Cargando…

Metformin enhances the cytotoxic effect of nilotinib and overcomes nilotinib resistance in chronic myeloid leukemia cells

BACKGROUND/AIMS: Nilotinib 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...

Descripción completa

Detalles Bibliográficos
Autores principales: Na, Yoo Jin, Yu, Eun Sang, Kim, Dae Sik, Lee, Dae-Hee, Oh, Sang Cheul, Choi, Chul Won
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Korean Association of Internal Medicine 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009173/
https://www.ncbi.nlm.nih.gov/pubmed/32241082
http://dx.doi.org/10.3904/kjim.2019.336
_version_ 1783672829451960320
author Na, Yoo Jin
Yu, Eun Sang
Kim, Dae Sik
Lee, Dae-Hee
Oh, Sang Cheul
Choi, Chul Won
author_facet Na, Yoo Jin
Yu, Eun Sang
Kim, Dae Sik
Lee, Dae-Hee
Oh, Sang Cheul
Choi, Chul Won
author_sort Na, Yoo Jin
collection PubMed
description BACKGROUND/AIMS: Nilotinib 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. METHODS: We 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. RESULTS: Sub-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. CONCLUSIONS: This study suggested that combination therapy with metformin and nilotinib may have clinical benefits of enhancing antileukemia efficacy and overcoming resistance to nilotinib.
format Online
Article
Text
id pubmed-8009173
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher The Korean Association of Internal Medicine
record_format MEDLINE/PubMed
spelling pubmed-80091732021-04-02 Metformin enhances the cytotoxic effect of nilotinib and overcomes nilotinib resistance in chronic myeloid leukemia cells Na, Yoo Jin Yu, Eun Sang Kim, Dae Sik Lee, Dae-Hee Oh, Sang Cheul Choi, Chul Won Korean J Intern Med Original Article BACKGROUND/AIMS: Nilotinib 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. METHODS: We 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. RESULTS: Sub-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. CONCLUSIONS: This study suggested that combination therapy with metformin and nilotinib may have clinical benefits of enhancing antileukemia efficacy and overcoming resistance to nilotinib. The Korean Association of Internal Medicine 2021-03 2020-04-03 /pmc/articles/PMC8009173/ /pubmed/32241082 http://dx.doi.org/10.3904/kjim.2019.336 Text en Copyright © 2021 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
Na, Yoo Jin
Yu, Eun Sang
Kim, Dae Sik
Lee, Dae-Hee
Oh, Sang Cheul
Choi, Chul Won
Metformin enhances the cytotoxic effect of nilotinib and overcomes nilotinib resistance in chronic myeloid leukemia cells
title Metformin enhances the cytotoxic effect of nilotinib and overcomes nilotinib resistance in chronic myeloid leukemia cells
title_full Metformin enhances the cytotoxic effect of nilotinib and overcomes nilotinib resistance in chronic myeloid leukemia cells
title_fullStr Metformin enhances the cytotoxic effect of nilotinib and overcomes nilotinib resistance in chronic myeloid leukemia cells
title_full_unstemmed Metformin enhances the cytotoxic effect of nilotinib and overcomes nilotinib resistance in chronic myeloid leukemia cells
title_short Metformin enhances the cytotoxic effect of nilotinib and overcomes nilotinib resistance in chronic myeloid leukemia cells
title_sort metformin enhances the cytotoxic effect of nilotinib and overcomes nilotinib resistance in chronic myeloid leukemia cells
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009173/
https://www.ncbi.nlm.nih.gov/pubmed/32241082
http://dx.doi.org/10.3904/kjim.2019.336
work_keys_str_mv AT nayoojin metforminenhancesthecytotoxiceffectofnilotinibandovercomesnilotinibresistanceinchronicmyeloidleukemiacells
AT yueunsang metforminenhancesthecytotoxiceffectofnilotinibandovercomesnilotinibresistanceinchronicmyeloidleukemiacells
AT kimdaesik metforminenhancesthecytotoxiceffectofnilotinibandovercomesnilotinibresistanceinchronicmyeloidleukemiacells
AT leedaehee metforminenhancesthecytotoxiceffectofnilotinibandovercomesnilotinibresistanceinchronicmyeloidleukemiacells
AT ohsangcheul metforminenhancesthecytotoxiceffectofnilotinibandovercomesnilotinibresistanceinchronicmyeloidleukemiacells
AT choichulwon metforminenhancesthecytotoxiceffectofnilotinibandovercomesnilotinibresistanceinchronicmyeloidleukemiacells