Abstract 5214: Synergistic activity of aspirin, atenolol and metformin in the inhibition of angiogenesis, local and metastatic growth of breast cancer by targeting both neoplastic and microenvironment cells

We have recently described that the human white adipose tissue (WAT) contains progenitors with cooperative roles in breast cancer (BC) angiogenesis, local and metastatic progression (Martin-Padura et al, 2012; Orecchioni et al, 2013). The biguanide metformin (met), commonly used for type 2 diabetes, might have activity against BC and we found it able to inhibit angiogenesis in vivo (Dallaglio et al, 2014; Orecchioni et al, 2014). We studied met and another biguanide, phenformin (phe), in vitro and in vivo in orthotopic NSG murine models of local and metastatic BC. As met is frequently administered with aspirin or atenolol in diabetic/obese patients, we studied in vitro and vivo their association. In vitro, biguanides activated AMPK, inhibited complex 1 of the respiratory chain and induced apoptosis of BC and WAT endothelial cells. Aspirin was synergistic with met and phe in inducing apoptosis of estrogen receptor+ BC cells. This synergistic effect was less evident in triple negative BC cells. In co-culture, biguanides significantly inhibited the production of several angiogenic proteins. In vivo, biguanides inhibited local and metastatic growth of triple negative and HER2+ BC in immune-competent and immune-deficient mice orthotopically injected with BC. Biguanides also inhibited local and metastatic BC growth in a genetically engineered model of HER2+ BC. In vivo, biguanides increased pimonidazole binding (but not HIF-1 expression) of WAT progenitors, reduced tumor microvesse...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Tumor Biology Source Type: research