Synergistic Cytotoxicity of Histone Deacetylase and Poly-ADP Ribose Polymerase Inhibitors and Decitabine in Breast and Ovarian Cancer Cells: Implications for Novel Therapeutic Combinations
Abstract
:1. Introduction
2. Results
2.1. Sensitivity of Breast and Ovarian Cancer Cell Lines to HDACis, PARPis, and Decitabine
2.2. Synergistic Cytotoxicity of HDACis, PARPis, and Decitabine in Breast and Ovarian Cancer Cell Lines
2.3. Drug-Mediated Inhibition of Cell Proliferation and PARylation, and Effects on Survival and Apoptosis Protein Markers
2.4. The Three-Drug Combinations Inhibit PARylation and Enhance Cleavage of Caspase 3 and PARP1
2.5. HDACi, PARPi, and Decitabine Combinations Affect the Levels of Proteins Involved in DNA Damage Response and Repair
3. Discussion
4. Materials and Methods
4.1. Cell Lines and Drugs
4.2. Determination of IC50 and Drug Synergism
4.3. Colony Formation/Clonogenic Assay
4.4. MTT Assay and Western Blot Analysis
4.5. Drug Concentrations for Colony Formation/Clonogenic Assay, MTT Assay, and Western Blot Analysis
4.6. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ATM | Ataxia–Telangiectasia Mutated protein |
ATRX | Alpha Thalassemia/Mental Retardation Syndrome X-Linked protein |
BRCA | Breast Cancer gene |
c-MYC | Cellular Myelocytomatosis oncogene |
CI | Combination Index (used in drug synergism analysis) |
DCIS | Ductal Carcinoma In Situ |
DNAPKcs | DNA-Dependent Protein Kinase Catalytic Subunit |
Fa | Fractions affected (refers to cell death in drug synergism analysis) |
FDA | U.S. Food and Drug Administration |
HDACis | Histone Deacetylase Inhibitors |
IC50 | Half-Maximal Inhibitory Concentration |
JAK–STAT | Janus Kinase–Signal Transducer and Activator of Transcription |
MTT | 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyl Tetrazolium Bromide |
NuRD | Nucleosome Remodeling and Deacetylase complex |
PARPis | Poly(ADP Ribose) Polymerase Inhibitors |
PD-L1 | Programmed Death (Ligand) 1 |
PBS | Phosphate-Buffered Saline |
TNF | Tumor Necrosis Factor |
UHFR1 | Ubiquitin-Specific |
Histone | H2A and H2B Deubiquitinase Factor R1 |
γ-H2AX | Phosphorylated Histone H2AX |
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Breast Cancer Cell Lines | ||||||||||
MDA-MB-231 | MCF-7 | |||||||||
Pano | SAHA | TLZ | OLA | DAC | Pano | SAHA | TLZ | OLA | DAC | |
Cell Proliferation | ||||||||||
PTD | <0.0001 | <0.0001 | <0.0001 | 0.003 | 0.003 | <0.0001 | ||||
POD | <0.0001 | <0.0001 | <0.0001 | 0.003 | 0.0009 | <0.0001 | ||||
STD | <0.0001 | <0.0001 | <0.0001 | 0.0001 | 0.001 | <0.0001 | ||||
SOD | <0.0001 | <0.0001 | <0.0001 | <0.0001 | 0.0002 | <0.0001 | ||||
Apoptosis | ||||||||||
PTD | <0.0001 | 0.0001 | <0.0001 | 0.011 | 0.068 | 0.014 | ||||
POD | <0.0001 | 0.0001 | 0.0001 | 0.021 | 0.1 | 0.022 | ||||
STD | <0.0001 | 0.0001 | <0.0001 | 0.004 | 0.031 | 0.005 | ||||
SOD | <0.0001 | 0.0001 | 0.0001 | 0.036 | 0.13 | 0.046 | ||||
Ovarian Cancer Cell Lines | ||||||||||
HEY-T30 | SKOV-3 | |||||||||
Pano | SAHA | TLZ | OLA | DAC | Pano | SAHA | TLZ | OLA | DAC | |
Cell Proliferation | ||||||||||
PTD | <0.0001 | <0.0001 | <0.0001 | 0.0004 | <0.0001 | <0.0001 | ||||
POD | <0.0001 | <0.0001 | <0.0001 | 0.0008 | <0.0001 | <0.0001 | ||||
STD | <0.0001 | <0.0001 | <0.0001 | 0.0005 | 0.0005 | <0.0001 | ||||
SOD | <0.0001 | <0.0001 | <0.0001 | 0.0008 | 0.0003 | <0.0001 | ||||
Apoptosis | ||||||||||
PTD | 0.0008 | 0.0003 | 0.001 | 0.037 | 0.001 | <0.0001 | ||||
POD | 0.0101 | 0.0006 | 0.01 | 0.037 | 0.002 | <0.0001 | ||||
STD | 0.0002 | 0.0003 | 0.001 | 0.002 | 0.003 | <0.0001 | ||||
SOD | 0.004 | 0.0006 | 0.01 | 0.006 | 0.008 | 0.0001 |
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Valdez, B.C.; Tsimberidou, A.M.; Yuan, B.; Baysal, M.A.; Chakraborty, A.; Andersen, C.R.; Andersson, B.S. Synergistic Cytotoxicity of Histone Deacetylase and Poly-ADP Ribose Polymerase Inhibitors and Decitabine in Breast and Ovarian Cancer Cells: Implications for Novel Therapeutic Combinations. Int. J. Mol. Sci. 2024, 25, 9241. https://doi.org/10.3390/ijms25179241
Valdez BC, Tsimberidou AM, Yuan B, Baysal MA, Chakraborty A, Andersen CR, Andersson BS. Synergistic Cytotoxicity of Histone Deacetylase and Poly-ADP Ribose Polymerase Inhibitors and Decitabine in Breast and Ovarian Cancer Cells: Implications for Novel Therapeutic Combinations. International Journal of Molecular Sciences. 2024; 25(17):9241. https://doi.org/10.3390/ijms25179241
Chicago/Turabian StyleValdez, Benigno C., Apostolia M. Tsimberidou, Bin Yuan, Mehmet A. Baysal, Abhijit Chakraborty, Clark R. Andersen, and Borje S. Andersson. 2024. "Synergistic Cytotoxicity of Histone Deacetylase and Poly-ADP Ribose Polymerase Inhibitors and Decitabine in Breast and Ovarian Cancer Cells: Implications for Novel Therapeutic Combinations" International Journal of Molecular Sciences 25, no. 17: 9241. https://doi.org/10.3390/ijms25179241