Shikonin impairs mitochondrial activity to selectively target leukemia cells
Background: Acute myeloid leukemia (AML) is a hematopoietic malignancy that results from the accumulation of undifferentiated myeloid cells in the peripheral blood and bone marrow. Limited therapeutics contribute to unfavorable patient outcomes, highlighting the need for novel therapeutics to improv...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-08-01
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| Series: | Phytomedicine Plus |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2667031322000835 |
| _version_ | 1811336538184744960 |
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| author | Alessia Roma Matthew Tcheng Nawaz Ahmed Sarah Walker Preethi Jayanth Mark D. Minden Julie A. Reisz Angelo D'Alessandro Jakub Rohlena Paul A. Spagnuolo |
| author_facet | Alessia Roma Matthew Tcheng Nawaz Ahmed Sarah Walker Preethi Jayanth Mark D. Minden Julie A. Reisz Angelo D'Alessandro Jakub Rohlena Paul A. Spagnuolo |
| author_sort | Alessia Roma |
| collection | DOAJ |
| description | Background: Acute myeloid leukemia (AML) is a hematopoietic malignancy that results from the accumulation of undifferentiated myeloid cells in the peripheral blood and bone marrow. Limited therapeutics contribute to unfavorable patient outcomes, highlighting the need for novel therapeutics to improve prognosis. We previously demonstrated that shikonin, a constituent of Lithospermum erythrorhizon, preferentially targets bulk AML cells through inhibition of electron transport chain complex II. Hypothesis/Purpose: In this study, we aim to further characterize the anti-leukemia effects of shikonin in vitro and in vivo. Methods: AML cell lines and patient-derived cells were used to assess the cytotoxic effect of shikonin in vitro and in vivo. Respirometry, stable-isotope tracing, flow cytometry, and immunoblotting were used to assess the metabolic changes which precede shikonin-mediated cell death. Results: Shikonin induced cytotoxicity in AML cell lines and patient-derived cells while sparing normal hematopoietic cells through a reactive-oxygen species (ROS) dependent mechanism. Shikonin (2.5 mg/kg) reduced patient-derived AML cell engraftment in mouse bone marrow without toxicity. Mechanistically, it increased mitochondrial ROS, impaired oxidative tricarboxylic acid cycling, and reprogrammed metabolism towards glycolysis. Chronic cellular exposure to shikonin resulted in a unique phenotype characterized by decreased mitochondrial activity and increased glycolysis. Consistent with this, cells with increased glycolytic and antioxidant capacities were less sensitive to shikonin. Conclusion: Together, these results highlight shikonin as a mitochondria-targeting agent and provide further insight into its anti-AML activity. |
| first_indexed | 2024-04-13T17:40:57Z |
| format | Article |
| id | doaj.art-d6cba8b6f3d64bb79a2161045226f5c7 |
| institution | Directory Open Access Journal |
| issn | 2667-0313 |
| language | English |
| last_indexed | 2024-04-13T17:40:57Z |
| publishDate | 2022-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Phytomedicine Plus |
| spelling | doaj.art-d6cba8b6f3d64bb79a2161045226f5c72022-12-22T02:37:12ZengElsevierPhytomedicine Plus2667-03132022-08-0123100300Shikonin impairs mitochondrial activity to selectively target leukemia cellsAlessia Roma0Matthew Tcheng1Nawaz Ahmed2Sarah Walker3Preethi Jayanth4Mark D. Minden5Julie A. Reisz6Angelo D'Alessandro7Jakub Rohlena8Paul A. Spagnuolo9Department of Food Science, University of Guelph, Guelph, ON N1G 2W1, CanadaDepartment of Food Science, University of Guelph, Guelph, ON N1G 2W1, CanadaDepartment of Food Science, University of Guelph, Guelph, ON N1G 2W1, CanadaDepartment of Food Science, University of Guelph, Guelph, ON N1G 2W1, CanadaDepartment of Food Science, University of Guelph, Guelph, ON N1G 2W1, CanadaPrincess Margaret Cancer Center, Ontario Cancer Institute, Toronto, Ontario, CanadaDepartment of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO, USADepartment of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO, USAInstitute of Biotechnology, Czech Academy of Sciences, Prague-West, Vestec, Czech RepublicDepartment of Food Science, University of Guelph, Guelph, ON N1G 2W1, Canada; Corresponding author.Background: Acute myeloid leukemia (AML) is a hematopoietic malignancy that results from the accumulation of undifferentiated myeloid cells in the peripheral blood and bone marrow. Limited therapeutics contribute to unfavorable patient outcomes, highlighting the need for novel therapeutics to improve prognosis. We previously demonstrated that shikonin, a constituent of Lithospermum erythrorhizon, preferentially targets bulk AML cells through inhibition of electron transport chain complex II. Hypothesis/Purpose: In this study, we aim to further characterize the anti-leukemia effects of shikonin in vitro and in vivo. Methods: AML cell lines and patient-derived cells were used to assess the cytotoxic effect of shikonin in vitro and in vivo. Respirometry, stable-isotope tracing, flow cytometry, and immunoblotting were used to assess the metabolic changes which precede shikonin-mediated cell death. Results: Shikonin induced cytotoxicity in AML cell lines and patient-derived cells while sparing normal hematopoietic cells through a reactive-oxygen species (ROS) dependent mechanism. Shikonin (2.5 mg/kg) reduced patient-derived AML cell engraftment in mouse bone marrow without toxicity. Mechanistically, it increased mitochondrial ROS, impaired oxidative tricarboxylic acid cycling, and reprogrammed metabolism towards glycolysis. Chronic cellular exposure to shikonin resulted in a unique phenotype characterized by decreased mitochondrial activity and increased glycolysis. Consistent with this, cells with increased glycolytic and antioxidant capacities were less sensitive to shikonin. Conclusion: Together, these results highlight shikonin as a mitochondria-targeting agent and provide further insight into its anti-AML activity.http://www.sciencedirect.com/science/article/pii/S2667031322000835ShikoninAcute myeloid leukemiaComplex IISuccinate dehydrogenaseMitochondria |
| spellingShingle | Alessia Roma Matthew Tcheng Nawaz Ahmed Sarah Walker Preethi Jayanth Mark D. Minden Julie A. Reisz Angelo D'Alessandro Jakub Rohlena Paul A. Spagnuolo Shikonin impairs mitochondrial activity to selectively target leukemia cells Phytomedicine Plus Shikonin Acute myeloid leukemia Complex II Succinate dehydrogenase Mitochondria |
| title | Shikonin impairs mitochondrial activity to selectively target leukemia cells |
| title_full | Shikonin impairs mitochondrial activity to selectively target leukemia cells |
| title_fullStr | Shikonin impairs mitochondrial activity to selectively target leukemia cells |
| title_full_unstemmed | Shikonin impairs mitochondrial activity to selectively target leukemia cells |
| title_short | Shikonin impairs mitochondrial activity to selectively target leukemia cells |
| title_sort | shikonin impairs mitochondrial activity to selectively target leukemia cells |
| topic | Shikonin Acute myeloid leukemia Complex II Succinate dehydrogenase Mitochondria |
| url | http://www.sciencedirect.com/science/article/pii/S2667031322000835 |
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