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

Synergistic inhibition of tumor cell proliferation by metformin and mito-metformin in the presence of iron chelators. Oncotarget. 2019 May 28;10(37):3518-3532 Authors: Cheng G, Zielonka J, Hardy M, Ouari O, Chitambar CR, Dwinell MB, Kalyanaraman B Abstract 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 toxic...
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research