Revealing the Potential Application of EC-Synthetic Retinoid Analogues in Anticancer Therapy
Abstract
:1. Introduction
2. Results
2.1. EC19 and EC23 Induce Cell Death In Vitro
2.2. Synergistic Effect of Retinoids and 5-Fluorouracil (5-FU) in Caco-2 Cells
2.3. Apoptotic Effects of Retinoids in Caco-2 Cells
2.4. Synthetic Retinoids Induce Cell Cycle Arrest and Reduce Cellular Proliferation
2.5. Effect of ATRA and Synthetic Retinoids on Cell Invasion
2.6. EC19 Reduced Intracellular Glutamate in Caco-2 Cells
2.7. EC19 and EC23 Reduce the Antioxidant Capacity of Caco-2 Cells
2.8. Gene Expression Analysis of Multiple Signaling Genes Affected by ATRA and EC-Synthetic Retinoids Treatments in Caco-2 Cells
2.8.1. Gene Expression Analysis of Retinoic Acid Receptors (RARs)
2.8.2. Gene Expression Analysis of Key Apoptosis-Related Genes
2.8.3. Gene Expression Analysis of Retinoic Acid-Induced 2 (RAI2) Expression in Caco-2 Cells
2.8.4. Gene Expression Analysis of WRN Expression in Caco-2 Cells
2.8.5. Gene Expression of Migration-Related Genes in Caco-2 Cells
2.9. Western Blotting Analysis of Key Apoptosis-Related Proteins
2.10. Morphological and Immunocytochemistry Analysis of Caco-2 Cells Treated with Synthetic EC-Retinoids
3. Discussion
3.1. Potent Antiproliferation with Minimal Cytotoxicity of EC-Synthetic Retinoids
3.2. Caco-2 Cells is In Vitro Model for Further Anticancer Screening
3.3. A Promising Synergistic Combination with 5-FU in Caco-2 Cells
3.4. The Antiproliferative Effect of EC19 and EC23 in Caco-2 Cells is Due to Early Apoptosis and Cell Cycle Arrest
3.5. Differential Transactivation of RARs Explains the Differential Sensitivity of Caco-2 Cells
3.6. Phenotypic Perturbations Seen under Microscope are Pertinent to Apoptosis Induction
3.7. The Molecular Changes of EC-Synthetic Retinoids on Transcriptomic and Proteomic Levels
3.8. The Modulation of Cyt-C Expression with EC-Synthetic Retinoids Treatment is Indicative of Intrinsic Apoptosis Induction
3.9. EC19-Induced Apoptosis in Caco-2 Cells Involves the Induction of p53 Protein Expression
3.10. The Reduction of the Intracellular Glutamate Pool May Further Explain the Superior Activity of EC19 over EC23 in Caco-2 Cells
3.11. EC-Synthetic Retinoids are Pro-Oxidants that Promote Cellular Vulnerability to Oxidative Stress
3.12. Retinoids Reduce the Metastatic Potential of Caco-2 Cells via Modifying the Expression of Relevant Genes
4. Materials and Methods
4.1. Retinoids Solution
4.2. Cell Culture
4.3. Antiproliferation assay and Selectivity Index (SI) Calculation
4.4. Isobologram Analysis of Combined Drug Effect
4.5. Detection of Apoptosis Using Annexin V (AV)/Propidium Iodide (PI) Assay
4.6. Cell Cycle Analysis
4.7. Gene Expression Analysis of Multiple Signaling Key Genes
4.8. Western Blotting
4.9. Cell Invasion Assay
4.10. Measurement of Intracellular and Secreted Glutamate
4.11. Total Antioxidant Capacity (TAC)
4.12. Immunocytochemistry (ICC) and Detection of Morphological Changes
4.13. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Sample Availability
References
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Cell Line | * IC50 (µM) ± SEM and Corresponding SI | |||||
---|---|---|---|---|---|---|
ATRA | EC19 | EC23 | ||||
IC50 | SI | IC50 | SI | IC50 | SI | |
WI-38 | 34.0 ± 1.1 | 1 | 48.4 ± 1.2 | 1 | 8.01 ± 0.13 | 1 |
Vero | >100 | 1 | >100 | 1 | 35.23 ± 1.02 | 1 |
HepG2 | 36.2 ± 1.9 | 0.94 ± 0.02 | 42.2 ± 0.92 | 1.2 ± 0.002 | 0.74 ± 0.001 | 10.82 ± 1.0 |
Huh7 | >100 | <1 | >100 | 0.14 ±0.01 | >100 | 0.02 ± 0.001 |
Caco-2 | 58.0 ± 1.0 | 0.59 ± 0.01 | 10.8 ± 0.1 | 4.5 ± 0.01 | 14.7 ± 0.73 | 0.54 ±0.01 |
HCT-116 | >100 | <1 | >100 | <1 | 44.46 ± 1.1 | 0.18 ± 0.003 |
HT-29 | 0.002 ± 0.01 | >1 | >100 | <1 | >100 | <1 |
MCF-7 | 99 ± 0.26 | 0.34 ± 0.01 | 9.4 ± 0.13 | 5.18 ± 0.1 | 5.56 ± 0.01 | 1.44 ± 0.004 |
MDA-MB 231 | >100 | <1 | >100 | <1 | >100 | <1 |
DU-145 | >100 | <1 | 86.9 ± 2.0 | 0.56 ± 0.001 | >100 | <1 |
PC3 | >100 | <1 | >100 | <1 | >100 | <1 |
A549 | 84.7 ± 3.2 | 0.4 ± 0.01 | >100 | <1 | >100 | <1 |
Drug | IC50 (µM) | ×IC50 (µM) (Combination) with 5-FU | Individual IC50 (µM) (Combination) | DRI | CI | |
---|---|---|---|---|---|---|
5-FU | Retinoid | |||||
5-FU | 18.4 ± 0.6 | ---------------------------------------------------------- | ||||
ATRA | 58 ± 1.0 | 0.15 ± 0.01 | 2.8 ± 0.3 | 8.7 ± 0.9 | 6.9 ± 0.7 | 0.29 ± 0.03 ** |
EC19 | 10.8 ± 0.1 | 0.229 ± 0.03 | 4.21 ± 0.6 | 2.47 ± 0.3 | 4.5 ± 0.6 | 0.46 ± 0.06 ** |
EC23 | 14.7 ± 0.7 | 0.136 ± 0.02 | 2.5 ± 0.3 | 2 ± 0.2 | 7.5 ± 0.8 | 0.27 ± 0.03 ** |
Apoptosis Analysis of Caco-2 Cell Line | 12 h Treatment | 24 h Treatment | ||||||
---|---|---|---|---|---|---|---|---|
Control | ATRA | EC19 | EC23 | Control | ATRA | EC19 | EC23 | |
% viable cells (C−−) | 80.30 ± 7.9 | 87.99 ± 15.0 | 93.65 ± 14.0 | 91.61 ± 13.7 | 78.83 ± 6.4 | 52.4 ± 11.5 * | 24.5 ± 11.8 *** | 34.4 ± 18.3 *** |
% early apoptotic cells (C+−) | 19.61 ± 5.5 | 11.99 ± 1.9 | 6.30 ± 1.1 | 8.34 ± 1.1 | 20.20 ± 2.8 | 47.4 ± 2.5 ** | 75.3 ± 13.8 *** | 65.4 ± 18.4 *** |
% late apoptotic cells (C−+) | 0.00 | 0.00 | 0.01 | 0.01 | 0.0 | 0.0 | 0.0 | 0.0 |
% necrotic cells (C++) | 0.08 | 0.01 | 0.4 ± 0.1 | 0.05 | 0.95 ± 0.18 | 0.28± 0.17 | 0.18 ± 0.05 | 0.16 ± 0.14 |
% Apoptotic index (AI) | 20 | 12 | 6.3 | 8.3 | 18 | 63 | 84 | 89 |
Cell Cycle Analysis of Caco-2 Cell Line | Control | 12 h Treatment | 24 h Treatment | ||||
---|---|---|---|---|---|---|---|
ATRA | EC19 | EC23 | ATRA | EC19 | EC23 | ||
% SubG0-G1 | 0.24 ± 0.1 | 0.14 ± 0.1 | 0.29 ± 0.1 | 0.46 ± 0.1 | 1.6 ± 0.19 *** | 4.5 ± 0.6 *** | 3.9 ± 0.43 *** |
% G0-G1 | 67.2 ± 10.1 | 26.1 ± 3.6 | 39.1 ± 6.7 | 58.7 ± 8.2 | 37.1 ± 4.5 | 29.0 ± 4.1 | 32.7 ± 4.6 |
% S | 30.8 ± 1.1 | 57.5 ± 8.1 * | 51.5 ± 7.2 * | 34.0 ± 4.1 | 29.5 ± 3.5 | 44.0 ± 8.2 ** | 47.6 ± 9.1 ** |
% G2M | 1.74 ± 10.1 | 16.3 ± 1.9 * | 9.1 ± 1.3 * | 6.8 ± 0.8 * | 31.8 ± 4.8 *** | 22.5 ± 3.1 *** | 15.8 ± 1.9 *** |
%G2M/G0-G1 | 2.6 ± 0.2 | 62.5 ± 8.8 ** | 23.4 ± 2.8 * | 11.6 ± 1.7 * | 85.7 ± 16.3 *** | 77.6 ± 10.8 *** | 48.3 ± 6.8 ** |
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Abdelaal, M.R.; Soror, S.H.; Elnagar, M.R.; Haffez, H. Revealing the Potential Application of EC-Synthetic Retinoid Analogues in Anticancer Therapy. Molecules 2021, 26, 506. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26020506
Abdelaal MR, Soror SH, Elnagar MR, Haffez H. Revealing the Potential Application of EC-Synthetic Retinoid Analogues in Anticancer Therapy. Molecules. 2021; 26(2):506. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26020506
Chicago/Turabian StyleAbdelaal, Mohamed R., Sameh H. Soror, Mohamed R. Elnagar, and Hesham Haffez. 2021. "Revealing the Potential Application of EC-Synthetic Retinoid Analogues in Anticancer Therapy" Molecules 26, no. 2: 506. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26020506