Luteolin reduces cytarabine-resistant acute myeloid leukemia cell proliferation through the GSK3β/Nrf2 pathway.

Abstract

UNLABELLED: Cytarabine (Ara-C) is a core drug for the treatment of acute myeloid leukemia (AML), but its efficacy is often limited by drug resistance. Luteolin has been shown to inhibit AML cell proliferation and induce apoptosis; however, whether the combined application of both agents can further inhibit AML cell proliferation remains unclear. Ara-C-resistant cell models were established using HL-60/KG-1 cells, and Ara-C-resistant HL-60 cells were injected into nude mice to establish a xenograft animal model. Cell proliferation and apoptosis were detected using a CCK-8 assay, soft agar colony formation assay, and flow cytometry. Western blotting was used to detect protein expression. Luteolin significantly inhibited the proliferation of Ara-C-resistant AML cells. Compared with single-drug treatment, combined treatment with luteolin and Ara-C further reduced cell viability and colony formation ability and induced S-phase cell cycle arrest and apoptosis. Additionally, luteolin alone or in combination with Ara-C significantly inhibited the growth of drug-resistant AML xenograft tumors. Mechanistic studies revealed that luteolin significantly suppressed the expression of Nrf2 and its downstream antioxidant proteins HO-1 and NQO1, reduced intracellular GSH levels, and promoted ROS accumulation. The Nrf2 activator ML334 partially reversed the therapeutic effect of luteolin. Further investigation revealed that luteolin did not affect Keap1 expression but inhibited GSK3β phosphorylation, thereby activating GSK3β. The GSK3β inhibitor LiCl attenuated the ability of luteolin to promote Nrf2 ubiquitination and degradation. Luteolin inhibits the proliferation of Ara-C-resistant AML cells by activating GSK3β to promote Nrf2 ubiquitination and degradation, thereby inhibiting Nrf2-mediated antioxidant effects. The combined treatment of luteolin and Ara-C is more effective than either agent alone. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s10616-026-01106-4.

Key Findings

• Luteolin significantly inhibits proliferation of cytarabine-resistant acute myeloid leukemia (AML) cells.
• Combined treatment with luteolin and cytarabine further reduces cell viability, induces S-phase arrest, and promotes apoptosis compared to single treatments.
• Luteolin suppresses Nrf2 and downstream antioxidant proteins by activating GSK3β, promoting Nrf2 ubiquitination and degradation, which enhances therapeutic efficacy against drug-resistant AML.

Clinical Significance

Citation

Cui Tingting, Song Chunyan, Fan Xinet al.. Luteolin reduces cytarabine-resistant acute myeloid leukemia cell proliferation through the GSK3β/Nrf2 pathway. Cytotechnology. 2026-Dec.