Curcumin-Loaded Solid Lipid Nanoparticles Bypass P-Glycoprotein Mediated Doxorubicin Resistance in Triple Negative Breast Cancer Cells
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemicals and Materials
2.2. SLN Preparation and Characterization
2.3. Cell Lines
2.4. Co-Culture Models
2.5. Doxorubicin Accumulation
2.6. Cytotoxicity
2.7. Rhodamine 123 Efflux
2.8. Immunoblotting
2.9. Flow Cytometry
2.10. Quantitative Real Time-PCR (qRT-PCR)
2.11. Reactive Oxygen Species (ROS) Measurement
2.12. Nuclear Factor-kB (NF-kB) and Hypoxia Inducible Factor-1α (HIF-1α) Activity.
2.13. Chromatin Immunoprecipitation (ChIP)
2.14. In Vivo Tumor Growths and Hematochemical Parameters
2.15. Statistical Analysis
3. Results
3.1. CURC-Loaded SLNs Are More Effective than Free CURC in Increasing Doxorubicin Efficacy in Resistant Triple Negative Breast Cancer Cells
3.2. CURC-Loaded SLNs Decrease Pgp Activity and Expression
3.3. CURC-Loaded SLNs Decrease Pgp Transcription by Reducing Intracellular ROS and NF-kB Activity
3.4. CURC-Loaded SLNs Restore Doxorubicin Sensitivity by Down-Regulating ROS/NF-kB/Pgp Axis in Resistant TNBC Cells Co-Cultured with Macrophages
3.5. CURC-Loaded SLNs Are Effective and Safe in Preclinical Models of Pgp-Expressing Mammary JC Tumors
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Components | CURC-SLN (w/w %) | CURC-CS-SLN (w/w %) |
---|---|---|
TL | 4.22 | - |
Cholesterol | - | 3.22 |
CS | - | 0.43 |
Epikuron®200 | 10.57 | 16.12 |
s-EA | 14.09 | - |
s-BL | - | 9.54 |
CURC | 0.63 | 0.64 |
Cremophor®RH60 | 3.52 | 9.54 |
NaTC | 3.53 | 9.03 |
1,2 Propanediol | 14.09 | - |
BenzOH | - | 6.71 |
s-W | 49.35 | 44.77 |
−Doxorubicin | Ctrl | CURC | CURC-CS-SLN | CURC-SLN |
LDH (U/L) | 7091 ± 639 | 7189 ± 409 | 6781 ± 1021 | 7112 ± 678 |
AST (U/L) | 89 ± 54 | 101 ± 43 | 121 ± 48 | 99 ± 29 |
ALT (U/L) | 38 ± 8 | 41 ± 8 | 37 ± 10 | 34 ± 8 |
AP (U/L) | 134 ± 49 | 139 ± 41 | 129 ± 29 | 139 ± 18 |
Creatinine (mg/L) | 0.056 ± 0.005 | 0.062 ± 0.010 | 0.062 ± 0.009 | 0.054 ± 0.008 |
CPK (U/L) | 314 ± 99 | 312 ± 83 | 382 ± 56 | 334 ± 39 |
CPK-MB (ng/mL) | 0.109 ± 0.058 | 0.118 ± 0.032 | 0.129 ± 0.045 | 0.118 ± 0.041 |
cTnI (pg/mL) | 1.011 ± 0.082 | 1.019 ± 0.032 | 1.008 ± 0.062 | 1.024 ± 0.029 |
cTnT (pg/mL) | 2.182 ± 0.213 | 2.178 ± 0.101 | 2.189 ± 0.123 | 1.897 ± 0.162 |
+doxorubicin | Ctrl | CURC | CURC-CS-SLN | CURC-SLN |
LDH (U/L) | 7561 ± 761 | 7192 ± 506 | 7821 ± 821 | 6523 ± 801 |
AST (U/L) | 103 ± 44 | 132 ± 45 | 105 ± 36 | 137 ± 89 |
ALT (U/L) | 36 ± 15 | 41 ± 18 | 39 ± 13 | 56 ± 19 |
AP (U/L) | 138 ± 25 | 167 ± 56 | 139 ± 44 | 168 ± 41 |
Creatinine (mg/L) | 0.083 ± 0.009 | 0.082 ± 0.009 | 0.093 ± 0.011 | 0.093 ± 0.010 |
CPK (U/L) | 556 ± 89 * | 571 ± 89 * | 562 ± 81 * | 504 ± 81 * |
CPK-MB (ng/mL) | 0.302 ± 0.71 * | 0.287 ± 0.045 * | 0.297 ± 0.062 * | 0.322 ± 0.016 * |
cTnI (pg/mL) | 1.021 ± 0.039 | 1.033 ± 0.046 | 1.031 ± 0.067 | 1.019 ± 0.052 |
cTnT (pg/mL) | 3.197 ± 0.209 * | 2.882 ± 0.172 * | 2.904 ± 0.209 * | 2.821 ± 0.178 * |
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Fathy Abd-Ellatef, G.-E.; Gazzano, E.; Chirio, D.; Ragab Hamed, A.; Belisario, D.C.; Zuddas, C.; Peira, E.; Rolando, B.; Kopecka, J.; Assem Said Marie, M.; et al. Curcumin-Loaded Solid Lipid Nanoparticles Bypass P-Glycoprotein Mediated Doxorubicin Resistance in Triple Negative Breast Cancer Cells. Pharmaceutics 2020, 12, 96. https://doi.org/10.3390/pharmaceutics12020096
Fathy Abd-Ellatef G-E, Gazzano E, Chirio D, Ragab Hamed A, Belisario DC, Zuddas C, Peira E, Rolando B, Kopecka J, Assem Said Marie M, et al. Curcumin-Loaded Solid Lipid Nanoparticles Bypass P-Glycoprotein Mediated Doxorubicin Resistance in Triple Negative Breast Cancer Cells. Pharmaceutics. 2020; 12(2):96. https://doi.org/10.3390/pharmaceutics12020096
Chicago/Turabian StyleFathy Abd-Ellatef, Gamal-Eldein, Elena Gazzano, Daniela Chirio, Ahmed Ragab Hamed, Dimas Carolina Belisario, Carlo Zuddas, Elena Peira, Barbara Rolando, Joanna Kopecka, Mohamed Assem Said Marie, and et al. 2020. "Curcumin-Loaded Solid Lipid Nanoparticles Bypass P-Glycoprotein Mediated Doxorubicin Resistance in Triple Negative Breast Cancer Cells" Pharmaceutics 12, no. 2: 96. https://doi.org/10.3390/pharmaceutics12020096
APA StyleFathy Abd-Ellatef, G.-E., Gazzano, E., Chirio, D., Ragab Hamed, A., Belisario, D. C., Zuddas, C., Peira, E., Rolando, B., Kopecka, J., Assem Said Marie, M., Sapino, S., Ramadan Fahmy, S., Gallarate, M., Zaki Abdel-Hamid, A.-H., & Riganti, C. (2020). Curcumin-Loaded Solid Lipid Nanoparticles Bypass P-Glycoprotein Mediated Doxorubicin Resistance in Triple Negative Breast Cancer Cells. Pharmaceutics, 12(2), 96. https://doi.org/10.3390/pharmaceutics12020096