Cyclodextrin Dispersion of Mebendazole and Flubendazole Improves In Vitro Antiproliferative Activity
Abstract
:1. Introduction
2. Materials and Methods
2.1. Preparation of Binary Conjugates
2.2. In Vitro Dissolution Studies
2.3. X-ray Diffraction
2.4. Thermal Analysis
2.5. FTIR Spectrometry
2.6. Cell Culture
2.7. Cell Viability Assessment
2.8. Molecular Docking Analysis
2.9. High-Resolution Respirometry Studies in Permeabilized Cells
- State 2CI: the basal respiration in a non-phosphorylating state; mitochondrial respiration dependent on CI (NADH-generating) substrates.
- OXPHOSCI: the active phosphorylating respiration in the presence of CI substrates.
- OXPHOSCI+CII: the active maximal phosphorylating respiration in the presence of CI and CII substrates.
- State 4CI+CII: the basal/leak respiration dependent on both CI and CII substrates in a non-phosphorylating state—after inhibition of ATP synthase.
- ETSCI+CII: mitochondrial respiration in a fully uncoupled state that reveals the maximal electron transport system capacity:
- ROX: the non-mitochondrial residual oxygen consumption—after CI and CIII inhibition by rotenone and antimycin A, respectively.
Data Acquisition and Statistical Analysis
2.10. HET-CAM Assay
3. Results and Discussion
3.1. In Vitro Dissolution Test
3.2. X-ray Diffraction
3.3. Thermal Analysis
3.4. FTIR Spectroscopy
3.5. FLU and MEB Exert Dose-Dependent Cytotoxic Effects
3.6. Molecular Docking
3.7. High-Resolution Respirometry Studies in Permeabilized Cells
3.8. CAM Assay
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
References
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Protein | PDB ID | Grid Box Center Coordinates | Grid Box Size | Conformers Generated Per Ligand |
---|---|---|---|---|
Apoptosis regulator Bcl-2 (Bcl-2) | 2W3L | center_x = 38.8892 center_y = 27.0675 center_z = −12.5145 | size_x = 13.7411 size_y = 11.5648 size_z = 9.6457 | 8 |
Apoptosis regulator Bcl-X (Bcl-XL) | 2YXJ | center_x = −8.8801 center_y = −14.5418 center_z = 10.0100 | size_x = 13.4584 size_y = 20.4060 size_z = 9.6457 | 8 |
Epidermal growth factor receptor 1 (EGFR1) | 4RJ8 | center_x = −53.5443 center_y = 1.1587 center_z = −25.1500 | size_x = 10.5346 size_y = 10.7549 size_z = 13.7560 | 8 |
Vascular endothelial growth factor receptor 2 | 3VHK | center_x = −27.5445 center_y = 26.9531 center_z = 16.6738 | size_x = 10.0752 size_y = 11.0246 size_z = 11.6961 | 8 |
RAC-alpha serine/threonine-protein kinase (AKT1) | 3CQU | center_x = 5.2027 center_y = 2.2676 center_z = 17.5609 | size_x = 14.7068 size_y = 14.4124 size_z = 9.3509 | 8 |
Mammalian target of rapamycin- target of rapamycin complex subunit LST8 (mTOR-LST8) | 4JT5 | center_x = 52.1512 center_y = −0.7990 center_z = −49.2709 | size_x = 14.3371 size_y = 11.0246 size_z = 810.8186 | 8 |
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (PI3Kγ) | 4FA6 | center_x = 45.2920 center_y = 14.3911 center_z = 31.0579 | size_x = 14.6994 size_y = 10.7549 size_z = 10.8186 | 8 |
Dual specificity mitogen-activated protein kinase 1 (MEK1) | 3EQG | center_x = −3.5569 center_y = 57.7644 center_z = 34.5863 | size_x = 14.7068 size_y = 10.9225 size_z = 9.7322 | 8 |
Mitogen-activated protein kinase 1 (ERK2) | 4G6N | center_x = 21.5960 center_y = 5.8329 center_z = 15.3508 | size_x = 14.4689 size_y = 11.4524 size_z = 10.8186 | 8 |
Bcl-2 | Bcl-XL | EGFR1 | VEGFR2 | AKT1 | mTOR | PI3K | MEK1 | ERK2 | |
---|---|---|---|---|---|---|---|---|---|
Free Binding Energy ∆G (kcal/mol) | |||||||||
Native ligand | −10.3 | −10 | −8.8 | −9.7 | −10.5 | −8.5 | −9.3 | −8.7 | −7.5 |
FLU | −7 | −8.3 | −7.5 | −9.6 | −8.9 | −8.2 | −8.2 | −9.4 | −7.7 |
MEB | −7 | −7.9 | −7.5 | −9.3 | −9.1 | −8.7 | −8 | −9.3 | −7.7 |
Samples | Irritation Score | Type of Effect |
---|---|---|
SLS 0.5% | 18.56 | Strong irritant |
HPBCD 10 mM | 0.0 | Non-irritant |
FLU 10 mM | 0.0 | Non-irritant |
FLU-HPBCD 10 mM | 0.0 | Non-irritant |
MEB 10 mM | 0.0 | Non-irritant |
MEB-HPBCD | 0.0 | Non-irritant |
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Minda, D.; Mioc, A.; Banciu, C.; Soica, C.; Racoviceanu, R.; Mioc, M.; Macasoi, I.; Avram, S.; Voicu, A.; Motoc, A.; et al. Cyclodextrin Dispersion of Mebendazole and Flubendazole Improves In Vitro Antiproliferative Activity. Processes 2021, 9, 2185. https://doi.org/10.3390/pr9122185
Minda D, Mioc A, Banciu C, Soica C, Racoviceanu R, Mioc M, Macasoi I, Avram S, Voicu A, Motoc A, et al. Cyclodextrin Dispersion of Mebendazole and Flubendazole Improves In Vitro Antiproliferative Activity. Processes. 2021; 9(12):2185. https://doi.org/10.3390/pr9122185
Chicago/Turabian StyleMinda, Daliana, Alexandra Mioc, Christian Banciu, Codruța Soica, Roxana Racoviceanu, Marius Mioc, Ioana Macasoi, Stefana Avram, Adrian Voicu, Andrei Motoc, and et al. 2021. "Cyclodextrin Dispersion of Mebendazole and Flubendazole Improves In Vitro Antiproliferative Activity" Processes 9, no. 12: 2185. https://doi.org/10.3390/pr9122185