Dofequidar(MS-209) is a novel quinoline compound, which can reverse P-glycoprotein (P-gp)-mediated MDR. In cell-based studies, MS-209 at 3 μM successfully mitigated docetaxel resistance in MDR cancer cells, maintaining this concentration in blood plasma for over 7 hours without significant toxicity[1]. MS-209 reinstates the sensitivity of SBC-3 / ADM cells to VP-16, ADM, and VCR in a dose-dependent manner[2]. MS-209 significantly reverses resistance to adriamycin (ADM) and vincristine (VCR) in established MDR tumor cell lines, such as 2780AD and KB-C1, and enhances the cytotoxic effects of ADM and VCR on a variety of human and mouse cell lines. Notably, in 4-1St cells, which show high resistance to ADM and VCR, a 3 μM concentration of MS-209 boosts the cytotoxicity of ADM and VCR by 88 and 350 times, respectively. Administering docetaxel at its maximal tolerated dose (MTD) demonstrated noticeable antitumor effects on HCT-15 tumor xenografts, known for their intrinsic resistance, with MS-209 further enhancing docetaxel's antitumor efficacy. In the case of MCF-7/ADM tumor xenografts, which express higher levels of P-gp, docetaxel alone at the MTD failed to exhibit antitumor effects. However, when combined with MS-209, the MTD of docetaxel significantly inhibited the growth of MCF-7/ADM tumors[1]. Intravenous injection of SBC-3 or SBC-3/ADM cells into severe combined immunodeficiency (SCID) mice, depleted of natural killer (NK) cells, resulted in metastatic colonies forming in the liver, kidneys, and lymph nodes, with SBC-3/ADM cells leading to quicker metastasis than SBC-3 cells. While VP-16 and ADM treatments reduced metastasis from SBC-3 cells, they did not affect metastasis from SBC-3/ADM cells. Although MS-209 alone did not impact metastasis from either cell type, its combination with VP-16 or ADM significantly reduced metastatic spread of SBC-3/ADM cells to various organs[2]. Oral administration of MS-209 along with ADM substantially increased the antitumor effects of ADM on Colon 26 and 4-1St tumors implanted subcutaneously in mice, surpassing the antitumor efficacy of ADM alone at its MTD[3].
Dofequidar 细胞实验
Cell Line
Concentration
Treated Time
Description
References
KB/BCRP cells
10 μM
3 days
Evaluate the effect of Dofequidar on KB/BCRP cell sensitivity to MXR, results showed Dofequidar reversed chemoresistance
Cancer Sci. 2009 Nov;100(11):2060-8.
K562/BCRP cells
1 µM, 10 µM
30 min
Evaluate the effect of Dofequidar on MXR accumulation, results showed Dofequidar inhibited MXR export
Cancer Sci. 2009 Nov;100(11):2060-8.
KM12 cells
1 µM, 10 µM
60 min
Dofequidar reduced the number of SP cells in KM12 cells in a dose-dependent manner
Cancer Sci. 2009 Nov;100(11):2060-8.
BSY-1 cells
1 µM, 10 µM
Dofequidar reduced the number of SP cells in BSY-1 cells in a dose-dependent manner
Cancer Sci. 2009 Nov;100(11):2060-8.
HeLa SP and NSP cells
3 µM
60 min
Dofequidar reversed the resistance of HeLa SP cells to MXR and topotecan, making their sensitivity similar to that of NSP cells
Cancer Sci. 2009 Nov;100(11):2060-8.
K562/BCRP cells
3 μM
30 min
Evaluate the inhibitory effect of Dofequidar on ABCG2/BCRP function; Dofequidar increased intracellular MXR concentration
Cancer Sci. 2009 Nov;100(11):2060-8.
Dofequidar 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
BALB/c nude mice
HeLa SP cell xenograft model
Oral
200 mg/kg
Administered on days 0, 4, and 8
Evaluate the therapeutic effect of Dofequidar combined with CPT-11 on SP cell xenografts, results showed combination therapy significantly inhibited tumor growth
Cancer Sci. 2009 Nov;100(11):2060-8.
BALB/c nude mice
HeLa SP cell xenograft model
Oral (dofequidar), Intravenous (CPT-11)
200 mg/kg
Days 0, 4, and 8
Evaluate the efficacy of Dofequidar combined with CPT-11 on SP cell xenografts; Combination therapy significantly inhibited tumor growth
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