Cerivastatin Synergizes with Trametinib and Enhances Its Efficacy in the Therapy of Uveal Melanoma
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Method
2.1. Cancer Cell Lines
2.2. Reagents
2.3. Drug Screening Assay
2.4. Cell Cycle Analysis
2.5. Annexin V-FITC/PI Apoptosis Analysis
2.6. Western Blotting Analysis
2.7. Xenograft Mouse Model
2.8. Microarray
2.9. Statistical Analysis
3. Results
3.1. Anti-Proliferative Activity of MEK and YAP/TAZ Inhibitors in UM Cell Lines
3.2. In Vitro Anti-Proliferative Activity of Trametinib-Based Combinations, in UM Cell Lines
3.3. The Combination of Trametinib and Cerivastatin Induces Apoptosis and Cell Cycle Arrest in UM Cell Lines
3.4. Trametinib and Cerivastatin Synergistic Concentrations Increase Apoptosis and Decrease Survival/Proliferation Pathways
3.5. Trametinib and Cerivastatin Synergistic Concentrations Down-Modulate Genes Involved in Cell Cycle Regulation and DNA Replication
3.6. Trametinib and Cerivastatin Synergistic Concentrations Inhibit the Growth of the Monosomic BAP1 Mutated UM Cell Line In Vivo
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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Name | Origin | GNAQ | GNA11 | BAP1 | chr3 Status | Reference |
---|---|---|---|---|---|---|
92.1 | primary | Q209L | WT | WT | trisomic | [34] |
MEL270 | primary $ | Q209P | WT | WT | disomic | [35] |
OMM1 | metastatic | Q209L | Q209L | WT | disomic | [36] |
OMM2.5 | metastatic $ | Q209P | WT | WT | disomic | [37] |
UPMM2 | primary | Q209L | WT | I586H fs * 57 | monosomic | [38] |
UPMM3 | primary | Q209P | WT | G45F48del | monosomic | [38] |
OMM2.5 | UPMM3 | MEL270 | 92.1 | OMM1 | UPMM2 | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Drug | Class | Unit | IC50 | SEM | IC50 | SEM | IC50 | SEM | IC50 | SEM | IC50 | SEM | IC50 | SEM |
trametinib | MEK-inhibitor | nM | 171.60 | ±44 | 16.39 | ±6 | 5.00 | ±1.4 | 9.90 | ±4.8 | 6500.00 | ±3983 | 8.10 | ±3 |
valproic acid | HDAC-inhibitor | mM | 40.90 | ±26.5 | 2.77 | ±93 | 10.88 | ±2.56 | 3.39 | ±0.98 | 9.56 | ±2.73 | 23.24 | ±2.34 |
verteporfin | Photosensitizer | µM | 8.22 | ±3.88 | 30.24 | ±1.44 | 18.67 | ±0.9 | 16.55 | ±0.788 | 13.15 | ±4.75 | 720.60 | ±703.5 |
cerivastatin | Statin | µM | 0.99 | ±0.16 | 0.35 | ±0.1 | 0.40 | ±0.09 | 1.56 | ±0.26 | 0.06 | ±0.02 | 0.38 | ±0.12 |
atorvastatin | Statin | µM | 62.11 | ±46.45 | 116.50 | ±96.26 | 137.30 | ±55.17 | na | na | 5.63 | ±0.62 | 50.75 | ±20.84 |
simvastatin | Statin | µM | 8.29 | ±0.8 | 8.32 | ±1.12 | 15.57 | ±5.9 | 115.40 | ±32.6 | 2.83 | ±0.34 | 36.17 | ±14.6 |
A: Trametinib and Valproic Acid (VPA) | |||||
Cell Line | Trametinib | VPA | Trametinib | VPA | Combination Index |
IC50 | Synergistic Concentration | ||||
nM | mM | nM | mM | ||
92.1 | 14.60 | 5.56 | 3.64 | 1.00 | 0.43 |
Mel270 | 7.13 | 14.65 | 2.24 | 1.00 | 0.38 |
Mel270 | 7.13 | 14.65 | 1.77 | 2.00 | 0.38 |
UPMM3 | 20.38 | 1.84 | 13.02 | 0.25 | 0.77 |
UPMM3 | 20.38 | 1.84 | 9.61 | 0.50 | 0.74 |
UPMM3 | 20.38 | 1.84 | 2.39 | 1.00 | 0.65 |
B: Trametinib and Verteporfin | |||||
Cell Line | Trametinib | Verteporfin | Trametinib | Verteporfin | Combination Index |
IC50 | Synergistic Concentration | ||||
nM | µM | nM | µM | ||
92.1 | 26.74 | 15.76 | 0.15 | 10.00 | 0.63 |
Mel270 | 1.20 | 17.78 | 0.00 | 10.00 | 0.56 |
UPMM3 | 11.08 | 28.84 | 0.43 | 10.00 | 0.39 |
UPMM3 | 11.08 | 28.84 | 0.55 | 14.00 | 0.53 |
C: Trametinib and Cerivastatin | |||||
Cell Line | Trametinib | Cerivastatin | Trametinib | Cerivastatin | Combination Index |
IC50 | Synergistic Concentration | ||||
nM | µM | nM | µM | ||
UPMM2 | 19.53 | 2.66 | 10.20 | 0.50 | 0.70 |
UPMM2 | 19.53 | 2.66 | 6.15 | 1.00 | 0.68 |
UPMM3 | 26.31 | 0.77 | 6.00 | 0.25 | 0.54 |
UPMM3 | 26.31 | 0.77 | 0.27 | 0.50 | 0.66 |
OMM2.5 * | 2286.00 | 1.11 | 71.00 | 0.25 | 0.25 |
OMM2.5 * | 2286.00 | 1.11 | 21.00 | 0.50 | 0.44 |
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Amaro, A.A.; Gangemi, R.; Emionite, L.; Castagnola, P.; Filaci, G.; Jager, M.J.; Tanda, E.T.; Spagnolo, F.; Mascherini, M.; Pfeffer, U.; et al. Cerivastatin Synergizes with Trametinib and Enhances Its Efficacy in the Therapy of Uveal Melanoma. Cancers 2023, 15, 886. https://doi.org/10.3390/cancers15030886
Amaro AA, Gangemi R, Emionite L, Castagnola P, Filaci G, Jager MJ, Tanda ET, Spagnolo F, Mascherini M, Pfeffer U, et al. Cerivastatin Synergizes with Trametinib and Enhances Its Efficacy in the Therapy of Uveal Melanoma. Cancers. 2023; 15(3):886. https://doi.org/10.3390/cancers15030886
Chicago/Turabian StyleAmaro, Adriana Agnese, Rosaria Gangemi, Laura Emionite, Patrizio Castagnola, Gilberto Filaci, Martine J. Jager, Enrica Teresa Tanda, Francesco Spagnolo, Matteo Mascherini, Ulrich Pfeffer, and et al. 2023. "Cerivastatin Synergizes with Trametinib and Enhances Its Efficacy in the Therapy of Uveal Melanoma" Cancers 15, no. 3: 886. https://doi.org/10.3390/cancers15030886
APA StyleAmaro, A. A., Gangemi, R., Emionite, L., Castagnola, P., Filaci, G., Jager, M. J., Tanda, E. T., Spagnolo, F., Mascherini, M., Pfeffer, U., & Croce, M. (2023). Cerivastatin Synergizes with Trametinib and Enhances Its Efficacy in the Therapy of Uveal Melanoma. Cancers, 15(3), 886. https://doi.org/10.3390/cancers15030886