Table 2.
The effect of SKLB610 on ABCB1-mediated multidrug resistance.
| Mean IC50a ± SD and (FRb) | |||
| Treatment | Concentration (μM) | OVCAR-8 (parental) [nM] | NCI-ADR-RES (resistant) [μM] |
| Colchicine | – | 23.96 ± 6.25 (1.0) | 2.75 ± 0.52 (1.0) |
| + SKLB610 | 0.5 | 25.78 ± 7.41 (0.9) | 3.07 ± 0.55 (0.9) |
| + SKLB610 | 1.0 | 26.72 ± 8.02 (0.9) | 3.58 ± 0.66 (0.8) |
| + SKLB610 | 2.0 | 26.08 ± 7.30 (0.9) | 2.74 ± 0.55 (1.0) |
| + SKLB610 | 3.0 | 25.91 ± 7.31 (0.9) | 2.70 ± 0.52 (1.0) |
| + Tariquidar | 1.0 | 24.44 ± 6.74 (1.0) | 46.79 ± 15.01 [nM]*** (59) |
| [nM] | [μM] | ||
| Vincristine | – | 15.47 ± 1.80 (1.0) | 6.09 ± 1.32 (1.0) |
| + SKLB610 | 0.5 | 16.83 ± 2.42 (0.9) | 6.06 ± 1.47 (1.0) |
| + SKLB610 | 1.0 | 16.37 ± 2.45 (0.9) | 5.33 ± 1.08 (1.1) |
| + SKLB610 | 2.0 | 15.35 ± 1.82 (1.0) | 4.12 ± 0.88 (1.5) |
| + SKLB610 | 3.0 | 16.05 ± 2.66 (1.0) | 3.13 ± 0.64** (1.9) |
| + Tariquidar | 1.0 | 13.34 ± 1.56 (1.2) | 29.96 ± 5.25 [nM]** (203) |
| [nM] | [μM] | ||
| Doxorubicin | – | 296.98 ± 35.69 (1.0) | 7.17 ± 0.77 (1.0) |
| + SKLB610 | 0.5 | 276.25 ± 22.13 (1.1) | 8.32 ± 0.80 (0.9) |
| + SKLB610 | 1.0 | 267.15 ± 30.99 (1.1) | 8.81 ± 0.93 (0.8) |
| + SKLB610 | 2.0 | 253.97 ± 28.85 (1.2) | 7.12 ± 0.62 (1.0) |
| + SKLB610 | 3.0 | 227.27 ± 28.82 (1.3) | 6.25 ± 0.62 (1.1) |
| + Tariquidar | 1.0 | 261.99 ± 33.88 (1.1) | 0.33 ± 0.05*** (21.7) |
| Treatment | Concentration (μM) | KB-3–1 (parental) [nM] | KB-V1 (resistant) [μM] |
| Colchicine | – | 11.35 ± 4.35 (1.0) | 1.29 ± 0.16 (1.0) |
| + SKLB610 | 0.5 | 11.72 ± 4.58 (1.0) | 1.59 ± 0.18 (0.8) |
| + SKLB610 | 1.0 | 11.78 ± 4.68 (1.0) | 1.71 ± 0.23 (0.8) |
| + SKLB610 | 2.0 | 12.00 ± 4.78 (0.9) | 1.59 ± 0.25 (0.8) |
| + SKLB610 | 3.0 | 11.82 ± 4.75 (1.0) | 1.34 ± 0.23 (1.0) |
| + Tariquidar | 1.0 | 11.73 ± 4.62 (1.0) | 14.18 ± 5.29 [nM]*** (91) |
| [nM] | [nM] | ||
| Vincristine | – | 1.46 ± 0.41 (1.0) | 1609.50 ± 381.83 (1.0) |
| + SKLB610 | 0.5 | 1.75 ± 0.54 (0.8) | 1385.80 ± 308.97 (1.2) |
| + SKLB610 | 1.0 | 1.90 ± 0.62 (0.8) | 1289.69 ± 299.71 (1.2) |
| + SKLB610 | 2.0 | 1.82 ± 0.58 (0.8) | 1005.78 ± 230.61 (1.6) |
| + SKLB610 | 3.0 | 1.96 ± 0.66 (0.7) | 912.63 ± 214.78 (1.8) |
| + Tariquidar | 1.0 | 1.49 ± 0.41 (1.0) | 2.79 ± 0.51** (577) |
| [nM] | [μM] | ||
| Doxorubicin | – | 47.03 ± 8.60 (1.0) | 2.10 ± 0.22 (1.0) |
| + SKLB610 | 0.5 | 42.56 ± 6.70 (1.1) | 2.27 ± 0.22 (0.9) |
| + SKLB610 | 1.0 | 40.90 ± 7.40 (1.1) | 2.18 ± 0.22 (1.0) |
| + SKLB610 | 2.0 | 41.54 ± 7.72 (1.1) | 2.34 ± 0.28 (0.9) |
| + SKLB610 | 3.0 | 42.95 ± 7.76 (1.1) | 1.69 ± 0.21 (1.2) |
| + Tariquidar | 1.0 | 47.09 ± 9.26 (1.0) | 0.15 ± 0.02*** (14.0) |
| Treatment | Concentration (μM) | pcDNA3.1-HEK293 (parental) [nM] | MDR19-HEK293 (resistant) [nM] |
| Colchicine | – | 14.57 ± 4.88 (1.0) | 147.25 ± 29.93 (1.0) |
| + SKLB610 | 0.5 | 14.75 ± 5.02 (1.0) | 181.71 ± 38.28 (0.8) |
| + SKLB610 | 1.0 | 13.77 ± 4.57 (1.1) | 169.78 ± 46.56 (0.9) |
| + SKLB610 | 2.0 | 13.96 ± 4.54 (1.0) | 198.09 ± 49.60 (0.7) |
| + SKLB610 | 3.0 | 13.69 ± 4.56 (1.1) | 175.21 ± 49.45 (0.8) |
| + Tariquidar | 1.0 | 15.00 ± 5.05 (1.0) | 11.53 ± 4.10** (12.8) |
| [nM] | [nM] | ||
| Vincristine | – | 3.76 ± 0.60 (1.0) | 547.08 ± 110.31 (1.0) |
| + SKLB610 | 0.5 | 3.25 ± 0.44 (1.2) | 655.39 ± 104.48 (0.8) |
| + SKLB610 | 1.0 | 3.26 ± 0.46 (1.2) | 572.03 ± 138.76 (1.0) |
| + SKLB610 | 2.0 | 3.36 ± 0.56 (1.1) | 523.91 ± 111.69 (1.0) |
| + SKLB610 | 3.0 | 3.43 ± 0.62 (1.1) | 418.40 ± 65.50 (1.3) |
| + Tariquidar | 1.0 | 2.10 ± 0.32* (1.8) | 1.75 ± 0.37** (312.6) |
| [nM] | [nM] | ||
| Doxorubicin | – | 20.71 ± 3.84 (1.0) | 413.62 ± 56.02 (1.0) |
| + SKLB610 | 0.5 | 24.43 ± 5.45 (0.8) | 462.24 ± 43.34 (0.9) |
| + SKLB610 | 1.0 | 27.63 ± 6.51 (0.7) | 496.15 ± 76.15 (0.8) |
| + SKLB610 | 2.0 | 24.55 ± 4.28 (0.8) | 501.70 ± 76.17 (0.8) |
| + SKLB610 | 3.0 | 23.72 ± 4.25 (0.9) | 461.56 ± 64.79 (0.9) |
| + Tariquidar | 1.0 | 21.05 ± 3.76 (1.0) | 63.71 ± 6.71*** (6.5) |
Abbreviations: FR, fold-reversal.
**
p < 0.01
***
p < 0.001.
a
IC50 values were calculated as described in the legend to Table 1.
b
FR values were calculated by dividing the IC50 value of a known ABCB1 substrate drug by the IC50 value of the same substrate drug in the presence of SKLB610 or tariquidar.