Globospiramine from Voacanga globosa Exerts Robust Cytotoxic and Antiproliferative Activities on Cancer Cells by Inducing Caspase-Dependent Apoptosis in A549 Cells and Inhibiting MAPK14 (p38α): In Vitro and Computational Investigations
Abstract
:1. Introduction
2. Materials and Methods
2.1. Test Compounds and Culture Conditions
2.2. In Vitro Cytotoxicity and Antiproliferative Activity Assessment
2.2.1. MTT Assay
2.2.2. CellTiter-Blue® Assay
2.2.3. SRB Viability Assay
2.3. Apoptosis Assays
2.3.1. Caspase–Glo® 3/7 Apoptosis Assay
2.3.2. CellEventTM Caspase 3/7 and TMRM Staining
2.4. Western Blot Analysis
2.5. HeLa Cell Membrane Permeability Assay
2.6. Network Pharmacology Analysis
2.6.1. Prediction of Target Genes
2.6.2. Protein–Protein Interaction Analysis
2.6.3. GO and KEGG Pathway Enrichment Analyses
2.7. Molecular Docking to MAPK14 (p38α)
2.8. Molecular Dynamics (MD) Simulation
2.9. Profiling of Drug-Likeness and Toxicity Risks
2.10. Statistical Analysis
3. Results
3.1. Alkaloids 1–3, Especially 1, Exhibits In Vitro Cytotoxic and Antiproliferative Activities
3.2. Globospiramine (1) Induces Caspase-Dependent Apoptosis in A549 Cells in a Concentration-Dependent Manner
3.3. Globospiramine (1) Did Not Cause Rapid Loss of Membrane Integrity in HeLa Cells
3.4. MAPK14 (p38α) as the Putative Molecular Target of Globospiramine (1) Based on Network Pharmacology and Molecular Docking
3.5. Molecular Dynamics Simulations Showed Stability of Globospiramine (1) Inside the MAPK14 or p38α Binding Domain
3.6. Globospiramine (1) Was Predicted to Have No Toxicity Risks and Favorable Drug-Likeness
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Cell Lines | Test Compounds | Positive Controls | |||
---|---|---|---|---|---|
Globospiramine (1) | Deoxyvobtusine (2) | Vobtusine Lactone (3) | Epothilone B | Imatinib | |
Cytotoxicity IC50 (µM) | MTT Assay | |||||
L929 | 0.05 | 40.93 | 4.64 | 0.001 | - |
KB3.1 (HeLa derivative) | 0.22 | 11.60 | 4.64 | 3.27 × 10−5 | - |
A431 | 0.18 | >50 | 10.23 | 0.0001 | - |
MCF-7 | 0.11 | >50 | 5.46 | 9.55 × 10−5 | - |
A549 | 0.18 | >50 | 10.64 | 4.23 × 10−5 | - |
PC-3 | 0.01 | >50 | 2.32 | 5.87 × 10−5 | - |
SKOV-3 | 0.08 | >50 | 11.05 | 0.0001 | - |
Antiproliferative activity GI50 (µM) | CellTiter Blue Assay | |||||
HUVEC | 7.37 | >50 | 22.10 | - | 14.87 |
K-562 | 1.91 | >50 | 7.64 | - | 0.14 |
Test Compounds | Cell Lines IC50 (uM) | |||||
---|---|---|---|---|---|---|
HCC1806 | HCC1937 | MDA-MB-453 | MDA-MB-231 | BT-549 | HeLa | |
Globospiramine (1) | 0.154 | 0.282 | 0.546 | 0.387 | 0.470 | 0.300 |
Paclitaxel | 0.014 | >0.16 | 0.002 | 0.028 | >0.16 | - |
Combrestatin A4 | >0.1 | >0.1 | >0.1 | 0.038 | >0.1 | 0.003 |
Targets | BE (kcal/mol) | Interactions | BE (kcal/mol) Positive Control |
---|---|---|---|
RAC-α serine/threonine-protein kinase (AKT1) | −9.2 | Thr160, Thr291, Asn279 (H-bond), Phe442 (pi-pi T-shaped), Glu234 (salt bridge, C-H bond), Gly159 (C-H bond), Asp292 (pi-anion), Leu295 (pi-alkyl) | −8.6 a |
RAC-β Serine/Threonine-Protein Kinase (AKT2) | −2.9 | Ly160 (H-bond), Asp440, Phe163, Glu279 (attractive charge), Glu279 (C-H bond) | |
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit α isoform–chain A (PIK3CA) | −8.5 | Asp926, Arg281 (attractive charge, pi-cation), Arg852, Val851 (alkyl) | −8.7 b |
Mitogen-activated protein kinase 14 (p38α) | −9.8 | Val30 (alkyl, pi-alkyl, C-H bond), Gly33 (C-H bond) | −8.1 c |
Tumor necrosis factor Receptor 1 (TNRF1) | −7.9 | Val95, Arg92, Ala61 (alkyl, pi-alkyl), Ser108 (C-H bond) | −9.9 d |
Tumor necrosis factor Receptor 2 (TNRF2) | −9.0 | Lys120 (H-bond), Pro117 (alkyl, pi-alkyl, C-H bond), Arg119 (alkyl, pi-alkyl), Arg122 (pi-cation), Leu118 (unfavorable positive-positive, vdW) | −6.5 e |
Physicochemical Properties | Accepted/Threshold Values | Predicted Values for |
---|---|---|
Rotatable bonds | ≤ 10 | 3 |
TPSA (Å2) | ≤140 | 113.04 |
Drug-likeness based on VR | Yes (no violation) | |
Pharmacokinetic Profile | ||
GI absorption | High | |
BBB-permeant | No | |
Toxicity Risks | ||
Mutagenicity | None | |
Tumorigenicity | None | |
Irritant toxicity | None | |
Reproductive toxicity | None |
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© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
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Manzano, J.A.H.; Abellanosa, E.A.; Aguilar, J.P.; Brogi, S.; Yen, C.-H.; Macabeo, A.P.G.; Austriaco, N. Globospiramine from Voacanga globosa Exerts Robust Cytotoxic and Antiproliferative Activities on Cancer Cells by Inducing Caspase-Dependent Apoptosis in A549 Cells and Inhibiting MAPK14 (p38α): In Vitro and Computational Investigations. Cells 2024, 13, 772. https://doi.org/10.3390/cells13090772
Manzano JAH, Abellanosa EA, Aguilar JP, Brogi S, Yen C-H, Macabeo APG, Austriaco N. Globospiramine from Voacanga globosa Exerts Robust Cytotoxic and Antiproliferative Activities on Cancer Cells by Inducing Caspase-Dependent Apoptosis in A549 Cells and Inhibiting MAPK14 (p38α): In Vitro and Computational Investigations. Cells. 2024; 13(9):772. https://doi.org/10.3390/cells13090772
Chicago/Turabian StyleManzano, Joe Anthony H., Elian Angelo Abellanosa, Jose Paolo Aguilar, Simone Brogi, Chia-Hung Yen, Allan Patrick G. Macabeo, and Nicanor Austriaco. 2024. "Globospiramine from Voacanga globosa Exerts Robust Cytotoxic and Antiproliferative Activities on Cancer Cells by Inducing Caspase-Dependent Apoptosis in A549 Cells and Inhibiting MAPK14 (p38α): In Vitro and Computational Investigations" Cells 13, no. 9: 772. https://doi.org/10.3390/cells13090772
APA StyleManzano, J. A. H., Abellanosa, E. A., Aguilar, J. P., Brogi, S., Yen, C.-H., Macabeo, A. P. G., & Austriaco, N. (2024). Globospiramine from Voacanga globosa Exerts Robust Cytotoxic and Antiproliferative Activities on Cancer Cells by Inducing Caspase-Dependent Apoptosis in A549 Cells and Inhibiting MAPK14 (p38α): In Vitro and Computational Investigations. Cells, 13(9), 772. https://doi.org/10.3390/cells13090772