Abstract
Recent studies have demonstrated that several chelators possess marked potential as potent anti-neoplastic drugs and as agents that can ameliorate some of the adverse effects associated with standard chemotherapy. Anti-cancer treatment employs combinations of several drugs that have different mechanisms of action. However, data regarding the potential interactions between iron chelators and established chemotherapeutics are lacking. Using estrogen receptor-positive MCF-7 breast cancer cells, we explored the combined anti-proliferative potential of four iron chelators, namely: desferrioxamine (DFO), salicylaldehyde isonicotinoyl hydrazone (SIH), (E)-N′-[1-(2-hydroxy-5-nitrophenyl)ethyliden] isonicotinoyl hydrazone (NHAPI), and di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), plus six selected anti-neoplastic drugs. These six agents are used for breast cancer treatment and include: paclitaxel, 5-fluorouracil, doxorubicin, methotrexate, tamoxifen and 4-hydroperoxycyclophosphamide (an active metabolite of cyclophosphamide). Our quantitative chelator-drug analyses were designed according to the Chou-Talalay method for drug combination assessment. All combinations of these agents yielded concentration-dependent, anti-proliferative effects. The hydrophilic siderophore, DFO, imposed antagonism when used in combination with all six anti-tumor agents and this antagonistic effect increased with increasing dose. Conversely, synergistic interactions were observed with combinations of the lipophilic chelators, NHAPI or Dp44mT, with doxorubicin and also the combinations of SIH, NHAPI or Dp44mT with tamoxifen. The combination of Dp44mT with anti-neoplastic agents was further enhanced following formation of its redox-active iron and especially copper complexes. The most potent combinations of Dp44mT and NHAPI with tamoxifen were confirmed as synergistic using another estrogen receptor-expressing breast cancer cell line, T47D, but not estrogen receptor-negative MDA-MB-231 cells. Furthermore, the synergy of NHAPI and tamoxifen was confirmed using MCF-7 cells by electrical impedance data, a mitochondrial inner membrane potential assay and cell cycle analyses. This is the first systematic investigation to quantitatively assess interactions between Fe chelators and standard chemotherapies using breast cancer cells. These studies are vital for their future clinical development.
Highlights
Breast cancer is a common malignancy and is one of the leading causes of cancer deaths among women [1]
PTX was purchased from Cedarburg Hauser Pharmaceuticals (Denver, U.S.A.), 5FU was from Sandoz (Holzkirchen, Germany), MTX was obtained from Hospira (Lake Forrest, U.S.A.), DOX was from Teva Pharmaceuticals (Petach Tikva, Israel), TMX was from Sigma-Aldrich (Schnelldorf, Germany) and 4HC was from Santa Cruz Biotechnology (Santa Cruz, U.S.A.)
Of the chelators used in this study, DFO, salicylaldehyde isonicotinoyl hydrazone (SIH), and NHAPI displayed comparable antiproliferative properties, with IC50 values between 14.0–19.1 mM
Summary
Breast cancer is a common malignancy and is one of the leading causes of cancer deaths among women [1]. An accumulating body of evidence suggests a role for iron (Fe) in the etiology of breast cancer (reviewed in [2]). Rapidly growing and dividing cancer cells have a higher requirement for Fe (reviewed in [3,4]) and breast cancer cells possess multiple mechanisms to increase cellular Fe levels. Breast cancer cells: (1) express high levels of transferrin receptor 1 on their surface [5]; (2) demonstrate decreased expression of the Fe efflux protein, ferroportin1 [6]; and (3) synthesize transferrin, which is stimulated by estrogen receptor signaling and may increase Fe uptake via an autocrine mechanism [7]. High Fe levels have been identified as a risk factor for breast cancer development [11,12]
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