Phosphoinositide 3-Kinase (PI3K) Reactive Oxygen Species (ROS)-Activated Prodrug in Combination with Anthracycline Impairs PI3K Signaling, Increases DNA Damage Response and Reduces Breast Cancer Cell Growth
Abstract
:1. Introduction
2. Results
2.1. RIDR-PI-103 Has Increased Specificity in Breast Cancer Cells over Fibroblast and MCF10A Cells
2.2. Doxorubicin Induces ROS and Combination of RIDR-PI-103 and Doxorubicin Inhibits Breast Cancer Cell Viability
2.3. Doxorubicin in Combination with RIDR-PI-103 Suppresses Breast Cancer Cell Proliferation
2.4. Doxorubicin in Combination with RIDR-PI-103 Suppresses Matrigel Colony Formation
2.5. Doxorubicin and RIDR-PI-103 Suppress Breast Cancer Cell Migration
2.6. The Combination of Doxorubicin and RIDR-PI-103 Results in Enhanced Inhibition of PI3K Signaling and Activates DNA Damage Response
2.7. Pharmacokinetics Profile of RIDR-PI-103
3. Discussion
4. Materials and Methods
4.1. Cell Culture and Inhibitors
4.2. Immunoblot Analysis
4.3. Cell Viability Assay
4.4. Cell Proliferation Assay
4.5. Cell Migration Assay
4.6. Measurement of Intracellular ROS
4.7. Matrigel Colony Formation
4.8. Analytical Methods
4.9. Pharmacokinetic Analysis
4.10. Animal Studies
4.11. qPCR Analysis of Antioxidant mRNAs
4.12. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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PK Parameters | Observed Values |
---|---|
V/F | 89 L/kg |
K01 | 2.5 h−1 |
K10 | 0.075 h−1 |
AUC (0–72 h) | 2979.8 h·ng/mL |
Elimination T1/2 | 9.18 h |
Cl/F | 6.7 L/h/kg |
Tmax | 1.44 h |
Cmax | 201.5 ng/mL |
PK Parameters | Observed Values |
---|---|
V/F | 89 L/kg |
λz | 0.073 h−1 |
K10 | 0.073 h−1 |
AUC (0–72 h) | 3897.1 h·ng/mL |
Elimination T1/2 | 9.44 h |
Cl/F | 5.1 L/h/kg |
Tmax | 0.5 h |
Cmax | 192.8 ng/mL |
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Mishra, R.; Yuan, L.; Patel, H.; Karve, A.S.; Zhu, H.; White, A.; Alanazi, S.; Desai, P.; Merino, E.J.; Garrett, J.T. Phosphoinositide 3-Kinase (PI3K) Reactive Oxygen Species (ROS)-Activated Prodrug in Combination with Anthracycline Impairs PI3K Signaling, Increases DNA Damage Response and Reduces Breast Cancer Cell Growth. Int. J. Mol. Sci. 2021, 22, 2088. https://doi.org/10.3390/ijms22042088
Mishra R, Yuan L, Patel H, Karve AS, Zhu H, White A, Alanazi S, Desai P, Merino EJ, Garrett JT. Phosphoinositide 3-Kinase (PI3K) Reactive Oxygen Species (ROS)-Activated Prodrug in Combination with Anthracycline Impairs PI3K Signaling, Increases DNA Damage Response and Reduces Breast Cancer Cell Growth. International Journal of Molecular Sciences. 2021; 22(4):2088. https://doi.org/10.3390/ijms22042088
Chicago/Turabian StyleMishra, Rosalin, Long Yuan, Hima Patel, Aniruddha S. Karve, Haizhou Zhu, Aaron White, Samar Alanazi, Pankaj Desai, Edward J. Merino, and Joan T. Garrett. 2021. "Phosphoinositide 3-Kinase (PI3K) Reactive Oxygen Species (ROS)-Activated Prodrug in Combination with Anthracycline Impairs PI3K Signaling, Increases DNA Damage Response and Reduces Breast Cancer Cell Growth" International Journal of Molecular Sciences 22, no. 4: 2088. https://doi.org/10.3390/ijms22042088