Rare Stochastic Expression of O6-Methylguanine- DNA Methyltransferase (MGMT) in MGMT-Negative Melanoma Cells Determines Immediate Emergence of Drug-Resistant Populations upon Treatment with Temozolomide In Vitro and In Vivo
Abstract
:1. Introduction
2. Materials and Methods
2.1. Pharmacological Agents
2.2. Cell Lines
2.3. Colony Formation Assay
2.4. Generating Mass Cultures of TMZ-Treated Cells
2.5. Treatment with 5-Azacytidine
2.6. Immunoblots
2.7. MethyLight Analysis
2.8. Animal Model
2.9. Tissue Analysis
2.10. Statistical Analysis
3. Results
3.1. Sensitivity to TMZ Correlates with MGMT Protein Levels
3.2. MGMT-Negative, but Not MGMT-Positive, Cell Populations Adjust to TMZ Treatment
3.3. TMZ Resistance Emerges after Single Drug Treatment Even at Low Concentration
3.4. MGMT-Positive Cells Exist within an MGMT-Negative Population
3.5. MGMT Expression Is Not Regulated by Promoter Methylation
3.6. Other Resistance Mechanisms Are Present, but Are Considerably Rarer
3.7. Repeated TMZ Treatment Accelerates the Emergence of Resistance
3.8. Emergence of MGMT-Driven TMZ Resistance Occurs In Vivo
4. Discussion
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
5-AzaC | 5-Aza-deoxycytidine |
CFA | Colony-formation assay |
MGMT | O6-methylguanine-DNA methyltransferase |
MMR | Mismatch repair |
O6BG | O6-Benzylguanine |
TMZ | Temozolomide |
WB | Western blot |
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Chen, T.C.; Chan, N.; Minea, R.O.; Hartman, H.; Hofman, F.M.; Schönthal, A.H. Rare Stochastic Expression of O6-Methylguanine- DNA Methyltransferase (MGMT) in MGMT-Negative Melanoma Cells Determines Immediate Emergence of Drug-Resistant Populations upon Treatment with Temozolomide In Vitro and In Vivo. Cancers 2018, 10, 362. https://doi.org/10.3390/cancers10100362
Chen TC, Chan N, Minea RO, Hartman H, Hofman FM, Schönthal AH. Rare Stochastic Expression of O6-Methylguanine- DNA Methyltransferase (MGMT) in MGMT-Negative Melanoma Cells Determines Immediate Emergence of Drug-Resistant Populations upon Treatment with Temozolomide In Vitro and In Vivo. Cancers. 2018; 10(10):362. https://doi.org/10.3390/cancers10100362
Chicago/Turabian StyleChen, Thomas C., Nymph Chan, Radu O. Minea, Hannah Hartman, Florence M. Hofman, and Axel H. Schönthal. 2018. "Rare Stochastic Expression of O6-Methylguanine- DNA Methyltransferase (MGMT) in MGMT-Negative Melanoma Cells Determines Immediate Emergence of Drug-Resistant Populations upon Treatment with Temozolomide In Vitro and In Vivo" Cancers 10, no. 10: 362. https://doi.org/10.3390/cancers10100362