Table 3.
Effects of tivozanib on drug resistance in ABCG2-overexpressing cell lines.
| IC50 ± SD†; nM (resistance fold) | ||||
|---|---|---|---|---|
| Mitoxantrone | 35.7 ± 8.6 (1.0)‡ | 166.7 ± 14.1 (4.7) | 179.2 ± 15.4 (5.0) | 189.9 ± 11.1 (5.3) |
| Mitoxantrone + tivozanib 2.5 μM | 31.1 ± 9.8 (0.9) | 99.0 ± 5.6 (2.8)* | 38.0 ± 9.3 (1.1)* | 74.9 ± 14.5 (2.1)* |
| Mitoxantrone + tivozanib 5 μM | 25.6 ± 5.0 (0.7) | 77.4 ± 6.2 (2.2)* | 26.9 ± 2.3 (0.8)* | 24.4 ± 4.0 (0.7)* |
| Mitoxantrone + FTC 2.5 μM | 37.5 ± 6.7 (1.0) | 28.7 ± 2.6 (0.8)* | 29.9 ± 2.5 (0.7)* | 26.9 ± 4.6 (0.8)* |
| SN-38 | 2.1 ± 1.3 (1.0)‡ | 71.6 ± 9.9 (34.1) | 152.1 ± 11.9 (72.4) | 162.1 ± 18.4 (81.0) |
| SN-38 + tivozanib 2.5 μM | 2.3 ± 1.4 (1.0) | 20.7 ± 5.4 (9.9)* | 22.3 ± 5.7 (10.6)* | 62.1 ± 8.9 (29.6)* |
| SN-38 + tivozanib 5 μM | 2.1 ± 0.8 (1.0) | 13.3 ± 3.2 (6.3)* | 5.4 ± 1.1 (2.6)* | 5.6 ± 1.4 (2.7)* |
| SN-38 + FTC 2.5 μM | 2.0 ± 1.2 (1.0) | 2.4 ± 1.0 (1.1)* | 1.7 ± 1.3 (0.8)* | 2.4 ± 1.2 (1.1)* |
| Doxorubicin | 16.6 ± 5.2 (1.0)‡ | 62.1 ± 2.5 (3.8) | 167.5 ± 14.3 (10.1) | 133.2 ± 30.3 (8.0) |
| Doxorubicin + tivozanib 2.5 μM | 18.4 ± 2.2 (1.1) | 42.2 ± 7.2 (2.5)* | 20.8 ± 4.5 (1.3)* | 29.0 ± 5.7 (1.8)* |
| Doxorubicin + tivozanib 5 μM | 19.9 ± 5.5 (1.2) | 30.0 ± 5.0 (1.8)* | 17.1 ± 3.3 (1.1)* | 21.0 ± 6.4 (1.3)* |
| Doxorubicin + FTC 2.5 μM | 17.0 ± 7.0 (1.0) | 21.7 ± 11.1 (1.3)* | 18.0 ± 1.9 (1.0)* | 17.0 ± 9.5 (1.0)* |
| Cisplatin | 2296.5 ± 253.4 (1.0) | 1588.7 ± 247.5 (0.7) | 1764.0 ± 208.6 (0.7) | 2128.0 ± 224.1 (0.9) |
| Cisplatin + tivozanib 2.5 μM | 2611.0 ± 243.6 (1.1) | 1851.6 ± 385.1 (0.8) | 1863.4 ± 177.7 (0.8) | 2610.8 ± 343.7 (1.1) |
| Cisplatin + tivozanib 5 μM | 2468.9 ± 191.7 (1.1) | 1626.0 ± 242.9 (0.7) | 2106.4 ± 166.1 (1.3) | 2533.0 ± 203.5 (1.1) |
| Cisplatin + FTC 2.5 μM | 2531.2 ± 343.9 (1.1) | 1998.3 ± 163.9 (0.9) | 2543.5 ± 159.1 (1.1) | 2525.6 ± 253.0 (1.1) |
†
Values represent the mean ± SD of at least three independent experiments, each performed in triplicate.
‡
Resistance fold was calculated by dividing the IC50 values of mitoxantrone, SN-38, doxorubicin or cisplatin of ABCG2-overexpressing cell lines in the presence or absence of reversal agents by the IC50 values of substrates of the HEK293/pcDNA3.1 cell line.
*
p < 0.05.
FTC: Fumitremorgin C; SD: Standard deviation.