Synergistic Drug Combinations Prevent Resistance in ALK+ Anaplastic Large Cell Lymphoma
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Chemicals, Antibodies and Cells
2.2. Long-Term Cell Cultures
2.3. Proliferation Assays, Synergy and Statistical Analysis
2.4. Cell Cycle and Apoptosis
2.5. Soft Agar Colony Assay
2.6. Western Blot Analysis
2.7. Quantitative Real-Time PCR
2.8. 3D Matrix-Embedded Cell Cultures
2.9. In Vivo Experiments
3. Results
3.1. Upfront Combined Treatments Prevent the Selection of Resistant Clones in ALK+ ALCL Cells
3.2. Synergistic Interaction of Crizotinib with Decitabine, CHO and Trametinib
3.3. Combined Treatments Enhance Apoptosis in vitro and Tumor Growth Inhibition in Mice
3.4. Molecular Effects of Combined Therapies
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Combination | Cell Line | Ratio | EC50 | EC75 | EC90 | Mean | Level of Synergism | |
---|---|---|---|---|---|---|---|---|
CRI:DEC | Karpas 299 | 1:1 | 0.000 | 0.006 | 0.007 | 0.004 | Very Strong Synergism | |
Karpas 299 | 1:4 | 0.226 | 0.189 | 0.206 | 0.207 | Strong Synergism | ||
Karpas 299 | 1:20 | 0.509 | 0.512 | 0.560 | 0.527 | Synergism | ||
Karpas 299 | 1:100 | 0.142 | 0.336 | 0.811 | 0.429 | Synergism | ||
SU-DHL-1 | 5:1 | 0.448 | 0.301 | 0.203 | 0.317 | Synergism | ||
SU-DHL-1 | 1:1 | 0.644 | 0.632 | 0.631 | 0.636 | Synergism | ||
SU-DHL-1 | 1:2 | 0.442 | 0.265 | 0.165 | 0.291 | Strong Synergism | ||
SU-DHL-1 | 1:5 | 0.779 | 0.675 | 0.641 | 0.698 | Synergism | ||
SUP-M2 | 5:1 | 1.080 | 0.713 | 0.481 | 0.758 | Moderate Synergism | ||
SUP-M2 | 1:1 | 0.711 | 0.839 | 1.110 | 0.887 | Slight Synergism | ||
SUP-M2 | 1:2 | 0.536 | 0.391 | 0.351 | 0.426 | Synergism | ||
SUP-M2 | 1:5 | 0.000 | 0.001 | 0.038 | 0.013 | Very Strong Synergism | ||
U937 | 1:1 | >10 | >10 | >10 | >10 | Very Strong Antagonism | ||
U937 | 1:2 | >10 | >10 | >10 | >10 | Very Strong Antagonism | ||
CRI:CHO | Karpas 299 | 1:22 | 0.087 | 0.185 | 0.405 | 0.226 | Strong Synergism | |
Karpas 299 | 1:50 | 0.426 | 0.545 | 0.698 | 0.556 | Synergism | ||
Karpas 299 | 1:66 | 0.432 | 0.346 | 0.284 | 0.354 | Synergism | ||
Karpas 299 | 1:150 | 0.500 | 0.625 | 0.781 | 0.635 | Synergism | ||
SU-DHL-1 | 1:40 | 0.236 | 0.359 | 0.555 | 0.383 | Synergism | ||
SU-DHL-1 | 1:20 | 0.268 | 0.418 | 0.662 | 0.449 | Synergism | ||
SU-DHL-1 | 1:10 | 1.298 | 1.420 | 1.571 | 1.430 | Moderate Antagonism | ||
SUP-M2 | 1:16 | 0.579 | 0.521 | 0.473 | 0.524 | Synergism | ||
SUP-M2 | 1:32 | 0.845 | 0.715 | 0.611 | 0.724 | Moderate Synergism | ||
SUP-M2 | 1:64 | 0.869 | 0.759 | 0.667 | 0.765 | Moderate Synergism | ||
U937 | 1:40 | 1.015 | 0.915 | 0.830 | 0.920 | Nearly Additive | ||
U937 | 1:20 | 1.096 | 1.044 | 1.008 | 1.050 | Nearly Additive | ||
U937 | 1:10 | 1.207 | 1.287 | 1.407 | 1.300 | Moderate Antagonism | ||
CRI:TRAM | Karpas 299 | 1:1 | 0.616 | 0.589 | 0.563 | 0.589 | Synergism | |
Karpas 299 | 1:2 | 0.510 | 0.477 | 0.448 | 0.478 | Synergism | ||
Karpas 299 | 1:4 | 0.228 | 0.336 | 0.538 | 0.367 | Synergism | ||
Karpas 299 | 1:3 | 0.433 | 0.480 | 0.553 | 0.489 | Synergism | ||
SU-DHL-1 | 1:9 | 0.967 | 0.665 | 0.461 | 0.698 | Synergism | ||
SU-DHL-1 | 1:3 | 0.758 | 0.572 | 0.438 | 0.589 | Synergism | ||
SU-DHL-1 | 1:1 | 0.450 | 0.321 | 0.244 | 0.338 | Synergism | ||
SU-DHL-1 | 3:1 | 0.046 | 0.053 | 0.068 | 0.056 | Very Strong Synergism | ||
SUP-M2 | 1:2 | 0.483 | 0.542 | 0.615 | 0.546 | Synergism | ||
SUP-M2 | 1:1 | 0.579 | 0.599 | 0.624 | 0.600 | Synergism | ||
SUP-M2 | 2:1 | 0.132 | 0.266 | 0.538 | 0.312 | Synergism | ||
U937 | 1:1 | >10 | >10 | >10 | >10 | Very Strong Antagonism | ||
U937 | 1:3 | >10 | >10 | >10 | >10 | Very Strong Antagonism |
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Arosio, G.; Sharma, G.G.; Villa, M.; Mauri, M.; Crespiatico, I.; Fontana, D.; Manfroni, C.; Mastini, C.; Zappa, M.; Magistroni, V.; et al. Synergistic Drug Combinations Prevent Resistance in ALK+ Anaplastic Large Cell Lymphoma. Cancers 2021, 13, 4422. https://doi.org/10.3390/cancers13174422
Arosio G, Sharma GG, Villa M, Mauri M, Crespiatico I, Fontana D, Manfroni C, Mastini C, Zappa M, Magistroni V, et al. Synergistic Drug Combinations Prevent Resistance in ALK+ Anaplastic Large Cell Lymphoma. Cancers. 2021; 13(17):4422. https://doi.org/10.3390/cancers13174422
Chicago/Turabian StyleArosio, Giulia, Geeta G. Sharma, Matteo Villa, Mario Mauri, Ilaria Crespiatico, Diletta Fontana, Chiara Manfroni, Cristina Mastini, Marina Zappa, Vera Magistroni, and et al. 2021. "Synergistic Drug Combinations Prevent Resistance in ALK+ Anaplastic Large Cell Lymphoma" Cancers 13, no. 17: 4422. https://doi.org/10.3390/cancers13174422