Inhibition of PARP Sensitizes Chondrosarcoma Cell Lines to Chemo- and Radiotherapy Irrespective of the IDH1 or IDH2 Mutation Status
Abstract
:1. Introduction
2. Results
2.1. Chondrosarcoma Cell Lines Are Variably Sensitive to PARP Inhibition, Irrespective of the IDH Mutation Status
2.2. PARP Inhibition Minimally Induces Apoptosis and Causes a G2/M Phase Cell Cycle Arrest in Chondrosarcoma Cell Lines
2.3. JJ012 Cells Have a Reduced Capacity to Sense DNA Damage, Independent of the IDH1 Mutation
2.4. Chondrosarcoma Cell Lines Are Homologous Recombination Proficient and Maintain Nominal Expression of ATM
2.5. The Combination of PARP Inhibition and Temozolomide Is Synergistic in Chondrosarcoma Cell Lines
2.6. PARP Inhibition Sensitizes Chondrosarcoma Cells to Radiation Which is Partially Rescued when Mutant IDH1 is Inhibited
3. Discussion
4. Materials and Methods
4.1. Compounds
4.2. Cell Culture
4.3. Cell Viability and Nuclei Count Assays
4.4. Apoptosis Assay
4.5. Cell Cycle Assay
4.6. Western Blotting
4.7. RAD51 Foci Assay
4.8. Next Generation RNA Sequencing Analysis
4.9. Methylation Array Analysis
4.10. Colony Formation Assay
4.11. Statistical Calculations and Image Analysis
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Appendix A
References
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Cell Line | Chondrosarcoma Subtype | IDH Mutation Status | GR50 (nM) | IC50 (nM) | GRInf (%) | EInf (%) |
---|---|---|---|---|---|---|
NDCS1 | Dedifferentiated | Wildtype | 34 | 25 | −54 | 0 |
MCS170 | Mesenchymal | Wildtype | 75 | - | 7 | 57 |
SW1353 | Central conventional | IDH2 R172S | 133 | 63 | −25 | 3 |
HT1080 | Dedifferentiated | IDH1 R132C | 188 | 61 | 10 | 11 |
CH3573 | Central conventional | Wildtype | 244 | 471 | −2 | 26 |
L2975 | Dedifferentiated | IDH2 R172W | 326 | 401 | 1 | 22 |
JJ012 | Central conventional | IDH1 R132G | 371 | 193 | −23 | 1 |
JJ012 + AGI-5198 | Central conventional | “Wildtype” | 659 | 303 | −11 | 0 |
L3252B | Dedifferentiated | Wildtype | 876 | 1442 | −75 | 0 |
L835 | Central conventional | IDH1 R132C | 1670 | - | 12 | 68 |
CH2879 | Central conventional | Wildtype | 1726 | 1103 | −90 | 1 |
CH2879 + AGI-5198 | Central conventional | Wildtype | 4280 | 4060 | −16 | 22 |
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Venneker, S.; Kruisselbrink, A.B.; Briaire-de Bruijn, I.H.; de Jong, Y.; van Wijnen, A.J.; Danen, E.H.J.; Bovée, J.V.M.G. Inhibition of PARP Sensitizes Chondrosarcoma Cell Lines to Chemo- and Radiotherapy Irrespective of the IDH1 or IDH2 Mutation Status. Cancers 2019, 11, 1918. https://doi.org/10.3390/cancers11121918
Venneker S, Kruisselbrink AB, Briaire-de Bruijn IH, de Jong Y, van Wijnen AJ, Danen EHJ, Bovée JVMG. Inhibition of PARP Sensitizes Chondrosarcoma Cell Lines to Chemo- and Radiotherapy Irrespective of the IDH1 or IDH2 Mutation Status. Cancers. 2019; 11(12):1918. https://doi.org/10.3390/cancers11121918
Chicago/Turabian StyleVenneker, Sanne, Alwine B. Kruisselbrink, Inge H. Briaire-de Bruijn, Yvonne de Jong, Andre J. van Wijnen, Erik H.J. Danen, and Judith V.M.G. Bovée. 2019. "Inhibition of PARP Sensitizes Chondrosarcoma Cell Lines to Chemo- and Radiotherapy Irrespective of the IDH1 or IDH2 Mutation Status" Cancers 11, no. 12: 1918. https://doi.org/10.3390/cancers11121918