Table 3.
The effect of SKLB610 on ABCG2-mediated multidrug resistance.
| Mean IC50a ± SD and (FRb) | |||
|---|---|---|---|
| Treatment | Concentration | S1 (parental) [nM] | S1-MI-80 (resistant) |
| (μM) | [μM] | ||
| Mitoxantrone | – | 8.20 ± 1.15 (1.0) | 63.99 ± 4.49 (1.0) |
| + SKLB610 | 0.5 | 6.41 ± 1.02 (1.3) | 25.27 ± 2.83*** (2.5) |
| + SKLB610 | 1.0 | 7.26 ± 1.31 (1.1) | 14.05 ± 1.94*** (4.6) |
| + SKLB610 | 2.0 | 7.22 ± 1.51 (1.1) | 8.06 ± 1.06*** (7.9) |
| + SKLB610 | 3.0 | 5.52 ± 1.91 (15) | 4.22 ± 0.58*** (15.2) |
| + Ko143 | 1.0 | 6.86 ± 1.04 (1.2) | 0.73 ± 0.07*** (57.4) |
| [nM] | [μM] | ||
| SN-38 | – | 5.69 ± 0.82 (1.0) | 7.59 ± 2.16 (1.0) |
| + SKLB610 | 0.5 | 6.61 ± 0.92 (0.9) | 4.72 ± 1.69 (1.6) |
| + SKLB610 | 1.0 | 6.62 ± 0.86 (0.9) | 3.17 ± 1.23* (2.4) |
| + SKLB610 | 2.0 | 6.52 ± 0.90 (0.9) | 1.88 ± 0.49* (4.0) |
| + SKLB610 | 3.0 | 6.63 ± 1.00 (0.9) | 1.41 ± 0.39** (5.4) |
| + Ko143 | 1.0 | 6.78 ± 0.96 (0.8) | 110.32 ± 32.73 [nM]*** (69) |
| [nM] | [μM] | ||
| Topotecan | – | 47.97 ± 3.39 (1.0) | 15.55 ± 2.67 (1.0) |
| + SKLB610 | 0.5 | 49.86 ± 5.31 (1.0) | 4.76 ± 1.01** (3.3) |
| + SKLB610 | 1.0 | 48.74 ± 5.25 (1.0) | 3.98 ± 0.86** (3.9) |
| + SKLB610 | 2.0 | 44.91 ± 4.74 (1.1) | 3.09 ± 0.72** (5.0) |
| + SKLB610 | 3.0 | 43.41 ± 4.33 (1.1) | 1.97 ± 0.43*** (7.9) |
| + Ko143 | 1.0 | 44.36 ± 5.08 (1.1) | 0.33 ± 0.07*** (47.1) |
| Treatment | Concentration | H460 (parental) [nM] | H460-MX20 |
| μM) | (resistant) [nM] | ||
| Mitoxantrone | – | 35.04 ± 5.26 (1.0) | 841.13 ± 99.22 (1.0) |
| + SKLB610 | 0.5 | 24.57 ± 3.96 (1.4) | 337.64 ± 65.21** (2.5) |
| + SKLB610 | 1.0 | 20.13 ± 3.67* (1.7) | 228.04 ± 51.99*** (3.7) |
| + SKLB610 | 2.0 | 17.96 ± 3.15** (2.0) | 186.38 ± 44.86*** (4.5) |
| + SKLB610 | 3.0 | 17.87 ± 3.31** (2.0) | 175.70 ± 48.63*** (4.8) |
| + Ko143 | 1.0 | 17.83 ± 3.31** (2.0) | 86.46 ± 25.36*** (9.7) |
| [nM] | [μM] | ||
| SN-38 | – | 16.62 ± 1.98 (1.0) | 417.04 ± 77.66 (1.0) |
| + SKLB610 | 0.5 | 12.46 ± 1.76 (1.3) | 214.29 ± 46.00* (1.9) |
| + SKLB610 | 1.0 | 10.06 ± 1.63* (1.7) | 139.10 ± 31.03** (3.0) |
| + SKLB610 | 2.0 | 7.69 ± 1.24** (2.2) | 103.37 ± 25.14** (4.0) |
| + SKLB610 | 3.0 | 7.56 ± 1.30** (2.2) | 86.54 ± 22.74** (4.8) |
| + Ko143 | 1.0 | 4.90 ± 1.09*** (3.4) | 9.56 ± 2.62*** (43.6) |
| [nM] | [μM] | ||
| Topotecan | – | 139.14 ± 18.39 (1.0) | 1329.22 ± 308.64 (1.0) |
| + SKLB610 | 0.5 | 93.70 ± 13.58* (1.5) | 666.77 ± 149.84* (2.0) |
| + SKLB610 | 1.0 | 80.22 ± 11.64** (1.7) | 591.98 ± 126.24* (2.2) |
| + SKLB610 | 2.0 | 66.32 ± 10.30** (2.1) | 437.45 ± 96.69** (3.0) |
| + SKLB610 | 3.0 | 56.40 ± 9.16** (2.5) | 326.33 ± 75.55** (4.1) |
| + Ko143 | 1.0 | 48.96 ± 8.50** (2.8) | 85.75 ± 20.07** (15.5) |
| Treatment | Concentration | pcDNA3.1-HEK293 | R482-HEK293 |
| (μM) | (parental) [nM] | (resistant) [nM] | |
| Mitoxantrone | – | 4.76 ± 1.15 (1.0) | |
| + SKLB610 | 0.5 | 4.51 ± 0.83 (1.1) | 125.97 ± 17.05 (1.0) 63.54 ± 7.62** (2.0) |
| + SKLB610 | 1.0 | 4.47 ± 0.92 (1.1) | 55.34 ± 5.17** (2.3) |
| + SKLB610 | 2.0 | 4.48 ± 0.99 (1.1) | 38.78 ± 5.29** (3.2) |
| + SKLB610 | 3.0 | 4.38 ± 0.95 (1.1) | 31.27 ± 4.65*** (4.0) |
| + Ko143 | 1.0 | 4.29 ± 0.84 (1.1) | 12.20 ± 1.02*** (10.3) |
| SN-38 | – | [nM] 4.26 ± 0.97 (1.0) |
[nM] 335.81 ± 36.28 (1.0) |
| + SKLB610 | 0.5 | 4.27 ± 1.00 (1.0) | 131.70 ± 18.69*** (2.5) |
| + SKLB610 | 1.0 | 4.18 ± 1.03 (1.0) | 93.22 ± 17.39*** (3.6) |
| + SKLB610 | 2.0 | 3.97 ± 0.90 (1.1) | 49.99 ± 11.55*** (6.7) |
| + SKLB610 | 3.0 | 3.61 ± 0.75 (1.2) | 38.76 ± 7.92*** (8.7) |
| + Ko143 | 1.0 | 3.75 ± 0.87 (1.1) | 12.22 ± 2.43*** (27.4) |
| Topotecan | – | [nM] 37.24 ± 9.83 (1.0) |
[nM] 731.78 ± 89.04 (1.0) |
| + SKLB610 | 0.5 | 36.16 ± 9.12 (1.0) | 423.60 ± 53.13** (1.7) |
| + SKLB610 | 1.0 | 32.29 ± 7.10 (1.2) | 301.48 ± 44.27** (2.4) |
| + SKLB610 | 2.0 | 31.15 ± 7.84 (1.2) | 203.06 ± 29.44*** (3.6) |
| + SKLB610 | 3.0 | 28.80 ± 6.25 (1.3) | 170.08 ± 30.54*** (4.3) |
| + Ko143 | 1.0 | 34.71 ± 8.07 (1.1) | 138.25 ± 25.38*** (5.3) |
Abbreviations: FR, fold-reversal.
*
p < 0.05
**
p < 0.01
***
p < 0.001.
a
IC50 values calculation (see legend to Table 1).
b
FR values were calculated by dividing the IC50 value of a known ABCG2 substrate drug by the IC50 value of the same substrate drug in the presence of SKLB610 or Ko143.