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KMID : 0606920230310030319
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Biomolecules & Therapeutics
2023 Volume.31 No. 3 p.319 ~ p.329
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Inhibition of DNMT3B and PI3K/AKT/mTOR and ERK Pathways as a Novel Mechanism of Volasertib on Hypomethylating Agent-Resistant Cells
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Choi Eun-Ji
Koo Bon-Kwan
Hur Eun-Hye
Moon Ju-Hyun
Kim Ji-Yun
Park Han-Seung
Choi Yun-Suk
Lee Kyoo-Hyung
Lee Jung-Hee
Choi Eun-Kyung
Lee Je-Hwan
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Abstract
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Resistance to hypomethylating agents (HMAs) in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) is a concerning problem. Polo-like kinase 1 (PLK1) is a key cell cycle modulator and is known to be associated with an activation of the PI3K pathway, which is related to the stabilization of DNA methyltransferase 1 (DNMT1), a target of HMAs. We investigated the effects of volasertib on HMA-resistant cell lines (MOLM/AZA-1 and MOLM/DEC-5) derived from MOLM-13, and bone marrow (BM) samples obtained from patients with MDS (BM blasts >5%) or AML evolved from MDS (MDS/AML). Volasertib effectively inhibited the proliferation of HMA-resistant cells with suppression of DNMTs and PI3K/AKT/mTOR and ERK pathways. Volasertib also showed significant inhibitory effects against primary BM cells from patients with MDS or MDS/AML, and the effects of volasertib inversely correlated with DNMT3B expression. The DNMT3B-overexpressed AML cells showed primary resistance to volasertib treatment. Our data suggest that volasertib has a potential role in overcoming HMA resistance in patients with MDS and MDS/AML by suppressing the expression of DNMT3 enzymes and PI3K/AKT/mTOR and ERK pathways. We also found that DNMT3B overexpression might be associated with resistance to volasertib.
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KEYWORD
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Volasertib, Hypomethylating agent-resistance, DNA methyltransferase, PI3K/AKT/mTOR, ERK pathway
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