droxinostat also downregulated c-FLIP expression, induced caspase-8- and caspase-3/7-mediated apoptosis, and increased apoptosis in bicalutamide-treated cells. Droxinostat shows a significant action on gene transcription hence controlling tumor progression. Droxinostat (10 μM - 100 μM) sensitizes cells to apoptosis by decreasing c-FLIPL and c-FLIPS expression, reducing cell survival, and inducing apoptosis in MCF-7 breast cancer cells. In SCID mice models, Droxinostat (30 μM)-treated PPC-1 cells results in decreased distant tumor formation than untreated cells.
|Cell lines||PPC-1 cells|
|Preparation method||Viability of PPC-1 cells treated with 5809354 or 7271570 (0, 20, 40, 60, and 80 μM) with and without CH-11 (100 ng/mL) or cultured under adherent or suspension conditions and MEFs treated with 5809354 (0, 20, 40, 60, and 80 μM) under adherent or suspension conditions was assessed using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt reduction assay (Promega, Madison, WI) according to the manufacturer's protocols as previous described (18). The percent relative cell viability was expressed as (optical density of treated cells/optical density of controls) × 100%. Two independent experiments were performed in triplicate (n = 6).|
|Concentrations||0, 20, 40, 60, and 80 μM|
|Incubation time||30 h|
|Animal models||male SCID mice between 5 and 7 weeks of age prostate cancer cells in vivo|
|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 40 mg/mL
Ethanol 40 mg/mL
Elevation of c-FLIP in castrate-resistant prostate cancer antagonizes therapeutic response to androgen receptor-targeted therapy.
McCourt C, et al. Clin Cancer Res. 2012 Jul 15;18(14):3822-33. PMID: 22623731.
4-(4-Chloro-2-methylphenoxy)-N-hydroxybutanamide (CMH) targets mRNA of the c-FLIP variants and induces apoptosis in MCF-7 human breast cancer cells.
Bijangi-Vishehsaraei K, et al. Mol Cell Biochem. 2010 Sep;342(1-2):133-42. PMID: 20446019.
Selective inhibition of histone deacetylases sensitizes malignant cells to death receptor ligands.
Wood TE, et al. Mol Cancer Ther. 2010 Jan;9(1):246-56. PMID: 20053768.
Critical role for Fas-associated death domain-like interleukin-1-converting enzyme-like inhibitory protein in anoikis resistance and distant tumor formation.
Mawji IA, et al. J Natl Cancer Inst. 2007 May 16;99(10):811-22. PMID: 17505076.
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