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

Abstract

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.

Deep Phosphoproteomic Elucidation of Metformin-Signaling in Heterogenous Colorectal Cancer Cells

“…For instance, as for paclitaxel, metformin has been reported to sensitize ovarian, endometrial, melanoma, and prostate cancer cells to paclitaxel treatment (Dos Santos Guimaraes et al, 2018; Hanna et al, 2012; Ko et al, 2019; Lee and Park, 2021; Lengyel et al, 2015; Zhao et al, 2019). As for nilotinib, metformin has increased the efficacy of nilotinib in chronic myelogenous leukemia cell lines (Na et al, 2021). As for vorinostat, metformin and vorinostat have shown a synergy in overcoming EGFR tyrosine kinase inhibitor resistance in non-small cell lung cancer (Chen et al, 2017).…”

Identification and overcoming rituximab resistance in diffuse large B-cell lymphoma using next-generation sequencing

“…Our previous study showed that deferasirox induced apoptosis in human lymphoma cell lines [ 13 ]. Furthermore, in our previous studies, we developed tyrosine kinase resistant chronic myeloid leukemia (CML) cell lines by sequential exposure to gradually increasing concentrations of drug, and demonstrated that cotreatment with deferasirox and imatinib downregulated NF-κB activity and exerted a synergistic effect in imatinib-resistant CML cell line [ 28 , 29 ].…”

Mitochondrial oxidative phosphorylation is dispensable for survival of CD34+ chronic myeloid leukemia stem and progenitor cells

“…Based on the metabolic proteome, we seek compounds that may reverse the metabolic aberrations. The inhibitory effect of metformin on a number of cancer types as well as its synergistic effect with clinical available compounds have been proposed [ 47 – 49 ]. We expected that metformin could inhibit the increased expression of TCA proteins as well as known high TCA activity in CML stem/progenitor cells, thus result in killing of these cells.…”