Pharmacological inhibition of Peroxisome Proliferation-Activated Receptor Delta (PPARδ) imparts selective leukemia cell death
Abstract Background Acute myeloid leukemia (AML) is a devastating hematological malignancy with limited therapeutic options and poor survival outcomes. Therefore, the development of novel and selective anti-AML therapies is needed. 6-methoxydihydroavicine (6ME), a benzophenanthridine alkaloid, impar...
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BMC
2025-07-01
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| Series: | Cancer & Metabolism |
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| Online Access: | https://doi.org/10.1186/s40170-025-00402-5 |
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| author | Yingying Yang Ekaterina Parfenova Nikolina Vrdoljak Mark Minden Jessica Luc Andrew C. Doxey Paul A. Spagnuolo |
| author_facet | Yingying Yang Ekaterina Parfenova Nikolina Vrdoljak Mark Minden Jessica Luc Andrew C. Doxey Paul A. Spagnuolo |
| author_sort | Yingying Yang |
| collection | DOAJ |
| description | Abstract Background Acute myeloid leukemia (AML) is a devastating hematological malignancy with limited therapeutic options and poor survival outcomes. Therefore, the development of novel and selective anti-AML therapies is needed. 6-methoxydihydroavicine (6ME), a benzophenanthridine alkaloid, imparted selective AML cell death in vitro and in vivo. Mechanistically, 6ME inhibited fatty acid oxidation (FAO) by binding to and decreasing the activity of PPARδ, a transcription factor involved in FAO. Methods AML cell lines and patient-derived cells were used to assess the activity of 6ME in vitro and in vivo. Computational methods, immunoblotting, and co-IP-HPLC analysis assessed the molecular target, and cellular consequence of 6ME activity. Results 6ME induced cytotoxicity of AML cell lines (IC50: 1.0 ± 0.13 μM) and patient-derived cells while sparing normal hematopoietic cells. Mouse engraftment studies showed that 6ME (5 mg/kg, three times/week for 4 weeks) selectively reduced patient-derived AML cell engraftment without affecting hematopoietic cell engraftment or imparting toxicity. Mechanistically, 6ME bound to and inhibited PPARδ leading to downregulated FAO gene expression (i.e., CD36 and CPT2) and reduced fatty acid cellular uptake resulting in FAO inhibition. Conclusion Pharmacological inhibition of PPARδ with 6ME is a novel approach to inducing selective death in AML. |
| format | Article |
| id | doaj-art-d27d74ecd1a14ad081fad70e2b546da4 |
| institution | Kabale University |
| issn | 2049-3002 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer & Metabolism |
| spelling | doaj-art-d27d74ecd1a14ad081fad70e2b546da42025-08-20T03:46:21ZengBMCCancer & Metabolism2049-30022025-07-0113111810.1186/s40170-025-00402-5Pharmacological inhibition of Peroxisome Proliferation-Activated Receptor Delta (PPARδ) imparts selective leukemia cell deathYingying Yang0Ekaterina Parfenova1Nikolina Vrdoljak2Mark Minden3Jessica Luc4Andrew C. Doxey5Paul A. Spagnuolo6Department of Food Science, University of GuelphDepartment of Food Science, University of GuelphDepartment of Food Science, University of GuelphPrincess Margaret Cancer Center, Ontario Cancer InstituteUniversity of WaterlooUniversity of WaterlooDepartment of Food Science, University of GuelphAbstract Background Acute myeloid leukemia (AML) is a devastating hematological malignancy with limited therapeutic options and poor survival outcomes. Therefore, the development of novel and selective anti-AML therapies is needed. 6-methoxydihydroavicine (6ME), a benzophenanthridine alkaloid, imparted selective AML cell death in vitro and in vivo. Mechanistically, 6ME inhibited fatty acid oxidation (FAO) by binding to and decreasing the activity of PPARδ, a transcription factor involved in FAO. Methods AML cell lines and patient-derived cells were used to assess the activity of 6ME in vitro and in vivo. Computational methods, immunoblotting, and co-IP-HPLC analysis assessed the molecular target, and cellular consequence of 6ME activity. Results 6ME induced cytotoxicity of AML cell lines (IC50: 1.0 ± 0.13 μM) and patient-derived cells while sparing normal hematopoietic cells. Mouse engraftment studies showed that 6ME (5 mg/kg, three times/week for 4 weeks) selectively reduced patient-derived AML cell engraftment without affecting hematopoietic cell engraftment or imparting toxicity. Mechanistically, 6ME bound to and inhibited PPARδ leading to downregulated FAO gene expression (i.e., CD36 and CPT2) and reduced fatty acid cellular uptake resulting in FAO inhibition. Conclusion Pharmacological inhibition of PPARδ with 6ME is a novel approach to inducing selective death in AML.https://doi.org/10.1186/s40170-025-00402-56-methoxydihydroavicineAcute myeloid leukemiaPPARFatty acid oxidation |
| spellingShingle | Yingying Yang Ekaterina Parfenova Nikolina Vrdoljak Mark Minden Jessica Luc Andrew C. Doxey Paul A. Spagnuolo Pharmacological inhibition of Peroxisome Proliferation-Activated Receptor Delta (PPARδ) imparts selective leukemia cell death Cancer & Metabolism 6-methoxydihydroavicine Acute myeloid leukemia PPAR Fatty acid oxidation |
| title | Pharmacological inhibition of Peroxisome Proliferation-Activated Receptor Delta (PPARδ) imparts selective leukemia cell death |
| title_full | Pharmacological inhibition of Peroxisome Proliferation-Activated Receptor Delta (PPARδ) imparts selective leukemia cell death |
| title_fullStr | Pharmacological inhibition of Peroxisome Proliferation-Activated Receptor Delta (PPARδ) imparts selective leukemia cell death |
| title_full_unstemmed | Pharmacological inhibition of Peroxisome Proliferation-Activated Receptor Delta (PPARδ) imparts selective leukemia cell death |
| title_short | Pharmacological inhibition of Peroxisome Proliferation-Activated Receptor Delta (PPARδ) imparts selective leukemia cell death |
| title_sort | pharmacological inhibition of peroxisome proliferation activated receptor delta pparδ imparts selective leukemia cell death |
| topic | 6-methoxydihydroavicine Acute myeloid leukemia PPAR Fatty acid oxidation |
| url | https://doi.org/10.1186/s40170-025-00402-5 |
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