Table 3.
Chemosensitizing effect of TP-3654 on ABCG2-mediated multidrug resistance in ABCG2-overexpressing human cell lines.
| Treatment | Concentration (nM) |
Mean IC50 † ± SD and (FR ‡) | |
|---|---|---|---|
| S1 (Parental) (nM) | S1-M1-80 (Resistant) (μM) | ||
| Topotecan | - | 12.82 ± 3.16 (1.0) | 10.81 ± 0.91 (1.0) |
| +TP-3654 | 100 | 14.43 ± 3.06 (0.9) | 5.09 ± 0.76 ** (2.1) |
| +TP-3654 | 200 | 13.66 ± 3.22 (0.9) | 2.90 ± 0.64 *** (3.7) |
| +TP-3654 | 300 | 15.93 ± 3.49 (0.8) | 2.94 ± 0.70 *** (3.7) |
| +TP-3654 | 500 | 12.94 ± 2.63 (1.0) | 2.75 ± 0.73 *** (3.9) |
| +Ko143 | 1000 | 13.23 ± 2.63 (1.0) | 1.13 ± 0.24 *** (9.6) |
| (nM) | (nM) | ||
| SN-38 | - | 3.22 ± 0.54 (1.0) | 1804.90 ± 112.67 (1.0) |
| +TP-3654 | 100 | 4.14 ± 0.74 (0.8) | 706.84 ± 106.11 *** (2.6) |
| +TP-3654 | 200 | 3.32 ± 0.54 (1.0) | 517.32 ± 100.26 *** (3.5) |
| +TP-3654 | 300 | 3.67 ± 0.64 (0.9) | 443.73 ± 101.80 *** (4.1) |
| +TP-3654 | 500 | 3.14 ± 0.62 (1.0) | 304.09 ± 81.75 *** (5.9) |
| +Ko143 | 1000 | 2.69 ± 0.47 (1.2) | 104.36 ± 22.88 *** (17.3) |
| (nM) | (μM) | ||
| Mitoxantrone | - | 5.65 ± 0.48 (1.0) | 35.04 ± 6.71 (1.0) |
| +TP-3654 | 100 | 5.10 ± 0.34 (1.1) | 10.50 ± 1.03 ** (3.3) |
| +TP-3654 | 200 | 5.94 ± 0.42 (1.0) | 5.42 ± 0.57 ** (6.5) |
| +TP-3654 | 300 | 5.92 ± 0.36 (1.0) | 2.53 ± 0.25 ** (13.8) |
| +TP-3654 | 500 | 6.22 ± 0.44 (0.9) | 1.30 ± 0.11 *** (27.0) |
| +Ko143 | 1000 | 5.34 ± 0.61 (1.1) | 0.36 ± 0.04 *** (58.4) |
| Treatment |
Concentration
(nM) |
H460 (Parental)
(nM) |
H460-MX20 (Resistant) (nM) |
| Topotecan | - | 60.21 ± 10.05 (1.0) | 737.60 ± 145.43 (1.0) |
| +TP-3654 | 100 | 26.93 ± 4.35 ** (2.2) | 161.36 ± 26.08 ** (4.6) |
| +TP-3654 | 200 | 20.54 ± 3.24** (2.9) | 76.96 ± 12.29 ** (9.6) |
| +TP-3654 | 300 | 21.23 ± 2.99 ** (2.8) | 51.10 ± 10.63 ** (14.4) |
| +TP-3654 | 500 | 16.81 ± 2.34 ** (3.6) | 37.09 ± 6.65 ** (19.9) |
| +Ko143 | 1000 | 21.53 ± 3.25 ** (2.8) | 25.10 ± 5.50 ** (29.4) |
| (nM) | (nM) | ||
| SN-38 | - | 6.10 ± 1.21 (1.0) | 246.21 ± 44.64 (1.0) |
| +TP-3654 | 100 | 4.29 ± 0.66 (1.4) | 27.87 ± 2.58 ** (8.8) |
| +TP-3654 | 200 | 3.61 ± 0.33 * (1.7) | 18.00 ± 2.98 *** (13.7) |
| +TP-3654 | 300 | 1.98 ± 0.22 ** (3.1) | 9.20 ± 1.33 *** (26.8) |
| +TP-3654 | 500 | 2.05 ± 0.19 ** (3.0) | 7.72 ± 1.92 *** (31.9) |
| +Ko143 | 1000 | 2.10 ± 0.27 ** (2.9) | 2.57 ± 0.66 *** (95.8) |
| (nM) | (nM) | ||
| Mitoxantrone | - | 15.42 ± 1.83 (1.0) | 996.71 ± 127.75 (1.0) |
| +TP-3654 | 100 | 8.83 ± 0.99 ** (1.7) | 841.73 ± 187.29 (1.2) |
| +TP-3654 | 200 | 10.45 ± 1.95 * (1.5) | 388.45 ± 40.35 ** (2.6) |
| +TP-3654 | 300 | 13.19 ± 2.74 (1.2) | 261.46 ± 55.67 *** (3.8) |
| +TP-3654 | 500 | 16.46 ± 2.58 (0.9) | 153.79 ± 28.65 *** (6.5) |
| +Ko143 | 1000 | 10.28 ± 1.78 * (1.5) | 208.89 ± 29.46 *** (4.8) |
| Treatment |
Concentration
(nM) |
pcDNA3.1-HEK293 (Parental) (nM) |
R482-HEK293
(Resistant) (nM) |
| Topotecan | - | 24.19 ± 4.95 (1.0) | 430.30 ± 67.85 (1.0) |
| +TP-3654 | 100 | 24.72 ± 5.60 (1.0) | 149.56 ± 31.21 ** (2.9) |
| +TP-3654 | 200 | 26.34 ± 6.76 (0.9) | 81.88 ± 14.13 *** (5.3) |
| +TP-3654 | 300 | 24.80 ± 5.40 (1.0) | 73.56 ± 11.35 *** (5.8) |
| +TP-3654 | 500 | 27.06 ± 6.68 (0.9) | 49.04 ± 8.91 *** (8.8) |
| +Ko143 | 1000 | 26.34 ± 5.49 (0.9) | 41.75 ± 8.49 *** (10.3) |
| (nM) | (nM) | ||
| SN-38 | - | 2.61 ± 0.80 (1.0) | 177.87 ± 31.96 (1.0) |
| +TP-3654 | 100 | 2.67 ± 0.48 (1.0) | 53.98 ± 17.04 ** (3.3) |
| +TP-3654 | 200 | 2.83 ± 0.55 (0.9) | 27.40 ± 7.04 ** (6.5) |
| +TP-3654 | 300 | 2.34 ± 0.50 (1.1) | 34.31 ± 5.22 ** (5.2) |
| +TP-3654 | 500 | 2.55 ± 0.55 (1.0) | 25.26 ± 4.19 ** (7.0) |
| +Ko143 | 1000 | 2.73 ± 0.76 (1.0) | 9.35 ± 1.76 *** (19.0) |
| (nM) | (nM) | ||
| Mitoxantrone | - | 4.28 ± 0.39 (1.0) | 114.49 ± 9.59 (1.0) |
| +TP-3654 | 100 | 3.88 ± 0.29 (1.1) | 45.56 ± 5.97 *** (2.5) |
| +TP-3654 | 200 | 4.02 ± 0.33 (1.1) | 28.76 ± 4.28 *** (4.0) |
| +TP-3654 | 300 | 3.98 ± 0.38 (1.1) | 29.92 ± 5.17 *** (3.8) |
| +TP-3654 | 500 | 4.20 ± 0.36 (1.0) | 19.06 ± 3.83 *** (6.0) |
| +Ko143 | 1000 | 4.15 ± 0.48 (1.0) | 12.88 ± 1.79 *** (8.9) |
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 Ko143. * p < 0.05; ** p < 0.01; *** p < 0.001.