Synergistic inhibition of tumor cell proliferation by metformin and mito-metformin in the presence of iron chelators
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Gang Cheng1,2, Jacek Zielonka1,2,3, Micael Hardy7, Olivier Ouari7, Christopher R. Chitambar1,4, Michael B. Dwinell3,5,6 and Balaraman Kalyanaraman1,2,3
1 Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI 53226, USA
2 Free Radical Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
3 Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
4 Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
5 Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
6 Department of Surgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA
7 Aix Marseille University, CNRS, ICR, UMR 7273, Marseille 13013, France
Keywords: iron chelators; mitochondria-targeting agents; cancer cell proliferation; biguanide; metformin analogs
Received: March 21, 2019 Accepted: May 02, 2019 Published: May 28, 2019
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.
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