Table 1.
Reversal effect of SIS3 on drug resistance mediated by ABCB1 and ABCG2.
| Treatment | Concentration (μM) |
Mean IC50† ± SD and (FR‡) |
|
|---|---|---|---|
| KB-3–1 [nM] | KB-V-1 [nM] | ||
| Colchicine | - | 5.09 ± 1.88 (1.0) | 808.13 ± 41.30 (1.0) |
| + SIS3 | 0.1 | 5.11 ± 1.85 (1.0) | 523.77 ± 40.35** (1.5) |
| + SIS3 | 0.2 | 5.16 ± 1.92 (1.0) | 367.13 ± 43.11*** (2.2) |
| + SIS3 | 0.5 | 5.31 ± 2.07 (1.0) | 136.60 ± 15.69*** (5.9) |
| + SIS3 | 0.7 | 5.10 ± 2.02 (1.0) | 45.51 ± 6.19*** (17.8) |
| + Verapamil | 5.0 | 2.86 ± 1.17 (1.8) | 71.44 ± 7.96*** (11.3) |
| Paclitaxel | - | 1.99 ± 0.53 (1.0) | 2273.60 ± 218.05 (1.0) |
| + SIS3 | 0.1 | 1.90 ± 0.46 (1.0) | 635.44 ± 37.69*** (3.6) |
| + SIS3 | 0.2 | 1.89 ± 0.48 (1.1) | 323.36 ± 42.78*** (7.0) |
| + SIS3 | 0.5 | 2.15 ± 0.50 (1.0) | 92.37 ± 12.79*** (24.6) |
| + SIS3 | 0.7 | 2.08 ± 0.48 (1.0) | 48.19 ± 9.47*** (47.2) |
| + Verapamil | 5.0 | 2.56 ± 0.73 (0.8) | 89.06 ± 12.26*** (25.5) |
|
OVCAR-8 [nM] |
NCI-ADR-RES [nM] |
||
| Colchicine | - | 18.62 ± 3.45 (1.0) | 1730.54 ± 317.81 (1.0) |
| + SIS3 | 0.1 | 19.29 ± 3.28 (1.0) | 1019.80 ± 216.52* (1.7) |
| + SIS3 | 0.2 | 19.74 ± 3.14 (1.0) | 681.85 ± 148.18** (2.5) |
| + SIS3 | 0.5 | 17.65 ± 3.09 (1.1) | 277.86 ± 56.22** (6.2) |
| + SIS3 | 0.7 | 16.56 ± 3.09 (1.1) | 142.47 ± 16.16** (12.1) |
| + Verapamil | 5.0 | 11.92 ± 2.56 (1.6) | 518.26 ± 96.19** (3.3) |
| Paclitaxel | - | 79.60 ± 23.93 (1.0) | 6385.00 ± 959.34 (1.0) |
| + SIS3 | 0.1 | 73.43 ± 25.60 (1.1) | 3147.20 ± 267.22** (2.0) |
| + SIS3 | 0.2 | 62.07 ± 20.33 (1.3) | 2102.74 ± 267.40** (3.0) |
| + SIS3 | 0.5 | 58.53 ± 16.68 (1.4) | 466.38 ± 46.62*** (13.7) |
| + SIS3 | 0.7 | 53.56 ± 12.95 (1.5) | 328.34 ± 51.72*** (19.4) |
| + Verapamil | 5.0 | 46.90 ± 15.15 (1.7) | 184.35 ± 22.73*** (34.6) |
|
pcDNA-HEK293 [nM] |
MDR19-HEKS293 [nM] |
||
| Colchicine | - | 8.20 ± 2.42 (1.0) | 183.66 ± 35.56 (1.0) |
| + SIS3 | 0.1 | 8.14 ± 2.26 (1.0) | 111.59 ± 23.66* (1.6) |
| + SIS3 | 0.2 | 8.09 ± 2.33 (1.0) | 66.03 ± 15.18** (2.8) |
| + SIS3 | 0.5 | 7.18 ± 1.80 (1.1) | 45.05 ± 8.65** (4.1) |
| + SIS3 | 0.7 | 7.98 ± 2.38 (1.0) | 26.76 ± 5.17** (6.9) |
| + Verapamil | 5.0 | 8.14 ± 2.44 (1.0) | 40.40 ± 9.30** (4.5) |
| Paclitaxel | - | 1.53 ± 0.26 (1.0) | 835.30 ± 128.85 (1.0) |
| + SIS3 | 0.1 | 1.24 ± 0.18 (1.2) | 479.04 ± 36.49** (1.7) |
| + SIS3 | 0.2 | 1.25 ± 0.19 (1.2) | 297.83 ± 48.57** (2.8) |
| + SIS3 | 0.5 | 1.27 ± 0.20 (1.2) | 73.94 ± 9.18*** (11.3) |
| + SIS3 | 0.7 | 1.20 ± 0.17 (1.3) | 60.43 ± 5.05*** (13.8) |
| + Verapamil | 5.0 | 0.90 ± 0.16* (1.7) | 6.14 ± 1.23*** (136.0) |
|
H460 [nM] |
H460-MX20 [nM] |
||
| SN-38 | - | 4.49 ± 1.02 (1.0) | 138.71 ± 32.27 (1.0) |
| + SIS3 | 0.1 | 4.15 ± 1.07 (1.1) | 36.67 ± 8.01** (3.8) |
| + SIS3 | 0.2 | 5.14 ± 0.90 (0.9) | 20.52 ± 5.35** (6.8) |
| + SIS3 | 0.5 | 3.76 ± 0.67 (1.2) | 11.65 ± 3.48** (11.9) |
| + SIS3 | 0.7 | 3.34 ± 0.58 (1.3) | 4.84 ± 1.28** (28.7) |
| + Ko143 | 1 | 4.10 ± 0.75 (1.1) | 4.45 ± 1.06** (31.2) |
| Mitoxantrone | - | 13.73 ± 1.19 (1.0) | 488.15 ± 81.40 (1.0) |
| + SIS3 | 0.1 | 20.54 ± 5.79 (0.7) | 342.70 ± 85.71 (1.4) |
| + SIS3 | 0.2 | 15.61 ± 4.68 (0.9) | 227.99 ± 58.92* (2.1) |
| + SIS3 | 0.5 | 16.70 ± 4.84 (0.8) | 77.22 ± 18.04** (6.3) |
| + SIS3 | 0.7 | 17.00 ± 5.41 (0.8) | 55.71 ± 21.69** (8.8) |
| + Ko143 | 1 | 15.93 ± 5.27 (0.9) | 70.14 ± 19.37** (7.0) |
|
S1 [nM] |
S1-M1–80 [μM] |
||
| SN-38 | - | 2.32 ± 0.28 (1.0) | 3.83 ± 0.65 (1.0) |
| + SIS3 | 0.1 | 2.58 ± 0.30 (0.9) | 2.33 ± 0.30* (1.6) |
| + SIS3 | 0.2 | 2.76 ± 0.32 (0.8) | 1.05 ± 0.12** (3.6) |
| + SIS3 | 0.5 | 2.36 ± 0.26 (1.0) | 0.32 ± 0.03*** (12.0) |
| + SIS3 | 0.7 | 2.31 ± 0.29 (1.0) | 0.23 ± 0.02*** (16.7) |
| + Ko143 | 1 | 2.22 ± 0.28 (1.0) | 0.05 ± 0.01*** (76.6) |
| Mitoxantrone | - | 11.48 ± 2.70 (1.0) | 24.09 ± 5.80 (1.0) |
| + SIS3 | 0.1 | 9.60 ± 2.21 (1.2) | 15.17 ± 2.82 (1.6) |
| + SIS3 | 0.2 | 9.61 ± 2.49 (1.2) | 6.95 ± 1.22** (3.5) |
| + SIS3 | 0.5 | 8.20 ± 2.01 (1.4) | 2.79 ± 0.48** (8.6) |
| + SIS3 | 0.7 | 8.03 ± 2.09 (1.4) | 1.88 ± 0.33** (12.8) |
| + Ko143 | 1 | 10.42 ± 2.56 (1.1) | 0.87 ± 0.13** (27.7) |
|
pcDNA-HEK293 [nM] |
R482-HEKS293 [nM] |
||
| SN-38 | - | 6.53 ± 0.98 (1.0) | 535.00 ± 63.14 (1.0) |
| + SIS3 | 0.1 | 5.88 ± 0.95 (1.1) | 114.69 ± 21.08*** (4.7) |
| + SIS3 | 0.2 | 5.51 ± 0.84 (1.2) | 50.09 ± 11.35*** (10.7) |
| + SIS3 | 0.5 | 5.38 ± 0.83 (1.2) | 17.61 ± 3.69*** (30.4) |
| + SIS3 | 0.7 | 5.17 ± 0.83 (1.3) | 10.96 ± 2.16*** (48.8) |
| + Ko143 | 1 | 5.50 ± 0.87 (1.2) | 7.18 ± 1.73*** (74.5) |
| Mitoxantrone | - | 0.74 ± 0.11 (1.0) | 122.15 ± 16.21 (1.0) |
| + SIS3 | 0.1 | 1.00 ± 0.13 (0.7) | 29.48 ± 2.72*** (4.1) |
| + SIS3 | 0.2 | 0.90 ± 0.13 (0.8) | 15.94 ± 2.14*** (7.7) |
| + SIS3 | 0.5 | 0.62 ± 0.09 (1.2) | 10.95 ± 1.65*** (11.2) |
| + SIS3 | 0.7 | 0.65 ± 0.07 (1.1) | 8.74 ± 1.42*** (14.0) |
| + Ko143 | 1 | 0.81 ± 0.12 (0.9) | 7.14 ± 1.10*** (17.1) |
Abbreviation: FR, fold-reversal.
† IC50 values are mean ± SD calculated from dose-response curves obtained from three independent experiments using cytotoxicity assay as described in Materials and methods.
‡ FR values were calculated by dividing IC50 values of cells treated with a particular anticancer drug in the absence of SIS3 or a reference inhibitor by IC50 values of cells treated with the same anticancer drug in the presence of SIS3 or a reference inhibitor.
*
P < 0.05;
**
P < 0.01;
***
P < 0.001