APR-246—The Mutant TP53 Reactivator—Increases the Effectiveness of Berberine and Modified Berberines to Inhibit the Proliferation of Pancreatic Cancer Cells
Abstract
:1. Introduction
2. Materials and Methods
2.1. Cell Lines
2.2. Sources of APR-246, BBR and NAX Compounds
2.3. Transduction of MIA-PaCa-2 and PANC-28 Cells with a Vector Encoding WT-TP53 or an Empty Vector Control
2.4. Measurements of Cellular Proliferation
2.5. Clonogenicity Assays
2.6. Statistical Analysis
3. Results
3.1. Effects of the Mutant TP53 Reactivator on Two PDAC Cell Lines
3.2. Interactions between Berberine (BBR), Chemically Modified BBRs (NAX Compounds) and APR-246 in MIA-PaCa-2 + pLXSN and MIA-PaCa-2 + WT-TP53 Cells
3.3. Abilities of Low Doses of BBR or NAX060 to Increase the Cytotoxicity of APR-246 and Decrease Clonogenicity of MIA-PaCa-2 Cells Containing and Lacking WT-TP53
3.4. Interactions between Berberine (BBR), Chemically Modified BBRs (NAX Compounds) and APR-246 in PANC-28 + pLXSN and PANC-28 + WT-TP53 Cells
3.5. Abilities of Low Doses of BBR or NAX060 to Increase the Cytotoxicity of APR-246 and Decrease Clonogenicity of PANC-28 Cells Containing and Lacking WT-TP53
4. Discussion
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Berberine or NAX Compound | MIA-PaCa-2 + pLXSN (-APR-246) | MIA-PaCa-2 + pLXSN (+12.5 nM APR-246) | p Value and Statistical Significance Symbol | Fold Change +/− APR-246 | MIA-PaCa-2 + WT-TP53 (-APR-246) | MIA-PaCa-2 + WT-TP53 (+12.5 nM APR-246) | p Value and Statistical Significance Symbol | Fold Change +/− APR-246 |
Berberine | 1200 nM | 1100 nM | p = 0.047, * | 1.1 × ↓ | 1100 nM | 1000 nM | p = 1, NS | 1.1 × ↓ |
NAX012 | 1000 nM | 1000 nM | p = 1, NS | 1 × | 700 nM | 700 nM | p = 1, NS | 1 × |
NAX014 | 1100 nM | 1000 nM | p = 0.048, * | 1.1 × ↓ | 700 nM | 160 nM | p < 0.0001, *** | 4.4 × ↓ |
NAX035 | 500 nM | 450 nM | p = 0.035, * | 1.1 × ↓ | 300 nM | 16 nM | p < 0.0001, *** | 18.8 × ↓ |
NAX038 | 600 nM | 500 nM | p < 0.0001, *** | 1.2 × ↓ | 380 nM | 300 nM | p = 0.004, ** | 1.3 × ↓ |
NAX042 | 380 nM | 300 nM | p = 0.005, * | 1.3 × ↓ | 300 nM | 13 nM | p < 0.0001, *** | 23 × ↓ |
NAX053 | 300 nM | 200 nM | p = 0.0002, ** | 1.5 × ↓ | 200 nM | 2 nM | p < 0.0001, *** | 100 × ↓ |
NAX054 | >2000 nM | >2000 nM | p = 1, NS | 1 × | >2000 nM | 1000 nM | p < 0.0001, *** | >2 × ↓ |
NAX060 | 800 nM | 400 nM | p < 0.0001, *** | 2 × ↓ | 220 nM | 2 nM | p < 0.0001, *** | 110 × ↓ |
NAX075 | >2000 nM | 500 nM | p < 0.0001, *** | >4 × ↓ | 1000 nM | 2.8 nM | p < 0.0001, *** | 357 × ↓ |
NAX077 | >2000 nM | 800 nM | p < 0.0001, *** | >2.5 × ↓ | 1900 nM | 1100 nM | p = 0.0052, * | 1.7 × ↓ |
NAX111 | 300 nM | 100 nM | p < 0.0001, *** | 3 × ↓ | 250 nM | 200 nM | p < 0.0001, *** | 1.3 × ↓ |
Berberine or NAX Compound | PANC-28 + pLXSN (-APR-246) | PANC-28 + pLXSN (+12.5 nM APR-246) | p Value and Statistical Significance Symbol | Fold Change +/−APR-246 | PANC-28 + WT-TP53 (-APR-246) | PANC-28 + WT-TP53 (-APR-246) | p Value and Statistical Significance Symbol | Fold Change +/− APR-246 |
Berberine | 1600 nM | 1500 nM | p = 0.119, NS | 1.1 × ↓ | 1000 nM | 18 nM | p < 0.0001, *** | 55.6 × ↓ |
NAX012 | 2000 nM | 500 nM | p < 0.0001, *** | 4 × ↓ | 800 nM | 5.5 nM | p < 0.0001, *** | 145 × ↓ |
NAX014 | 1200 nM | 700 nM | p = 0.0002, ** | 1.7 × ↓ | 500 nM | 2 nM | p < 0.0001, *** | 250 × ↓ |
NAX035 | 700 nM | 700 nM | p = 1, NS | 1 × | 50 nM | 4 nM | p < 0.0001, *** | 12.5 × ↓ |
NAX038 | 2000 nM | 1000 nM | p < 0.0001, *** | 2 × ↓ | 120 nM | 2.2 nM | p < 0.0001, *** | 54.5 × ↓ |
NAX042 | 1500 nM | 1000 nM | p < 0.0001, *** | 1.5 × ↓ | 32 nM | 7 nM | p < 0.0001, *** | 4.6 × ↓ |
NAX053 | 600 nM | 600 nM | p = 1, NS | 1 × | 65 nM | 4 nM | p < 0.0001, *** | 16.3 × ↓ |
NAX054 | >2000 nM | >2000 nM | p = 1, NS | 1 × | >2000 nM | >2000 nM | p = 1, NS | 1 × |
NAX060 | 450 nM | 200 nM | p < 0.0001, *** | 2.3 × ↓ | 120 nM | 9 nM | p < 0.0001, *** | 13.3 × ↓ |
NAX075 | 1200 nM | 1200 nM | p = 1, NS | 1 × | 1000 nM | 45 nM | p < 0.0001, *** | 22.2 × ↓ |
NAX077 | 1700 nM | 1700 nM | p = 1, NS | 1 × | 1500 nM | 1.5 nM | p < 0.0001, *** | 1000 × ↓ |
NAX111 | 1000 nM | 1000 nM | p = 1, NS | 1 × | 150 nM | 6 nM | p < 0.0001, *** | 25 × ↓ |
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McCubrey, J.A.; Abrams, S.L.; Steelman, L.S.; Cocco, L.; Ratti, S.; Martelli, A.M.; Lombardi, P.; Gizak, A.; Duda, P. APR-246—The Mutant TP53 Reactivator—Increases the Effectiveness of Berberine and Modified Berberines to Inhibit the Proliferation of Pancreatic Cancer Cells. Biomolecules 2022, 12, 276. https://doi.org/10.3390/biom12020276
McCubrey JA, Abrams SL, Steelman LS, Cocco L, Ratti S, Martelli AM, Lombardi P, Gizak A, Duda P. APR-246—The Mutant TP53 Reactivator—Increases the Effectiveness of Berberine and Modified Berberines to Inhibit the Proliferation of Pancreatic Cancer Cells. Biomolecules. 2022; 12(2):276. https://doi.org/10.3390/biom12020276
Chicago/Turabian StyleMcCubrey, James Andrew, Stephen L. Abrams, Linda S. Steelman, Lucio Cocco, Stefano Ratti, Alberto M. Martelli, Paolo Lombardi, Agnieszka Gizak, and Przemysław Duda. 2022. "APR-246—The Mutant TP53 Reactivator—Increases the Effectiveness of Berberine and Modified Berberines to Inhibit the Proliferation of Pancreatic Cancer Cells" Biomolecules 12, no. 2: 276. https://doi.org/10.3390/biom12020276