Table 2.
Chemosensitizing effect of TP-3654 on ABCB1-mediated multidrug resistance in ABCB1-overexpressing human cell lines.
| Treatment | Concentration (nM) |
Mean IC50 † ± SD and (FR ‡) | |
|---|---|---|---|
| OVCAR-8 (Parental) (nM) |
NCI-ADR-RES (Resistant) (μM) |
||
| Paclitaxel | - | 3.82 ± 0.62 (1.0) | 9.37 ± 1.47 (1.0) |
| +TP-3654 | 100 | 4.47 ± 0.65 (0.9) | 10.12 ± 1.20 (0.9) |
| +TP-3654 | 200 | 4.18 ± 0.61 (0.9) | 9.34 ± 1.24 (1.0) |
| +TP-3654 | 300 | 4.46 ± 0.66 (0.9) | 9.17 ± 1.15 (1.0) |
| +TP-3654 | 500 | 4.12 ± 0.47 (0.9) | 7.36 ± 0.84 (1.3) |
| +tariquidar | 1000 | 3.56 ± 0.59 (1.1) | 12.74 ± 1.32 (nM) *** (735) |
| (nM) | (μM) | ||
| Doxorubicin | - | 248.55 ± 52.08 (1.0) | 6.30 ± 0.67 (1.0) |
| +TP-3654 | 100 | 242.57 ± 41.55 (1.0) | 7.26 ± 1.11 (0.9) |
| +TP-3654 | 200 | 226.91 ± 51.04 (1.1) | 8.35 ± 1.15 (0.8) |
| +TP-3654 | 300 | 190.94 ± 35.52 (1.3) | 7.63 ± 1.12 (0.8) |
| +TP-3654 | 500 | 201.04 ± 48.62 (1.2) | 6.86 ± 0.87 (0.9) |
| +tariquidar | 1000 | 216.42 ± 50.37 (1.1) | 0.36 ± 0.07 *** (17.5) |
| (nM) | (nM) | ||
| Colchicine | - | 33.25 ± 11.26 (1.0) | 1827.27 ± 229.42 (1.0) |
| +TP-3654 | 100 | 34.30 ± 13.08 (1.0) | 2300.41 ± 525.88 (0.8) |
| +TP-3654 | 200 | 35.92 ± 13.87 (0.9) | 2185.00 ± 387.82 (0.8) |
| +TP-3654 | 300 | 35.99 ± 12.62 (0.9) | 2135.46 ± 235.40 (0.9) |
| +TP-3654 | 500 | 32.94 ± 12.25 (1.0) | 2672.43 ± 581.86 (0.7) |
| +tariquidar | 1000 | 34.98 ± 12.35 (0.9) | 65.29 ± 23.07 *** (28.0) |
| Treatment |
Concentration
(nM) |
KB-3-1 (Parental)
(nM) |
KB-V-1 (Resistant)
(nM) |
| Paclitaxel | - | 2.31 ± 0.75 (1.0) | 2083.57 ± 250.53 (1.0) |
| +TP-3654 | 100 | 2.46 ± 0.64 (0.9) | 2269.00 ± 245.85 (0.9) |
| +TP-3654 | 200 | 2.26 ± 0.52 (1.0) | 2171.55 ± 290.13 (1.0) |
| +TP-3654 | 300 | 2.07 ± 0.48 (1.1) | 2263.61 ± 271.75 (0.9) |
| +TP-3654 | 500 | 2.15 ± 0.42 (1.1) | 1648.56 ± 187.39 (1.3) |
| +tariquidar | 1000 | 2.24 ± 0.59 (1.0) | 2.16 ± 0.59 *** (964.6) |
| (nM) | (μM) | ||
| Doxorubicin | - | 174.34 ± 41.49 (1.0) | 2.27 ± 0.21 (1.0) |
| +TP-3654 | 100 | 153.79 ± 43.44 (1.1) | 2.66 ± 0.21 (0.9) |
| +TP-3654 | 200 | 161.07 ± 44.68 (1.1) | 2.33 ± 0.20 (1.0) |
| +TP-3654 | 300 | 209.34 ± 59.06 (0.8) | 1.85 ± 0.19 (1.2) |
| +TP-3654 | 500 | 153.50 ± 43.54 (1.1) | 1.95 ± 0.18 (1.1) |
| +tariquidar | 1000 | 185.90 ± 73.46 (0.9) | 79.29 ± 23.05 (nM) *** (28.6) |
| (nM) | (nM) | ||
| Colchicine | - | 20.59 ± 8.45 (1.0) | 854.44 ± 71.42 (1.0) |
| +TP-3654 | 100 | 20.55 ± 8.10 (1.0) | 921.75 ± 113.96 (0.9) |
| +TP-3654 | 200 | 20.98 ± 7.97 (1.0) | 808.36 ± 79.91 (1.1) |
| +TP-3654 | 300 | 19.43 ± 7.17 (1.1) | 947.28 ± 98.51 (0.9) |
| +TP-3654 | 500 | 20.56 ± 7.12 (1.0) | 914.81 ± 109.63 (0.9) |
| +tariquidar | 1000 | 19.00 ± 7.23 (1.1) | 20.36 ± 6.30 *** (42.0) |
| Treatment |
Concentration
(nM) |
pcDNA3.1-HEK293 (Parental) (nM) |
MDR19-HEK293
(Resistant) (nM) |
| Paclitaxel | - | 3.47 ± 0.67 (1.0) | 737.62 ± 126.44 (1.0) |
| +TP-3654 | 100 | 4.11 ± 0.97 (0.8) | 743.54 ± 146.73 (1.0) |
| +TP-3654 | 200 | 4.02 ± 0.74 (0.9) | 581.71 ± 90.37 (1.3) |
| +TP-3654 | 300 | 4.14 ± 0.75 (0.8) | 738.96 ± 108.01 (1.0) |
| +TP-3654 | 500 | 3.68 ± 0.63 (0.9) | 642.38 ± 132.50 (1.1) |
| +tariquidar | 1000 | 2.74 ± 0.43 (1.3) | 2.05 ± 0.39 *** (359.8) |
| (nM) | (nM) | ||
| Doxorubicin | - | 25.55 ± 6.31 (1.0) | 297.78 ± 51.34 (1.0) |
| +TP-3654 | 100 | 28.60 ± 7.10 (0.9) | 294.19 ± 52.47 (1.0) |
| +TP-3654 | 200 | 28.77 ± 7.62 (0.9) | 237.93 ± 46.90 (1.3) |
| +TP-3654 | 300 | 27.38 ± 7.99 (0.9) | 273.57 ± 78.20 (1.1) |
| +TP-3654 | 500 | 28.61 ± 9.59 (0.9) | 272.00 ± 69.14 (1.1) |
| +tariquidar | 1000 | 22.26 ± 5.37 (1.1) | 16.59 ± 2.33 *** (18.0) |
| (nM) | (nM) | ||
| Colchicine | - | 13.02 ± 2.79 (1.0) | 100.07 ± 21.01 (1.0) |
| +TP-3654 | 100 | 15.98 ± 4.05 (0.8) | 107.28 ± 21.50 (0.9) |
| +TP-3654 | 200 | 14.95 ± 3.73 (0.9) | 78.54 ± 15.95 (1.3) |
| +TP-3654 | 300 | 14.11 ± 3.10 (0.9) | 98.65 ± 20.29 (1.0) |
| +TP-3654 | 500 | 14.91 ± 3.50 (0.9) | 89.50 ± 22.14 (1.1) |
| +tariquidar | 1000 | 14.12 ± 3.29 (0.9) | 8.46 ± 2.66 ** (11.8) |
Abbreviation: FR, fold-reversal. † IC50 values are mean ± SD calculated from dose–response curves obtained from at least three independent experiments using cytotoxicity assay as described in Section 4. ‡ FR values were calculated by dividing IC50 values of cells treated with a particular substrate drug by IC50 values of cells treated with the same substrate drug in the presence of TP-3654 or tariquidar. ** p < 0.01; *** p < 0.001.