Preclinical Evaluation of Artesunate as an Antineoplastic Agent in Ovarian Cancer Treatment
Abstract
:1. Introduction
2. Materials and Methods
2.1. Cell Culture and Artesunate
2.2. Cell Viability Assays
2.3. 3D Organoids
2.3.1. Tumor Organoid (TO) Development
2.3.2. Chemosensitivity Screens
2.3.3. Gene Expression Analysis
2.4. DNA Damage Assay
2.5. Flow Cytometric Analysis of Cell Cycle
2.6. Drug Administration Sequence Assay
3. Results
3.1. Artesunate Has Antineoplastic Activity in Ovarian Cancer
3.2. RNAseq Analysis Comparing Resistant and Sensitive Organoids
3.3. Clinically Relevant Concentrations of Artesunate Induce G1 Arrest, but Not DNA Damage
3.4. Addition of Artesunate to Carboplatin and Paclitaxel Improves Antineoplastic Activity
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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General Category | Pathway ID | Pathway Description | p-Value | Differentially Expressed Genes |
---|---|---|---|---|
ROS/oxidative phosphorylation | GO:0000302 | response to reactive oxygen species | ↑ 0.0008 | ↑ AQP1, ↑ CRYAB, ↑ EGFR |
GO:0006979 | response to oxidative stress | ↑ 0.0056 | ↑ AQP1, ↑ CRYAB, ↑ EGFR | |
GO:0034614 | cellular response to reactive oxygen species | ↑ 0.0077 | ↑ AQP1, ↑ EGFR | |
GO:2000377 | regulation of reactive oxygen species metabolic process | ↑ 0.0098 | ↑ CRYAB, ↑ EGFR | |
GO:0072593 | reactive oxygen species metabolic process | ↑ 0.0212 | ↑ CRYAB, ↑ EGFR | |
GO:0034599 | cellular response to oxidative stress | ↑ 0.0241 | ↑ AQP1, ↑ EGFR | |
GO:2000378 | negative regulation of reactive oxygen species metabolic process | ↑ 0.045 | ↑ CRYAB | |
GO:0090324 | negative regulation of oxidative phosphorylation | ↓ 0.0018 | ↓ DNAJC15 | |
GO:0002082 | regulation of oxidative phosphorylation | ↓ 0.0074 | ↓ DNAJC15 | |
GO:0006119 | oxidative phosphorylation | ↓ 0.0352 | ↓ DNAJC15 | |
mitochondrial functon/cellular respiration | GO:1902957 | negative regulation of mitochondrial electron transport, NADH to ubiquinone | ↓ 0.0005 | ↓ DNAJC15 |
GO:1905447 | negative regulation of mitochondrial ATP synthesis coupled electron transport | ↓ 0.0005 | ↓ DNAJC15 | |
GO:1901856 | negative regulation of cellular respiration | ↓ 0.0010 | ↓ DNAJC15 | |
GO:1902956 | regulation of mitochondrial electron transport, NADH to ubiquinone | ↓ 0.0013 | ↓ DNAJC15 | |
GO:1905446 | regulation of mitochondrial ATP synthesis coupled electron transport | ↓ 0.0018 | ↓ DNAJC15 | |
GO:0005744 | TIM23 mitochondrial import inner membrane translocase complex | ↓ 0.0036 | ↓ DNAJC15 | |
GO:0043457 | regulation of cellular respiration | ↓ 0.0076 | ↓ DNAJC15 | |
GO:0006120 | mitochondrial electron transport, NADH to ubiquinone | ↓ 0.0135 | ↓ DNAJC15 | |
GO:0042775 | mitochondrial ATP synthesis coupled electron transport | ↓ 0.0235 | ↓ DNAJC15 | |
GO:0042773 | ATP synthesis coupled electron transport | ↓ 0.0238 | ↓ DNAJC15 | |
GO:0006626 | protein targeting to mitochondrion | ↓ 0.0248 | ↓ DNAJC15 | |
GO:1990542 | mitochondrial transmembrane transport | ↓ 0.0255 | ↓ DNAJC15 | |
GO:0022904 | respiratory electron transport chain | ↓ 0.0285 | ↓ DNAJC15 | |
GO:0098800 | inner mitochondrial membrane protein complex | ↓ 0.0332 | ↓ DNAJC15 | |
GO:0072655 | establishment of protein localization to mitochondrion | ↓ 0.0345 | ↓ DNAJC15 | |
GO:0045333 | cellular respiration | ↓ 0.0473 | ↓ DNAJC15 | |
cell cycle progression | GO:1900087 | positive regulation of G1/S transition of mitotic cell cycle | ↑ 0.0302 | ↑ EGFR |
GO:0045740 | positive regulation of DNA replication | ↑ 0.0302 | ↑ EGFR | |
GO:1902808 | positive regulation of cell cycle G1/S phase transition | ↑ 0.0384 | ↑ EGFR | |
GO:0045787 | positive regulation of cell cycle | ↑ 0.0391 | ↑ SMOC2, ↑ EGFR, ↓ MEIS2 | |
response to metal ion | GO:0010038 | response to metal ion | ↑ 0.0034 | ↑ AQP1, ↑ MT1A, ↑ EGFR |
GO:0071248 | cellular response to metal ion | ↑ 0.0005 | ↑ AQP1, ↑ MT1A, ↑ EGFR | |
Cell death/apoptosis | GO:0060548 | negative regulation of cell death | ↑ 0.0011 | ↑ AQP1, ↑ GABRB3, ↑ CD200,↑ CRYAB, ↑ EGFR |
GO:0043067 | regulation of programmed cell death | ↑ 0.0375 | ↑ AQP1, ↑ GABRB3, ↑ CRYAB,↑ EGFR | |
ATP metabolic process | GO:1903579 | negative regulation of ATP metabolic process | ↓ 0.0064 | ↓ DNAJC15 |
GO:1903578 | regulation of ATP metabolic process | ↓ 0.0300 | ↓ DNAJC15 | |
response to antineoplastic agent | GO:0097327 | response to antineoplastic agent | ↑ 0.0029 | ↑ AQP1, ↑ EGFR |
phosphatidylinositol-mediated signaling | GO:0048015 | phosphatidylinositol-mediated signaling | ↑ 0.0097 | ↑ RELN, ↑ EGFR |
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McDowell, A., Jr.; Hill, K.S.; McCorkle, J.R.; Gorski, J.; Zhang, Y.; Salahudeen, A.A.; Ueland, F.; Kolesar, J.M. Preclinical Evaluation of Artesunate as an Antineoplastic Agent in Ovarian Cancer Treatment. Diagnostics 2021, 11, 395. https://doi.org/10.3390/diagnostics11030395
McDowell A Jr., Hill KS, McCorkle JR, Gorski J, Zhang Y, Salahudeen AA, Ueland F, Kolesar JM. Preclinical Evaluation of Artesunate as an Antineoplastic Agent in Ovarian Cancer Treatment. Diagnostics. 2021; 11(3):395. https://doi.org/10.3390/diagnostics11030395
Chicago/Turabian StyleMcDowell, Anthony, Jr., Kristen S. Hill, Joseph Robert McCorkle, Justin Gorski, Yilin Zhang, Ameen A. Salahudeen, Fred Ueland, and Jill M. Kolesar. 2021. "Preclinical Evaluation of Artesunate as an Antineoplastic Agent in Ovarian Cancer Treatment" Diagnostics 11, no. 3: 395. https://doi.org/10.3390/diagnostics11030395
APA StyleMcDowell, A., Jr., Hill, K. S., McCorkle, J. R., Gorski, J., Zhang, Y., Salahudeen, A. A., Ueland, F., & Kolesar, J. M. (2021). Preclinical Evaluation of Artesunate as an Antineoplastic Agent in Ovarian Cancer Treatment. Diagnostics, 11(3), 395. https://doi.org/10.3390/diagnostics11030395