Synergistic inhibition of tumor cell proliferation by metformin and mito-metformin in the presence of iron chelators. - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Oncotarget Année : 2019

Synergistic inhibition of tumor cell proliferation by metformin and mito-metformin in the presence of iron chelators.

Résumé

We demonstrate that combined treatment with metformin (Met) or its mitochondria-targeted analog, mito-metformin (Mito-Met), and various iron chelators synergistically inhibits proliferation of pancreatic and triple-negative breast cancer cells. Previously, we reported that Met (at millimolar levels) and Mito-Met (at micromolar levels) inhibited pancreatic cancer cell proliferation. Inhibition of mitochondrial complex I and mitochondrial oxidative phosphorylation (OXPHOS) through stimulation of mitochondrial redox signaling was proposed as a key mechanism for decreased cancer cell proliferation. Because of its poor bioavailability, the use of Met as a "stand-alone" antitumor drug has been questioned. Iron chelators such as deferasirox (DFX) and dexrazoxane (DXR) exhibit antiproliferative effects in cancer cells. The potency of Met and Mito-Met was synergistically enhanced in the presence of iron chelators, DFX, N,N'-bis(2-hydroxyphenyl)ethylendiamine-N,N'-diacetic acid (HBED), and deferoxamine (DFO). Met, DXR (also ICRF-187), and DFO are FDA-approved drugs for treating diabetes, decreasing the incidence and severity of cardiotoxicity following chemotherapy, and mitigating iron toxicity, respectively. Thus, the synergistic antiproliferative effects of Met and Met analogs and iron chelators may have significant clinical relevance in cancer treatment. These findings may have implications in other OXPHOS-mediated cancer therapies.

Domaines

Chimie

Dates et versions

hal-02491548 , version 1 (26-02-2020)

Identifiants

Citer

Gang Cheng, Jacek Zielonka, Micael Hardy, Olivier Ouari, Christopher R. Chitambar, et al.. Synergistic inhibition of tumor cell proliferation by metformin and mito-metformin in the presence of iron chelators.. Oncotarget, 2019, 10 (37), pp.3518--3532. ⟨10.18632/oncotarget.26943⟩. ⟨hal-02491548⟩
11 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More