Pinostrobin modulates FOXO3 expression, nuclear localization, and exerts antileukemic effects in AML cells and zebrafish xenografts

Pei-Yi Chen; Ching-Yen Lin; Chia-Ling Wu; Pei Ying Keak; Je-Wen Liou; Wan-Yun Gao; Liang-In Lin; Jui-Hung Yen

doi:10.1016/j.cbi.2023.110729

Pinostrobin modulates FOXO3 expression, nuclear localization, and exerts antileukemic effects in AML cells and zebrafish xenografts

Chem Biol Interact. 2023 Nov 1:385:110729. doi: 10.1016/j.cbi.2023.110729. Epub 2023 Sep 28.

Authors

Pei-Yi Chen¹, Ching-Yen Lin², Chia-Ling Wu³, Pei Ying Keak², Je-Wen Liou⁴, Wan-Yun Gao⁵, Liang-In Lin⁶, Jui-Hung Yen⁷

Affiliations

¹ Laboratory of Medical Genetics, Genetic Counseling Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, 970374, Taiwan; Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, 970374, Taiwan.
² Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, 970374, Taiwan.
³ Laboratory of Medical Genetics, Genetic Counseling Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, 970374, Taiwan.
⁴ Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien, 970374, Taiwan.
⁵ Institute of Medical Sciences, Tzu Chi University, Hualien, 970374, Taiwan.
⁶ Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, 10048, Taiwan.
⁷ Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, 970374, Taiwan; Institute of Medical Sciences, Tzu Chi University, Hualien, 970374, Taiwan. Electronic address: imyenjh@gms.tcu.edu.tw.

PMID: 37777166
DOI: 10.1016/j.cbi.2023.110729

Abstract

Acute myeloid leukemia (AML) is a disease characterized by abnormal cell proliferation in the bone marrow and is the most common quickly progressive leukemia in adults. Pinostrobin, a flavonoid phytochemical, has been reported to exhibit antioxidant, anti-inflammatory, and anticancer properties. In this study, we aimed to investigate the antileukemic effects of pinostrobin and its molecular mechanisms in human AML cells. Our study found that pinostrobin (0-80 μM) significantly reduced the viability of human AML cells, with the pronounced cytotoxic effects observed in MV4-11 > MOLM-13 > HL-60 > U-937 > THP-1 cells. Pinostrobin was found to suppress leukemia cell proliferation, modulate cell cycle progression, promote cell apoptosis, and induce monocytic differentiation in MV4-11 cells. In animal studies, pinostrobin significantly suppressed the growth of leukemia cells in a zebrafish xenograft model. Microarray-based transcriptome analysis showed that the differentially expressed genes (DEGs) in pinostrobin-treated cells were strongly associated with enriched Gene Ontology (GO) terms related to apoptotic process, cell death, cell differentiation, cell cycle progression, and cell division. Combining DisGeNET and STRING database analysis revealed that pinostrobin upregulates forkhead box 3 (FOXO3), a tumor suppressor in cancer development, and plays an essential role in controlling AML cell viability. Our study demonstrated that pinostrobin increases FOXO3 gene expression and promotes its nuclear translocation, leading to the inhibition of cell growth. Finally, the study found that pinostrobin, when combined with cytarabine, synergistically reduces the viability of AML cells. Our current findings shed light on pinostrobin's mechanisms in inhibiting leukemia cell growth, highlighting its potential as a chemotherapeutic agent or nutraceutical supplement for AML prevention or treatment.

Keywords: AML; Cytarabine; FOXO3; Pinostrobin; Zebrafish xenograft.