Biricodar (VX-710, Incel) is a clinically applicable modulator of P-glycoprotein (Pgp) with potential chemosensitizing activity. Biricodar blood concentration at the time of mitoxantrone administration averaged 4.52 microg/ml. In 8226/Dox6 cells (Pgp), Biricodar (VX-710) increased mitoxantrone and daunorubicin uptake by 55 and 100%, respectively, increased their retention by 100 and 60%, respectively, and increased their cytotoxicity 3.1- and 6.9-fold, respectively. Biricodar (VX-710) modulates Pgp, MRP-1, and BCRP(R482), and has potential as a clinical broad-spectrum MDR modulator in malignancies such as the acute leukemias in which these proteins are expressed.
|Cell lines||HL60 cells line|
|Preparation method||Cytotoxicity Assays.
To study cytotoxicity in suspension cell lines, cells were plated in 96-well tissue culture plates at a density of 10,000 cells/well in RPMI 1640 supplemented with 10% FCS, 2 mm l-glutamine, 20 units/ml penicillin, and 20 μg/ml streptomycin. Drug was added to the culture medium to achieve final concentrations of 0.3 nm to 10 μm, with half-log increments, with and without VX-710 at a final concentration of 2.5 μM. The final volume of medium per well was 100 μl. Cells were incubated for 96 h at 37°C in a fully humidified atmosphere of 5% CO2 in air. Cell growth was assessed by the WST-1 colorimetric assay (Roche Diagnostics GmbH, Mannheim, Germany; Ref. 29 ), performed according to the manufacturer’s instructions. Briefly, 10 μl of WST-1 were added to each well, and culture plates were returned to the incubator for an additional 4 h. Subsequently, the absorbance at 450 nm (A450) and 600 nm (A600, background) was read for each well using a Microtek multiwell plate reader. Each drug exposure condition was assessed in quadruplicate.
|Incubation time||96 h|
|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 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.
P-glycoprotein antagonists confer synergistic sensitivity to short-chain ceramide in human multidrug-resistant cancer cells.
Chapman et al. Exp Cell Res. 2011 Jul 15;317(12):1736-45. PMID: 21396934.
Inhibition of antibiotic efflux in bacteria by the novel multidrug resistance inhibitors biricodar (VX-710) and timcodar (VX-853).
Mullin et al. Antimicrob Agents Chemother. 2004 Nov;48(11):4171-6. PMID: 15504837.
VX-710 (biricodar) increases drug retention and enhances chemosensitivity in resistant cells overexpressing P-glycoprotein, multidrug resistance protein, and breast cancer resistance protein.
Minderman et al. Clin Cancer Res. 2004 Mar 1;10(5):1826-34. PMID: 15014037.
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