Table 4.
Chemosensitizing effect of almonertinib on multidrug resistance mediated by ABCG2 in ABCG2-overexpressing human cell lines.
| Mean IC50† ± SD and (FR‡) | |||
|---|---|---|---|
| Treatment | Concentration (nM) |
H460 (parental) [nM] |
H460-MX20 (resistant) [nM] |
| Topotecan | - | 58.55 ± 7.77 (1.0) | 1648.90 ± 465.88 (1.0) |
| + almonertinib | 50 | 54.50 ± 6.71 (1.1) | 1551.00 ± 433.33 (1.1) |
| + almonertinib | 100 | 54.10 ± 6.30 (1.1) | 1800.21 ± 503.43 (0.9) |
| + almonertinib | 200 | 50.22 ± 6.38 (1.2) | 1613.53 ± 451.17 (1.0) |
| + almonertinib | 500 | 46.73 ± 6.29 (1.3) | 1219.52 ± 331.87 (1.4) |
| + Ko143 | 1000 | 27.85 ± 5.03** (2.1) | 121.54 ± 40.90** (13.6) |
| [nM] | [nM] | ||
| SN-38 | - | 16.30 ± 2.03 (1.0) | 524.35 ± 137.66 (1.0) |
| + almonertinib | 50 | 16.91 ± 2.14 (1.0) | 454.85 ± 105.21 (1.2) |
| + almonertinib | 100 | 17.23 ± 2.39 (0.9) | 454.36 ± 108.72 (1.2) |
| + almonertinib | 200 | 16.47 ± 2.07 (1.0) | 372.35 ± 85.17 (1.4) |
| + almonertinib | 500 | 15.17 ± 2.14 (1.1) | 319.94 ± 84.68 (1.6) |
| + Ko143 | 1000 | 4.85 ± 1.08*** (3.4) | 12.34 ± 4.68** (42.5) |
| [nM] | [nM] | ||
| Mitoxantrone | - | 38.83 ± 8.37 (1.0) | 851.68 ± 113.26 (1.0) |
| + almonertinib | 50 | 41.02 ± 7.87 (0.9) | 937.54 ± 90.37 (0.9) |
| + almonertinib | 100 | 37.80 ± 7.53 (1.0) | 890.69 ± 116.69 (1.0) |
| + almonertinib | 200 | 34.67 ± 6.04 (1.1) | 726.15 ± 127.91 (1.2) |
| + almonertinib | 500 | 28.28 ± 5.21 (1.4) | 815.60 ± 168.21 (1.0) |
| + Ko143 | 1000 | 27.69 ± 7.59 (1.4) | 109.17 ± 43.52*** (7.8) |
| Treatment | Concentration (nM) |
A549 (parental) [μM] |
A549-Bec150 (resistant) [μM] |
| Topotecan | - | 0.53 ± 0.12 (1.0) | 1.79 ± 0.26 (1.0) |
| + almonertinib | 50 | 0.69 ± 0.18 (0.8) | 1.80 ± 0.30 (1.0) |
| + almonertinib | 100 | 0.61 ± 0.16 (0.9) | 1.52 ± 0.25 (1.2) |
| + almonertinib | 200 | 0.58 ± 0.15 (0.9) | 1.34 ± 0.23 (1.3) |
| + almonertinib | 500 | 0.71 ± 0.21 (0.7) | 1.42 ± 0.23 (1.3) |
| + Ko143 | 1000 | 0.28 ± 0.08* (1.9) | 0.12 ± 0.02*** (14.9) |
| [nM] | [nM] | ||
| SN-38 | - | 22.51 ± 6.36 (1.0) | 200.14 ± 44.67 (1.0) |
| + almonertinib | 50 | 22.92 ± 6.03 (1.0) | 220.71 ± 48.70 (0.9) |
| + almonertinib | 100 | 22.26 ± 6.19 (1.0) | 213.95 ± 48.30 (0.9) |
| + almonertinib | 200 | 24.24 ± 7.08 (0.9) | 200.75 ± 46.44 (1.0) |
| + almonertinib | 500 | 19.11 ± 5.22 (1.2) | 145.86 ± 33.70 (1.4) |
| + Ko143 | 1000 | 14.73 ± 4.23 (1.5) | 6.44 ± 1.80** (31.1) |
| [nM] | [nM] | ||
| Mitoxantrone | - | 7.07 ± 1.93 (1.0) | 471.92 ± 111.19 (1.0) |
| + almonertinib | 50 | 6.74 ± 1.93 (1.0) | 528.13 ± 116.32 (0.9) |
| + almonertinib | 100 | 6.81 ± 2.09 (1.0) | 430.80 ± 87.59 (1.1) |
| + almonertinib | 200 | 7.14 ± 2.17 (1.0) | 324.75 ± 68.12 (1.5) |
| + almonertinib | 500 | 6.61 ± 2.11 (1.1) | 336.82 ± 66.32 (1.4) |
| + Ko143 | 1000 | 5.01 ± 1.51 (1.4) | 46.15 ± 10.30** (10.2) |
| Treatment | Concentration (nM) |
pcDNA3.1-HEK293 (parental) [nM] |
482R-5 (resistant) [nM] |
| Topotecan | - | 30.06 ± 5.27 (1.0) | 672.58 ± 182.46 (1.0) |
| + almonertinib | 50 | 32.66 ± 5.61 (0.9) | 1010.80 ± 314.06 (0.7) |
| + almonertinib | 100 | 33.64 ± 6.86 (0.9) | 829.73 ± 321.37 (0.8) |
| + almonertinib | 200 | 30.81 ± 6.04 (1.0) | 537.47 ± 170.83 (1.3) |
| + almonertinib | 500 | 31.98 ± 6.07 (0.9) | 402.33 ± 174.25 (1.7) |
| + Ko143 | 1000 | 30.42 ± 5.81 (1.0) | 70.43 ± 9.31** (9.5) |
| [nM] | [nM] | ||
| SN-38 | - | 2.30 ± 0.51 (1.0) | 66.52 ± 10.34 (1.0) |
| + almonertinib | 50 | 2.79 ± 0.58 (0.8) | 65.17 ± 10.10 (1.0) |
| + almonertinib | 100 | 2.92 ± 0.76 (0.8) | 70.73 ± 8.39 (0.9) |
| + almonertinib | 200 | 3.41 ± 0.88 (0.7) | 56.77 ± 4.70 (1.2) |
| + almonertinib | 500 | 3.42 ± 1.08 (0.7) | 57.59 ± 5.95 (1.2) |
| + Ko143 | 1000 | 2.52 ± 0.60 (0.9) | 3.48 ± 0.83*** (19.1) |
| [nM] | [nM] | ||
| Mitoxantrone | - | 1.77 ± 0.21 (1.0) | 36.12 ± 6.15 (1.0) |
| + almonertinib | 50 | 1.37 ± 0.22 (1.3) | 37.04 ± 6.85 (1.0) |
| + almonertinib | 100 | 1.36 ± 0.18 (1.3) | 31.91 ± 6.33 (1.1) |
| + almonertinib | 200 | 1.41 ± 0.23 (1.3) | 32.42 ± 6.57 (1.1) |
| + almonertinib | 500 | 2.15 ± 0.27 (0.8) | 25.83 ± 7.07 (1.4) |
| + Ko143 | 1000 | 2.08 ± 0.27 (0.9) | 3.86 ± 1.34*** (9.4) |
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 Materials and methods.
‡
FR values were calculated by dividing IC50 values of cells treated with a particular chemotherapeutic drug by IC50 values of cells treated with the same chemotherapeutic drug in the presence of almonertinib or Ko143.
*
p < 0.05;
**
p < 0.01;
***
p < 0.001.