Mechanisms of Antiproliferative Effects of Nobiletin, Scoparone, and Tangeretin Isolated from Citrus reticulata Peel Dichloromethane Extract in Acute Myeloid Leukemia Cells

Russo, C, Nahar, L ORCID: 0000-0002-1157-2405, Ismail, FMD ORCID: 0000-0002-3595-6665, Navarra, M and Sarker, S ORCID: 0000-0003-4038-0514 (2026) Mechanisms of Antiproliferative Effects of Nobiletin, Scoparone, and Tangeretin Isolated from Citrus reticulata Peel Dichloromethane Extract in Acute Myeloid Leukemia Cells. International Journal of Molecular Sciences, 27 (3). ISSN 1661-6596

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Abstract

Citrus reticulata Blanco peel is a dominant industrial waste that was recently revalued as a source of bioactive molecules. This study explored its phytochemical and antileukemic potentials. The bioassay-guided fractionation of the dichloromethane extract yielded nobiletin, scoparone, and tangeretin, which were identified spectroscopically. The extract, fractions, and compounds showed antiproliferative effects in both THP-1 and U937 cells, which were employed as in vitro models of acute myeloid leukemia (AML). According to cytofluorimetric analysis, the extract and fractions inhibited cell growth by both apoptosis and necrosis, whereas the single molecules induced apoptosis. This mechanism was mediated by the modulation of BAX and BCL-2 genes in both AML cell lines. Notably, each treatment drove THP-1 and U937 cells into the sub-G0 phase, together with an increase in the cell population in the G1 phase of the cell cycle, both of which were detected cytofluorimetrically. In line with these findings, the extract, fractions, and single molecules counteracted the overexpression of CYCLIN A1 in THP-1 cells while reducing the expression of CYCLIN D2 in U937 cells. Moreover, cell treatments attenuated the invasiveness of AML cells through the upregulation of TIMP-2 at the transcriptional level. Therefore, this study supports pharmaceutical interest in citrus waste for cancer management, providing evidence on its antileukemic potential in vitro.

Item Type:	Article
Uncontrolled Keywords:	0399 Other Chemical Sciences; 0604 Genetics; 0699 Other Biological Sciences; Chemical Physics; 3101 Biochemistry and cell biology; 3107 Microbiology; 3404 Medicinal and biomolecular chemistry
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) R Medicine > RS Pharmacy and materia medica
Divisions:	Pharmacy and Biomolecular Sciences
Publisher:	MDPI AG
Date of acceptance:	23 January 2026
Date of first compliant Open Access:	28 January 2026
Date Deposited:	28 Jan 2026 11:46
Last Modified:	28 Jan 2026 11:46
DOI or ID number:	doi.org/10.3390/ijms27031256
URI:	https://researchonline.ljmu.ac.uk/id/eprint/27998

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