A Novel Synthetic Dihydroindeno[1,2-b] Indole Derivative (LS-2-3j) Reverses ABCB1- and ABCG2-Mediated Multidrug Resistance in Cancer Cells
Abstract
:1. Introduction
2. Results
2.1. Cell Cytotoxity Assay
2.2. LS-2-3j Enhances the Sensitivity of Chemotherapeutic Agents
2.3. LS-2-3j Enhances the Accumulation of DOX and MITX
2.4. LS-2-3j Inhibits the Efflux of DOX and MITX
2.5. LS-2-3j Inhibits the ATPase Activity of ABCB1 and ABCG2
2.6. LS-2-3j Decreases the mRNA Expression Levels of ABCB1 and ABCG2
2.7. LS-2-3j Decreases the Protein Expression of ABCB1 and ABCG2
3. Discussion
4. Materials and Methods
4.1. Synthesis and Analysis of LS-3-2j
4.2. Chemicals and Regents
4.3. Cell Lines and Cell Culture
4.4. MTT Assay
4.5. Drug Intracellular Accumulation Assay
4.6. Drug Efflux Assay
4.7. ATPase Activity Assay
4.8. RNA Extraction and Real-Time PCR
4.9. Western Blot Analysis
4.10. Statistical Analysis
Author Contributions
Funding
Conflicts of Interest
References
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Sample Availability: Samples of the compounds are not available from the authors. |
Treatment | IC50 ± SD (μmol/L) (Reversal Fold, RF) | |||
MCF-7 | MCF-7/Adr | |||
Doxorubicin (DOX) | 0.298 ± 0.008 | (1.000) | 3.506 ± 0.637 | (1.000) |
+ LS-2-3j 0.25 μmol/L | 0.313 ± 0.019 | (0.953) | 0.827 ± 0.128 * | (4.241) |
+ LS-2-3j 0.5 μmol/L | 0.303 ± 0.012 | (0.986) | 0.471 ± 0.072 ** | (7.438) |
+ LS-2-3j 1 μmol/L | 0.300 ± 0.005 | (0.995) | 0.353 ± 0.031 ** | (9.937) |
+ VRP 10 μmol/L | 0.317 ± 0.017 | (0.941) | 0.274 ± 0.057 ** | (12.812) |
Cisplatin | 7.004 ± 0.662 | (1.000) | 4.363 ± 0.189 | (1.000) |
+ LS-2-3j 1 μmol/L | 7.316 ± 0.913 | (0.957) | 4.581 ± 0.234 | (0.952) |
Treatment | IC50 ± SD (μmol/L) (Reversal Fold, RF) | |||
K562 | K562/A02 | |||
DOX | 0.118 ± 0.001 | (1.000) | 13.317 ± 0.840 | (1.000) |
+ LS-2-3j 0.25 μmol/L | 0.118 ± 0.010 | (0.997) | 4.947 ± 0.580 * | (2.692) |
+ LS-2-3j 0.5 μmol/L | 0.127 ± 0.009 | (0.925) | 3.182 ± 0.162 * | (4.185) |
+ LS-2-3j 1 μmol/L | 0.126 ± 0.010 | (0.934) | 1.676 ± 0.269 ** | (7.944) |
+ VRP 10 μmol/L | 0.122 ± 0.007 | (0.962) | 1.180 ± 0.160 ** | (11.282) |
Cisplatin | 2.747 ± 0.227 | (1.000) | 3.768 ± 0.124 | (1.000) |
+ LS-2-3j 1 μmol/L | 2.223 ± 0.124 | (1.236) | 3.577 ± 0.314 | (1.053) |
KB | KB/VCR | |||
Vincristine (VCR) | 0.010 ± 0.001 | (1.000) | 1.126 ± 0.134 | (1.000) |
+ LS-2-3j 0.25 μmol/L | 0.010 ± 0.010 | (1.030) | 0.589 ± 0.114 * | (1.913) |
+ LS-2-3j 0.5 μmol/L | 0.011 ± 0.012 | (0.955) | 0.291 ± 0.045 * | (3.874) |
+ LS-2-3j 1 μmol/L | 0.011 ± 0.030 | (0.939) | 0.150 ± 0.022 ** | (7.531) |
+ VRP 10 μmol/L | 0.011 ± 0.001 | (0.935) | 0.115 ± 0.018 ** | (9.808) |
Cisplatin | 0.705 ± 0.263 | (1.000) | 1.183 ± 0.140 | (1.000) |
+ LS-2-3j 1 μmol/L | 0.703 ± 0.147 | (1.002) | 1.213 ± 0.118 | (0.975) |
Treatment | IC50 ± SD (μmol/L) (RF) | |||
---|---|---|---|---|
MCF-7 | MCF-7/ABCG2 | |||
Mitoxantrone (MITX) | 0.425 ± 0.014 | (1.000) | 3.550 ± 0.054 | (1.000) |
+ LS-2-3j 0.25 μmol/L | 0.434 ± 0.035 | (0.980) | 1.639 ± 0.177 * | (2.236) |
+ LS-2-3j 0.5 μmol/L | 0.462 ± 0.033 | (0.921) | 0.755 ± 0.021 * | (4.770) |
+ LS-2-3j 1 μmol/L | 0.436 ± 0.012 | (0.975) | 0.487 ± 0.050 ** | (7.479) |
+ Fumitremorgin C (FTC) 2.5 μmol/L | 0.444 ± 0.017 | (0.958) | 0.372 ± 0.023 ** | (8.793) |
Cisplatin | 7.004 ± 0.662 | (1.000) | 5.478 ± 0.882 | (1.000) |
+ LS-2-3j 1 μmol/L | 7.316 ± 0.913 | (0.957) | 5.248 ± 0.142 | (1.044) |
MCF-7 | MCF-7/Adr | |||
MITX | 0.425 ± 0.014 | (1.000) | 39.242 ± 0.035 | (1.000) |
+ LS-2-3j 0.25 μmol/L | 0.434 ± 0.035 | (0.980) | 30.141 ± 0.264 | (1.302) |
+ LS-2-3j 0.5 μmol/L | 0.462 ± 0.033 | (0.921) | 13.772 ± 0.210 * | (2.849) |
+ LS-2-3j 1 μmol/L | 0.436 ± 0.012 | (0.975) | 8.253 ± 0.805 ** | (4.755) |
+ FTC 2.5 μmol/L | 0.444 ± 0.017 | (0.958) | 4.891 ± 0.337 ** | (8.023) |
Cisplatin | 7.004 ± 0.662 | (1.000) | 8.995 ± 0.364 | (1.000) |
+ LS-2-3j 1 μmol/L | 7.316 ± 0.913 | (0.957) | 8.784 ± 0.963 | (1.024) |
293T | 293T/ABCG2 | |||
MITX | 0.187 ± 0.013 | (1.000) | 4.253 ± 0.200 | (1.000) |
+ LS-2-3j 0.25 μmol/L | 0.200 ± 0.005 | (0.934) | 1.739 ± 0.056 * | (2.446) |
+ LS-2-3j 0.5 μmol/L | 0.194 ± 0.004 | (0.963) | 1.205 ± 0.065 * | (3.530) |
+ LS-2-3j 1 μmol/L | 0.183 ± 0.008 | (1.020) | 0.707 ± 0.051 ** | (6.015) |
+ FTC 2.5 μmol/L | 0.189 ± 0.019 | (0.985) | 0.466 ± 0.016 ** | (9.120) |
Cisplatin | 1.983 ± 0.132 | (1.000) | 1.411 ± 0.197 | (1.000) |
+ LS-2-3j 1 μmol/L | 1.970 ± 0.184 | (1.006) | 1.551 ± 0.189 | (0.910) |
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Guo, C.; Liu, F.; Qi, J.; Ma, J.; Lin, S.; Zhang, C.; Zhang, Q.; Zhang, H.; Lu, R.; Li, X. A Novel Synthetic Dihydroindeno[1,2-b] Indole Derivative (LS-2-3j) Reverses ABCB1- and ABCG2-Mediated Multidrug Resistance in Cancer Cells. Molecules 2018, 23, 3264. https://doi.org/10.3390/molecules23123264
Guo C, Liu F, Qi J, Ma J, Lin S, Zhang C, Zhang Q, Zhang H, Lu R, Li X. A Novel Synthetic Dihydroindeno[1,2-b] Indole Derivative (LS-2-3j) Reverses ABCB1- and ABCG2-Mediated Multidrug Resistance in Cancer Cells. Molecules. 2018; 23(12):3264. https://doi.org/10.3390/molecules23123264
Chicago/Turabian StyleGuo, Chao, Fangyuan Liu, Jie Qi, Jiahui Ma, Shiqi Lin, Caiyun Zhang, Qian Zhang, Hangyu Zhang, Rong Lu, and Xia Li. 2018. "A Novel Synthetic Dihydroindeno[1,2-b] Indole Derivative (LS-2-3j) Reverses ABCB1- and ABCG2-Mediated Multidrug Resistance in Cancer Cells" Molecules 23, no. 12: 3264. https://doi.org/10.3390/molecules23123264