Imperatorin Restores Chemosensitivity of Multidrug-Resistant Cancer Cells by Antagonizing ABCG2-Mediated Drug Transport
Abstract
:1. Introduction
2. Results
2.1. Imperatorin Reverses ABCG2-Mediated Multidrug Resistance in Cancer Cells
2.2. Imperatorin Potentiates Topotecan-Induced Apoptosis in ABCG2-Overexpressing Cancer Cells
2.3. Imperatorin Inhibits the Drug Efflux Function of ABCG2
2.4. Imperatorin Does Not Induce Changes in the Protein Expression of ABCG2 in Multidrug-Resistant Cancer Cells
2.5. Imperatorin Stimulates the ATPase Activity of ABCG2
2.6. Docking of Imperatorin in the Drug-Binding Pocket of ABCG2
3. Discussion
4. Materials and Methods
4.1. Materials and Cell Culture
4.2. Cell Viability Assay and Multidrug Resistance Reversal Assay
4.3. Apoptosis Assay
4.4. Fluorescent Drug Accumulation Assay
4.5. Immunoblotting
4.6. ATPase Assay
4.7. Docking Analysis
4.8. Data Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Mean IC50 1 ± SD and (FR 2) | |||
---|---|---|---|
Treatment | Concentration (μM) | OVCAR-8 (Parental) [nM] | NCI-ADR-RES (Resistant) [μM] |
Colchicine | - | 34.08 ± 9.39 (1.0) | 3.39 ± 0.53 (1.0) |
+IMP | 1 | 29.11 ± 8.90 (1.2) | 4.23 ± 0.65 (0.8) |
+IMP | 2 | 40.97 ± 13.15 (0.8) | 4.20 ± 0.67 (0.8) |
+IMP | 5 | 34.62 ± 9.70 (1.0) | 4.73 ± 0.81 (0.7) |
+IMP | 10 | 33.81 ± 9.17 (1.0) | 4.51 ± 0.69 (0.8) |
+Tariquidar | 1 | 28.85 ± 7.53 (1.2) | 37.80 ± 12.70 [nM] *** (90) |
[nM] | [μM] | ||
Vincristine | - | 23.65 ± 2.88 (1.0) | 5.77 ± 0.92 (1.0) |
+IMP | 1 | 26.40 ± 3.04 (0.9) | 8.35 ± 1.72 (0.7) |
+IMP | 2 | 25.16 ± 2.55 (0.9) | 8.63 ± 1.86 (0.7) |
+IMP | 5 | 24.11 ± 2.38 (1.0) | 6.95 ± 1.56 (0.8) |
+IMP | 10 | 20.49 ± 2.75 (1.2) | 5.23 ± 0.97 (1.1) |
+Tariquidar | 1 | 21.48 ± 2.32 (1.1) | 76.34 ± 15.75 [nM] *** (76) |
[nM] | [μM] | ||
Paclitaxel | - | 4.67 ± 0.59 (1.0) | 11.54 ± 2.05 (1.0) |
+IMP | 1 | 4.44 ± 0.55 (1.1) | 11.10 ± 1.87 (1.0) |
+IMP | 2 | 4.92 ± 0.76 (0.9) | 11.12 ± 2.12 (1.0) |
+IMP | 5 | 4.62 ± 0.55 (1.0) | 12.35 ± 2.42 (0.9) |
+IMP | 10 | 4.23 ± 0.58 (1.1) | 9.33 ± 1.22 (1.2) |
+Tariquidar | 1 | 4.82 ± 0.72 (1.0) | 7.22 ± 0.73 [nM] *** (1598) |
Treatment | Concentration (μM) | KB-3-1 (parental) [nM] | KB-V1 (resistant) [μM] |
Colchicine | - | 10.45 ± 3.44 (1.0) | 1.38 ± 0.27 (1.0) |
+IMP | 1 | 9.74 ± 2.99 (1.1) | 1.41 ± 0.17 (1.0) |
+IMP | 2 | 10.26 ± 3.50 (1.0) | 1.53 ± 0.18 (0.9) |
+IMP | 5 | 11.34 ± 3.96 (0.9) | 1.52 ± 0.17 (0.9) |
+IMP | 10 | 11.00 ± 3.83 (1.0) | 2.01 ± 0.34 (0.7) |
+Tariquidar | 1 | 9.40 ± 2.97 (1.1) | 12.52 ± 4.61 [nM] *** (110) |
[nM] | [μM] | ||
Vincristine | - | 5.00 ± 1.23 (1.0) | 2.39 ± 0.43 (1.0) |
+IMP | 1 | 4.57 ± 1.08 (1.1) | 2.36 ± 0.38 (1.0) |
+IMP | 2 | 4.38 ± 0.96 (1.1) | 2.07 ± 0.36 (1.2) |
+IMP | 5 | 3.92 ± 0.92 (1.3) | 1.84 ± 0.31 (1.3) |
+IMP | 10 | 3.64 ± 0.82 (1.4) | 1.64 ± 0.30 (1.5) |
+Tariquidar | 1 | 3.74 ± 0.91 (1.3) | 5.15 ± 1.06 [nM] (464) |
[nM] | [μM] | ||
Paclitaxel | - | 1.93 ± 0.68 (1.0) | 3.54 ± 0.53 (1.0) |
+IMP | 1 | 1.95 ± 0.73 (1.0) | 3.33 ± 0.50 (1.1) |
+IMP | 2 | 1.69 ± 0.47 (1.1) | 3.46 ± 0.58 (1.0) |
+IMP | 5 | 1.81 ± 0.54 (1.1) | 2.94 ± 0.50 (1.2) |
+IMP | 10 | 1.74 ± 0.50 (1.1) | 2.70 ± 0.44 (1.3) |
+Tariquidar | 1 | 1.93 ± 0.70 (1.0) | 1.83 ± 0.63 [nM] *** (1934) |
Treatment | Concentration (μM) | pcDNA3.1-HEK293 (parental) [nM] | MDR19-HEK293 (resistant) [nM] |
Colchicine | - | 14.65 ± 4.29 (1.0) | 313.26 ± 70.20 (1.0) |
+IMP | 1 | 13.49 ± 2.96 (1.1) | 341.91 ± 63.09 (0.9) |
+IMP | 2 | 15.13 ± 3.87 (1.0) | 408.47 ± 55.45 (0.8) |
+IMP | 5 | 15.01 ± 3.60 (1.0) | 419.27 ± 63.99 (0.7) |
+IMP | 10 | 12.49 ± 3.58 (1.2) | 427.51 ± 45.23 (0.7) |
+Tariquidar | 1 | 12.75 ± 3.90 (1.1) | 13.06 ± 3.42 ** (24.0) |
[nM] | [μM] | ||
Vincristine | - | 17.14 ± 3.75 (1.0) | 1.75 ± 0.23 (1.0) |
+IMP | 1 | 16.87 ± 3.24 (1.0) | 1.93 ± 0.19 (0.9) |
+IMP | 2 | 17.89 ± 3.33 (1.0) | 1.41 ± 0.22 (1.2) |
+IMP | 5 | 15.66 ± 2.98 (1.1) | 1.54 ± 0.16 (1.1) |
+IMP | 10 | 14.88 ± 2.69 (1.2) | 1.48 ± 0.16 (1.2) |
+Tariquidar | 1 | 13.35 ± 2.87 (1.3) | 19.49 ± 2.13 [nM] *** (89.8) |
[nM] | [μM] | ||
Paclitaxel | - | 3.80 ± 0.87 (1.0) | 4.76 ± 0.83 (1.0) |
+IMP | 1 | 3.10 ± 0.53 (1.2) | 4.00 ± 0.62 (1.2) |
+IMP | 2 | 3.19 ± 0.58 (1.2) | 3.30 ± 0.51 (1.4) |
+IMP | 5 | 3.47 ± 0.64 (1.1) | 3.47 ± 0.49 (1.4) |
+IMP | 10 | 2.76 ± 0.48 (1.4) | 3.39 ± 0.58 (1.4) |
+Tariquidar | 1 | 2.48 ± 0.41 (1.5) | 4.76 ± 0.72 [nM] *** (1000) |
Mean IC50 1 ± SD and (FR 2) | |||
---|---|---|---|
Treatment | Concentration (μM) | S1 (Parental) [nM] | S1-MI-80 (Resistant) [μM] |
Mitoxantrone | - | 1.97 ± 0.34 (1.0) | 37.48 ± 5.45 (1.0) |
+IMP | 1 | 1.97 ± 0.26 (1.0) | 7.02 ± 0.87 *** (5.3) |
+IMP | 2 | 2.07 ± 0.25 (1.0) | 5.19 ± 0.84 *** (7.2) |
+IMP | 5 | 2.16 ± 0.23 (0.9) | 2.11 ± 0.26 *** (17.8) |
+IMP | 10 | 2.39 ± 0.24 (0.8) | 0.89 ± 0.10 *** (42.1) |
+Ko143 | 1 | 1.91 ± 0.31 (1.0) | 0.26 ± 0.04 *** (144.2) |
[nM] | [μM] | ||
SN-38 | - | 5.38 ± 1.12 (1.0) | 10.46 ± 2.71 (1.0) |
+IMP | 1 | 4.43 ± 0.86 (1.2) | 2.21 ± 0.46 ** (4.7) |
+IMP | 2 | 4.35 ± 0.94 (1.2) | 1.60 ± 0.33 ** (6.5) |
+IMP | 5 | 5.00 ± 1.17 (1.1) | 797.97 ± 142.95 [nM] ** (13.1) |
+IMP | 10 | 3.91 ± 1.00 (1.4) | 501.15 ± 91.75 [nM] ** (20.9) |
+Ko143 | 1 | 4.34 ± 0.91 (1.2) | 164.19 ± 33.28 [nM] ** (65.4) |
[nM] | [μM] | ||
Topotecan | - | 163.87 ± 19.28 (1.0) | 19.83 ± 2.43 (1.0) |
+IMP | 1 | 153.34 ± 23.11 (1.1) | 5.15 ± 0.67 *** (3.9) |
+IMP | 2 | 144.40 ± 22.21 (1.1) | 3.35 ± 0.48 *** (5.9) |
+IMP | 5 | 135.88 ± 22.43 (1.2) | 2.65 ± 0.27 *** (7.5) |
+IMP | 10 | 120.50 ± 21.51 (1.4) | 1.93 ± 0.24 *** (10.3) |
+Ko143 | 1 | 146.15 ± 18.37 (1.1) | 1.00 ± 0.12 *** (19.8) |
Treatment | Concentration (μM) | H460 (parental) [nM] | H460-MX20 (resistant) [nM] |
Mitoxantrone | - | 1.89 ± 0.34 (1.0) | 168.24 ± 38.97 (1.0) |
+IMP | 1 | 1.68 ± 0.22 (1.1) | 76.44 ± 13.14 * (2.2) |
+IMP | 2 | 1.46 ± 0.18 (1.3) | 46.79 ± 7.12 ** (3.6) |
+IMP | 5 | 1.11 ± 0.13 * (1.7) | 29.96 ± 5.22 ** (5.6) |
+IMP | 10 | 1.23 ± 0.20 * (1.5) | 15.07 ± 2.72 ** (11.2) |
+Ko143 | 1 | 1.35 ± 0.22 (1.4) | 9.99 ± 1.46 ** (16.8) |
[nM] | [nM] | ||
SN-38 | - | 8.36 ± 1.13 (1.0) | 341.27 ± 104.72 (1.0) |
+IMP | 1 | 5.68 ± 0.65 * (1.5) | 162.63 ± 57.39 (2.1) |
+IMP | 2 | 4.67 ± 0.67 ** (1.8) | 113.89 ± 42.89 * (3.0) |
+IMP | 5 | 4.25 ± 0.75 ** (2.0) | 89.98 ± 36.16 * (3.8) |
+IMP | 10 | 3.58 ± 0.69 ** (2.3) | 75.92 ± 34.46 * (4.5) |
+Ko143 | 1 | 2.29 ± 0.47 ** (3.7) | 8.54 ± 2.92 ** (40.0) |
[nM] | [nM] | ||
Topotecan | - | 244.27 ± 27.29 (1.0) | 1833.76 ± 465.26 (1.0) |
+IMP | 1 | 215.26 ± 26.33 (1.1) | 700.29 ± 226.08 * (2.6) |
+IMP | 2 | 186.94 ± 23.76 (1.3) | 618.64 ± 214.38 * (3.0) |
+IMP | 5 | 160.41 ± 23.62 * (1.5) | 467.41 ± 169.84 ** (3.9) |
+IMP | 10 | 130.68 ± 25.03 ** (1.9) | 333.46 ± 120.22 ** (5.5) |
+Ko143 | 1 | 116.24 ± 17.19 ** (2.1) | 88.12 ± 30.74 ** (20.8) |
Treatment | Concentration (μM) | pcDNA3.1-HEK293 (parental) [nM] | R482-HEK293 (resistant) [nM] |
Mitoxantrone | - | 13.36 ± 1.17 (1.0) | 111.37 ± 14.83 (1.0) |
+IMP | 1 | 12.80 ± 1.25 (1.0) | 62.41 ± 7.18 ** (1.8) |
+IMP | 2 | 13.34 ± 1.40 (1.0) | 58.94 ± 7.72 ** (1.9) |
+IMP | 5 | 11.57 ± 1.33 (1.2) | 48.56 ± 5.84 ** (2.3) |
+IMP | 10 | 12.58 ± 1.57 (1.1) | 44.19 ± 5.01 ** (2..5) |
+Ko143 | 1 | 12.24 ± 1.02 (1.1) | 15.59 ± 1.30 *** (7.1) |
[nM] | [nM] | ||
SN-38 | - | 3.02 ± 0.65 (1.0) | 425.18 ± 27.55 (1.0) |
+IMP | 1 | 3.08 ± 0.67 (1.0) | 180.40 ± 26.30 *** (2.4) |
+IMP | 2 | 2.77 ± 0.56 (1.1) | 133.51 ± 19.25 *** (3.2) |
+IMP | 5 | 3.01 ± 0.64 (1.0) | 110.63 ± 21.86 *** (3.8) |
+IMP | 10 | 2.82 ± 0.57 (1.1) | 61.76 ± 13.87 *** (6.9) |
+Ko143 | 1 | 2.61 ± 0.56 (1.2) | 10.87 ± 1.62 *** (39.1) |
[nM] | [nM] | ||
Topotecan | - | 123.83 ± 25.91 (1.0) | 2655.27 ± 495.12 (1.0) |
+IMP | 1 | 111.53 ± 20.56 (1.1) | 1687.77 ± 271.40 * (1.6) |
+IMP | 2 | 105.94 ± 21.17 (1.2) | 1275.03 ± 180.51 * (2.1) |
+IMP | 5 | 108.24 ± 20.17 (1.1) | 844.84 ± 145.95 ** (3.1) |
+IMP | 10 | 104.79 ± 18.96 (1.2) | 741.15 ± 103.20 ** (3.6) |
+Ko143 | 1 | 107.26 ± 20.85 (1.2) | 66.52 ± 17.79 *** (39.9) |
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Wu, C.-P.; Murakami, M.; Li, Y.-C.; Huang, Y.-H.; Chang, Y.-T.; Hung, T.-H.; Wu, Y.-S.; Ambudkar, S.V. Imperatorin Restores Chemosensitivity of Multidrug-Resistant Cancer Cells by Antagonizing ABCG2-Mediated Drug Transport. Pharmaceuticals 2023, 16, 1595. https://doi.org/10.3390/ph16111595
Wu C-P, Murakami M, Li Y-C, Huang Y-H, Chang Y-T, Hung T-H, Wu Y-S, Ambudkar SV. Imperatorin Restores Chemosensitivity of Multidrug-Resistant Cancer Cells by Antagonizing ABCG2-Mediated Drug Transport. Pharmaceuticals. 2023; 16(11):1595. https://doi.org/10.3390/ph16111595
Chicago/Turabian StyleWu, Chung-Pu, Megumi Murakami, Yen-Ching Li, Yang-Hui Huang, Yu-Tzu Chang, Tai-Ho Hung, Yu-Shan Wu, and Suresh V. Ambudkar. 2023. "Imperatorin Restores Chemosensitivity of Multidrug-Resistant Cancer Cells by Antagonizing ABCG2-Mediated Drug Transport" Pharmaceuticals 16, no. 11: 1595. https://doi.org/10.3390/ph16111595