New Insights into the Anticancer Effects and Toxicogenomic Safety of Two β-Lapachone Derivatives
Abstract
:1. Introduction
2. Results
2.1. Cellular Cytotoxicity
2.2. Morphological Alterations in HeLa
2.3. Flow Cytometry Analysis
2.4. In Vitro and In Silico Analyses of Kinase Inhibition
2.5. Toxicogenomic Safety
3. Discussion
3.1. Cellular Cytotoxic
3.2. BV3 and BV5 Increased Apoptosis in HeLa Cells
3.3. BV3 and BV5 Can Inhibit Kinases
3.4. BV3 and BV5 Have Toxicogenetic Safety
4. Materials and Methods
4.1. Reagents
4.2. Molecules
4.3. Cell Lines
4.4. Cell Viability and Determination of IC50
4.5. Selectivity Index (SI)
4.6. Morphological Analyses
4.7. Evaluation of the Induction of Apoptosis or Necrosis
4.8. Protein Kinase Assays
4.9. Molecular Docking
4.10. In Vivo Assessment of Toxicogenetic Safety
4.10.1. Groups and Administration Protocol
4.10.2. Alkaline Comet Assay
4.10.3. Micronucleus Assay
4.11. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Compounds and Kinases’ Inhibition (% of Residual Activity) | ||||||
---|---|---|---|---|---|---|
BV3 | BV5 | β-lap | ||||
Kinase | 1 µM | 10 µM | 1 µM | 10 µM | 1 µM | 10 µM |
CDK5/p25 | ≥100 | 44 | ≥100 | 62 | 74 | 88 |
CDK9/CyclinT | ≥100 | 67 | ≥100 | 78 | ≥100 | 72 |
HASPIN | ≥100 | ≥100 | ≥100 | ≥100 | ≥100 | 91 |
PIM1 | ≥100 | 18 | 94 | 42 | 56 | 42 |
GSK3β | 58 | 7 | 64 | 24 | 67 | 43 |
CK1ε | ≥100 | 98 | 98 | 86 | ≥100 | 94 |
ABL1 | 52 | 35 | 83 | 56 | 83 | 81 |
JAK3 | −3 | −9 | 64 | 4 | 65 | 69 |
Compound | JAK3 (3LXK) | GSK3β (1Q4L) | ||
---|---|---|---|---|
Free Binding Energy (kcal/mol) | Amino Acids Interactions | Free Binding Energy (kcal/mol) | Amino Acids Interactions | |
BV3 | −10.25 | Leu828, Gly829, Lys830, Gly831, Asn832 Gly834, Val836, Ala853, Val884, Met902, Arg953, Leu956, Ala966, Asp967 and Gly969 | −9.40 | Ile62, Gly63, Asn64, Val70, Ala83, Lys85, Glu97, Val110, Leu132, Asp133, Thr134, Val135, Pro136, Thr138, Arg141, Gln185, Leu188, Cys199, Asp200 and Phe201 |
BV5 | −10.08 | Leu828, Gly829, Lys830, Gly831, Val836, Ala853, Val884, Met902, Arg911, Arg953, Leu956 and Ala966 | −9.48 | Ile62, Val70, Ala83, Lys85, Met101, Leu132, Thr134, Gln185, Leu188, Cys199 and Asp200 |
β-Lapachone | −8.21 | Leu828, Val836, Ala853, Leu905, Leu956 and Ala966 | −7.32 | Val70, Ala83, Val110, Leu132, Leu188, Cys199 and Asp200 |
Co-crystallized ligand * | −8.99 | Leu828, Ala853, Val884, Met902, Leu905, Cys909, Arg953, Asn954, Leu956 and Ala966 | −9.94 | Ile62, Val70, Ala83, Lys85, Val110, Leu132, Val135, Arg141, Gln185, Leu188 and Cys199 |
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De Lima, J.R.; Da Silva Góes, A.J.; De Oliveira Borba, E.F.; da Silva, M.A.; Caiana, R.R.A.; Rodrigues, M.d.D.; De Lima Silva, M.S.; Chagas, C.A.; Baratte, B.; Robert, T.; et al. New Insights into the Anticancer Effects and Toxicogenomic Safety of Two β-Lapachone Derivatives. Pharmaceuticals 2025, 18, 837. https://doi.org/10.3390/ph18060837
De Lima JR, Da Silva Góes AJ, De Oliveira Borba EF, da Silva MA, Caiana RRA, Rodrigues MdD, De Lima Silva MS, Chagas CA, Baratte B, Robert T, et al. New Insights into the Anticancer Effects and Toxicogenomic Safety of Two β-Lapachone Derivatives. Pharmaceuticals. 2025; 18(6):837. https://doi.org/10.3390/ph18060837
Chicago/Turabian StyleDe Lima, José Rivaldo, Alexandre José Da Silva Góes, Elizabeth Fernanda De Oliveira Borba, Meykson Alexandre da Silva, Rodrigo Ribeiro Alves Caiana, Maria do Desterro Rodrigues, Mariza Severina De Lima Silva, Cristiano Aparecido Chagas, Blandine Baratte, Thomas Robert, and et al. 2025. "New Insights into the Anticancer Effects and Toxicogenomic Safety of Two β-Lapachone Derivatives" Pharmaceuticals 18, no. 6: 837. https://doi.org/10.3390/ph18060837
APA StyleDe Lima, J. R., Da Silva Góes, A. J., De Oliveira Borba, E. F., da Silva, M. A., Caiana, R. R. A., Rodrigues, M. d. D., De Lima Silva, M. S., Chagas, C. A., Baratte, B., Robert, T., Bach, S., Ourliac-Garnier, I., Marchand, P., & Da Silva, T. G. (2025). New Insights into the Anticancer Effects and Toxicogenomic Safety of Two β-Lapachone Derivatives. Pharmaceuticals, 18(6), 837. https://doi.org/10.3390/ph18060837