Mitochondrial-Mediated Apoptosis and Anti-Leukemic Effects of Tocotrienol Within the Protective Bone Marrow Microenvironment

Abstract

Abstract Purpose: Acute Myeloid Leukemia (AML) is a highly aggressive hematological malignancy driven by mutations in early hematopoietic cells, leading to uncontrolled myeloid cell proliferation. The development of efficacious and less toxic therapies remains a critical challenge. Methods: Herein, we evaluated the anti-leukemic potential of a 70% tocotrienol-enriched fraction (TEF), a vitamin E isoform, using different AML models. Results: TEF demonstrated selective cytotoxicity against AML cells, evidenced by low IC50 values and significant induction of apoptosis in AML cell lines and primary AML patient samples, with minimal impact on nonmalignant cells. Mechanistic studies revealed that the TEF treatment disrupted mitochondrial function, leading to reduced mitochondrial membrane potential and ROS generation in AML cells. This triggered the intrinsic apoptotic pathway, as indicated by decreased BCL2 and increased active caspase-3 levels. In a 3D bone marrow niche co-culture system, the treatment with TEF effectively diminished AML cell populations (OCI-AML3 and primary AML cells) while preserving mesenchymal stromal cells and endothelial cells. Importantly, administration of TEF reduced AML burden in leukemic mice. Conclusions: These comprehensive results suggest that the 70% tocotrienol-enriched fraction holds significant promise as a selective anti-neoplastic agent for AML, capable of targeting leukemic cells even within the protective bone marrow microenvironment.