5-Fluorouracil in Combination with Calcium Carbonate Nanoparticles Loaded with Antioxidant Thymoquinone against Colon Cancer: Synergistically Therapeutic Potential and Underlying Molecular Mechanism
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Preparation of CaCO3 NPs from Cockle Shells
2.3. Synthesis and Optimization of TQ-CaCO3 NPs
2.4. Physicochemical Characterization of CaCO3 NPs and TQ-CaCO3 NPs
2.4.1. Electron Microscopy and Zetasizer
2.4.2. Energy-Dispersive X-ray Spectroscopy, X-ray Diffractometer, and Fourier Transform Infrared Spectroscopy
2.5. In Vitro Compound Release Study
2.6. Biocompatibility Evaluation of CaCO3 NPs and TQ-CaCO3 NPs
2.6.1. Hemocompatibility Analysis
2.6.2. Toxicity Analysis in Brine Shrimp
2.6.3. Cytotoxicity Analysis
2.7. In Vitro Cell Experiments of TQ-CaCO3 NPs in Combination with 5-FU
2.7.1. MTT Assay
2.7.2. Synergism Analysis
2.7.3. Colony-Formation Assay
2.7.4. AO/PI Staining
2.7.5. Cell Cycle and Apoptosis Analysis
2.7.6. Wound-Healing Assay
2.7.7. The 3D Spheroid Culture
2.7.8. The 3D Spheroid-Inhibition Assay
2.8. Network Pharmacology
2.8.1. Target Prediction and Screening of 5-FU and TQ
2.8.2. Targets Collection and Screening of Colon Cancer
2.8.3. PPI, GO, and KEGG Analysis
2.9. Molecule Docking
2.10. Statistical Analysis
3. Results
3.1. Synthesis of the Optimal TQ-CaCO3 NPs
3.2. Characterization of CaCO3 NPs and TQ-CaCO3 NPs
3.3. CaCO3 NPs and TQ-CaCO3 NPs Exhibit Favorable Biocompatibility
3.4. TQ-CaCO3 NPs in Combination with 5-FU Inhibits the Proliferation of CT26 Cells
3.5. TQ-CaCO3 NPs in Combination with 5-FU Induces Cell Cycle Arrest and Apoptosis in CT26 Cells
3.6. TQ-CaCO3 NPs in Combination with 5-FU Inhibits the Migration of CT26 Cells
3.7. TQ-CaCO3 NPs in Combination with 5-FU Suppresses the Growth of CT26 Spheroids
3.8. Network Pharmacology
3.8.1. Potential Targets of Drugs and Colon Cancer
3.8.2. PPI Network and GO Functional Annotation
3.8.3. KEGG Pathway Enrichment Analysis
3.9. Molecular Docking
4. Discussion
5. Conclusion
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Nanoparticles | C (%) | O (%) | Ca (%) | Na (%) | N (%) | F (%) |
---|---|---|---|---|---|---|
CaCO3 NPs | 16.06 | 62.42 | 21.27 | 0.25 | 0 | 0 |
TQ-CaCO3 NPs | 17.42 | 62.00 | 20.58 | 0 | 0 | 0 |
TQ | 79.58 | 20.42 | 0 | 0 | 0 | 0 |
Nanoparticles | a (Å) | b (Å) | c (Å) | α (°) | β (°) | γ (°) | Crystallite Size (Å) | Crystallinity (%) |
---|---|---|---|---|---|---|---|---|
CaCO3 NPs | 4.96662 | 7.96480 | 5.74860 | 90 | 90 | 90 | 827 | 96.35 |
TQ-CaCO3 NPs | 4.96283 | 7.96530 | 5.74325 | 90 | 90 | 90 | 848 | 98.18 |
Peak Assignment | Wavenumber (cm−1) | |
---|---|---|
CaCO3 NPs | TQ-CaCO3 NPs | |
In-plane C-O bending | 707.47 | 707.47 |
Out of plane C-O bending | 854.80 | 851.60 |
Symmetric C-O stretching | 1082.21 | 1082.21 |
Asymmetric C-O stretching | 1450.53 | 1447.33 |
Symmetric C-O stretching; in-plane C-O bending | 1783.63 | 1783.63 |
Formulation | pH | Zero-Order Model R2 | First-Order Model R2 | Higuchi Model R2 | Hixon–Crowell Model R2 | Korsmeyer–Peppas Model | |
---|---|---|---|---|---|---|---|
R2 | n | ||||||
TQ-CaCO3 NPs | 7.4 | 0.95013 | 0.94527 | 0.98353 | 0.95486 | 0.98578 | 0.57060 |
6.5 | 0.92144 | 0.95302 | 0.98363 | 0.93512 | 0.98266 | 0.53670 | |
5.0 | 0.90526 | 0.92793 | 0.98557 | 0.92571 | 0.98765 | 0.45530 |
Targets | PDB ID | Ligands | Binding Energy (kcal/Mol) |
---|---|---|---|
MAP2K2 | 1S9I | 5-FU | −4.89 |
TQ | −6.12 | ||
CASP3 | 3KJF | 5-FU | −4.45 |
TQ | −4.57 | ||
PIK3CA | 5DXT | 5-FU | −4.80 |
TQ | −5.40 | ||
ESR1 | 6DFN | 5-FU | −5.07 |
TQ | −6.35 | ||
CYP3A4 | 8SO1 | 5-FU | −5.31 |
TQ | −6.79 | ||
CYP2C19 | 4GQS | 5-FU | −5.08 |
TQ | −6.25 | ||
CYP2C9 | 7RL2 | 5-FU | −5.19 |
TQ | −6.16 |
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Deng, X.; Yang, Z.; Chan, K.W.; Ismail, N.; Abu Bakar, M.Z. 5-Fluorouracil in Combination with Calcium Carbonate Nanoparticles Loaded with Antioxidant Thymoquinone against Colon Cancer: Synergistically Therapeutic Potential and Underlying Molecular Mechanism. Antioxidants 2024, 13, 1030. https://doi.org/10.3390/antiox13091030
Deng X, Yang Z, Chan KW, Ismail N, Abu Bakar MZ. 5-Fluorouracil in Combination with Calcium Carbonate Nanoparticles Loaded with Antioxidant Thymoquinone against Colon Cancer: Synergistically Therapeutic Potential and Underlying Molecular Mechanism. Antioxidants. 2024; 13(9):1030. https://doi.org/10.3390/antiox13091030
Chicago/Turabian StyleDeng, Xi, Zhongming Yang, Kim Wei Chan, Norsharina Ismail, and Md Zuki Abu Bakar. 2024. "5-Fluorouracil in Combination with Calcium Carbonate Nanoparticles Loaded with Antioxidant Thymoquinone against Colon Cancer: Synergistically Therapeutic Potential and Underlying Molecular Mechanism" Antioxidants 13, no. 9: 1030. https://doi.org/10.3390/antiox13091030