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Background <p>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.</p> Methods <p>AML cell lines and patient-derived cells were used to assess the activity of 6ME in vitro and in vivo<i>.</i> Computational methods, immunoblotting, and co-IP-HPLC analysis assessed the molecular target, and cellular consequence of 6ME activity.</p> Results <p>6ME induced cytotoxicity of AML cell lines (IC<sub>50</sub>: 1.0 ± 0.13&#xa0;μM) and patient-derived cells while sparing normal hematopoietic cells. Mouse engraftment studies showed that 6ME (5&#xa0;mg/kg, three times/week for 4&#xa0;weeks) selectively reduced patient-derived AML cell engraftment without affecting hematopoietic cell engraftment or imparting toxicity. Mechanistically, 6ME bound to and inhibited&#xa0;PPARδ leading to&#xa0;downregulated FAO gene expression (i.e., CD36 and CPT2) and reduced fatty acid cellular uptake resulting in FAO inhibition.</p> Conclusion <p>Pharmacological inhibition of PPARδ with 6ME is a novel approach to inducing selective death in AML.</p>

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Pharmacological inhibition of Peroxisome Proliferation-Activated Receptor Delta (PPARδ) imparts selective leukemia cell death

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月25日

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  • Yingying Yang,
  • Ekaterina Parfenova,
  • Nikolina Vrdoljak,
  • Mark Minden,
  • Jessica Luc,
  • Andrew C. Doxey,
  • Paul A. Spagnuolo

摘要

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.