ArticleThe Korean journal of internal medicine2021
Metformin enhances the cytotoxic effect of nilotinib and overcomes nilotinib resistance in chronic myeloid leukemia cells.
Article in The Korean journal of internal medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 10 citations in OpenAlex.
- Molecular Secrets Revealed: How Diabetes may be Paving the Way for Leukemia.Current treatment options in oncology · 2024Review
- Research Progress on the Use of Metformin in Leukemia Treatment.Current treatment options in oncology · 2024Review
- Identification and overcoming rituximab resistance in diffuse large B-cell lymphoma using next-generation sequencing.The Korean journal of internal medicine · 2023Article
- Action Mechanism of Metformin and Its Application in Hematological Malignancy Treatments: A Review.Biomolecules · 2023Review
- Hydroxycitric Acid Inhibits Chronic Myelogenous Leukemia Growth through Activation of AMPK and mTOR Pathway.Nutrients · 2022Article
- Mitochondrial oxidative phosphorylation is dispensable for survival of CD34Cell death & disease · 2022Article
- Mechanisms, Clinical Phenotype and Potential Risk Prediction for Cardiovascular Toxicity Induced by Tyrosine Kinase Inhibitors In Chronic Myeloid Leukemia.Dose-response : a publication of International Hormesis SocietyReview
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
BACKGROUND/
aimsNilotinib is used for treating patients with imatinib-sensitive or -resistant chronic myeloid leukemia (CML); however, nilotinib-resistant cases have been observed in recent years. In addition, a considerable number of patients receiving nilotinib developed diabetes. Metformin is a front-line drug for the treatment of type 2 diabetes, and several studies have shown that diabetes patients treated with metformin have reduced incidence of cancer. This study aimed to define the effect of metformin on CML cells to determine whether metformin overcomes nilotinib resistance, and to identify novel targets for the treatment of nilotinib resistance.
methodsWe observed the effects of metformin and nilotinib on K562 and KU812 human CML cell lines. Nilotinib-resistant CML cell lines were generated by exposing cells to gradually increasing doses of nilotinib. Then, we investigated the driving force that makes resistance to nilotinib and the effect of metformin on the driving force.
resultsSub-toxic doses of metformin enhanced nilotinib efficacy by reducing Bcl-xL expression, which induces apoptosis in CML cells. Next, we generated nilotinib-resistant K562 and KU812 cell lines that overexpressed the c-Jun N-terminal kinase (JNK) gene. JNK silencing by a JNK inhibitor restored sensitivity to nilotinib. Furthermore, metformin was effective in decreasing phosphorylated JNK levels, restoring nilotinib sensitivity. Combined treatment with nilotinib and metformin was more effective than combined treatment with nilotinib and a JNK inhibitor in terms of cell proliferation inhibition.
conclusionThis study suggested that combination therapy with metformin and nilotinib may have clinical benefits of enhancing antileukemia efficacy and overcoming resistance to nilotinib.
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