In vitro investigation of the potential effects of the selective ALK/IGF-1R inhibitor AZD3463 in breast cancer
Project no. 20726 · Status: Kapanmış (Yayın bekleniyor) · 2019
Summary
In our study, we aimed to investigate the anticancer effect of AZD3463 when used alone or in combination with an antidiabetic drug, metformin, in different types of breast cancer models under high glucose conditions, the possible interaction type with metformin, and the molecular mechanisms of the effects. Antiproliferative effect was evaluated by WST-1 test, interaction type was evaluated by isobologram analysis. The effects on apoptosis and mitochondrial membrane potential were determined using flow cytometry, and the effects on ROS formation were determined spectrophotometrically. Gene expressions in related pathways were investigated by qRT-PCR. The results revealed that AZD3463 significantly reduced cell viability in MDA-MB-231 and MCF-7 breast adenocarcinoma cells and breast cancer stem cells. More importantly, AZD3463 and metformin interacted synergistically in MDA-MB-231 cells and additively in stem cells. These results were shown for the first time in our study. In our study, we provided findings that the effects of AZD3463 and/or AZD3463+metformin combination may be related to ROS formation and apoptotic cell death. Gene expression changes in related pathways also support these results. As a result, the effect of AZD3463 on breast adenocarcinoma cells, as well as stem cells, and the synergistic interaction of its combination with metformin in cancer types that are difficult to treat, such as MDA-MB-231, are promising for the use of this compound in the treatment of breast cancer. Keywords: AZD3463, breast cancer, hyperglycemia, stem cell