TABLE 1

Effects of neratinib in reversing ABCB1-, ABCG2-, and ABCC1-mediated drug resistance

Cell survival rates were determined with MTT assays, as described under Materials and Methods. Data are the mean ± S.D. of at least three independent experiments performed in triplicate. The fold reversal of MDR was calculated by dividing the IC50 for cells with the anticancer agent in the absence of neratinib, VRP, or fumitremorgin C by that in the presence of neratinib, VRP, or fumitremorgin C.

CompoundsIC50 (Reversal)
KBKBv200 (ABCB1)MCF-7MCF-7Adr (ABCB1)MCF-7/FLV1000 (ABCG2)HL60HL60/Adr (ABCC1)
μM (fold)
Doxorubicin0.031 ± 0.006 (1.00)7.122 ± 0.430 (1.00)
    + 0.25 μM Neratinib0.025 ± 0.004 (1.26)2.135 ± 0.103 (3.34)*
    + 0.5 μM Neratinib0.018 ± 0.003 (1.69)*1.550 ± 0.278 (4.60)**
    + 1.0 μM Neratinib0.014 ± 0.003 (2.20)*0.588 ± 0.207 (12.11)**
    + 10 μM Verapamil0.029 ± 0.004 (0.94)0.250 ± 0.070 (28.45)**
Vincristine0.0025 ± 0.0002 (1.00)1.440 ± 0.130 (1.00)
    + 0.25 μM Neratinib0.0025 ± 0.0004 (1.00)0.765 ± 0.070 (1.88)**
    + 0.5 μM Neratinib0.0025 ± 0.0003 (1.00)0.269 ± 0.028 (5.36)**
    + 1.0 μM Neratinib0.0021 ± 0.0003 (1.16)0.035 ± 0.002 (41.17)**
    + 10 μM Verapamil0.0023 ± 0.0004 (1.06)0.018 ± 0.001 (82.48)**
Paclitaxel0.0016 ± 0.0002 (1.00)0.222 ± 0.021 (1.00)
    + 0.25 μM Neratinib0.0016 ± 0.0002 (1.00)0.074 ± 0.009 (2.99)**
    + 0.5 μM Neratinib0.0015 ± 0.0001 (1.07)0.022 ± 0.004 (10.13)**
    + 1.0 μM Neratinib0.0017 ± 0.0002 (0.94)0.005 ± 0.001 (43.34)**
    + 10 μM Verapamil0.0016 ± 0.0003 (1.00)0.004 ± 0.001 (50.76)**
Cisplatin3.022 ± 0.30 (1.00)3.951 ± 0.40 (1.00)
    + 1.0 μM Neratinib2.888 ± 0.28 (1.05)3.354 ± 0.34 (0.97)
    + 10 μM Verapamil2.943 ± 0.30 (1.03)4.071 ± 0.40 (1.18)
Doxorubicin0.283 ± 0.02 (1.00)11.675 ± 1.186 (1.00)
    + 0.25 μM Neratinib0.262 ± 0.03 (1.08)2.413 ± 0.196 (4.84)**
    + 0.5 μM Neratinib0.215 ± 0.02 (1.31)*1.443 ± 0.27 (8.09)**
    + 1.0 μM Neratinib0.163 ± 0.01 (1.74)*0.944 ± 0.06 (12.37)**
    + 10 μM Verapamil0.285 ± 0.03 (0.99)0.478 ± 0.076 (24.40)**
Mitoxantrone0.115 ± 0.012 (1.00)6.723 ± 0.632 (1.00)
    + 0.125 μM Neratinib0.109 ± 0.011 (1.05)6.231 ± 0.611 (1.07)
    + 0.25 μM Neratinib0.107 ± 0.011 (1.07)6.081 ± 0.602 (1.11)
    + 0.5 μM Neratinib0.114 ± 0.010 (1.02)5.149 ± 0.521 (1.31)
    + 2.5 μM Fumitremorgin C0.109 ± 0.011 (1.06)0.276 ± 0.021 (24.36)**
Doxorubicin0.074 ± 0.007 (1.00)3.622 ± 0.313 (1.00)
    + 0.125 μM Neratinib0.078 ± 0.008 (0.95)3.668 ± 0.367 (1.12)
    + 0.25 μM Neratinib0.069 ± 0.006 (1.08)3.600 ± 0.360 (1.14)
    + 0.5 μM Neratinib0.061 ± 0.006 (1.21)3.083 ± 0.301 (1.18)
    + 40 μM MK5710.065 ± 0.006 (1.13)0.0825 ± 0.008 (5.50)**
  • * P < 0.05 versus the values obtained in the absence of neratinib, VRP, or fumitremorgin C.

  • ** P < 0.01 versus the values obtained in the absence of neratinib, VRP, or fumitremorgin C.