Altered therapeutic response to metronomic chemotherapyin a metabolic syndrome model of mice bearing a mammary adenocarcinoma: implication of intestinal ABC transporters

BARRANCO MM; SIGAL NICOLÁS; DEL GIUDICE A; SCHAROVSKY OG; MAINETTI L.E; HABIB MARTÍN; SYLVESTRE BEGNIS M; RICO M.J; VILLANUEVA SILVINA; DI CARLO BIANCA; ZECHINATTI F; ROZADOS V; GARCÍA FABIANA

Philadelphia

Congreso; American Association for Cancer Research ANNUAL MEETING 2021; 2021

Americn Association for Cancer Research

Breast cancer is one of the most prevalent and deadly cancers worldwide. Its prognosis depends on the cell type, as well as the age and comorbidities of eachpatient.A novel therapeutic approach is metronomic chemotherapy (MCT) characterized by chronic, low dose drug administration with therapeutic efficacy andlow or null toxicity as majoradvantages. The comorbidity that worsens cancerprognosis is metabolic syndrome(MS) characterized by obesity, insulinresistance, hyperglycemia, hypertriglyceridemia and hypercholesterolemia, and a chronic systemic inflammatory state.Theseconditions influencethe intestinal biochemical barrier, altering the multidrug resistance-associated protein 2 (Mrp2) and P-glycoprotein (P-gp)activities.Significantly, these two efflux pumps transport chemotherapeutics drugs such as cyclophosphamide (Cy). Our aim was to evaluate the effectiveness and toxicity of MCT with Cyin mice with metabolic syndromebearing a mammary adenocarcinoma. Simultaneously, the activities of the intestinal efflux transporters were assessed.CBi male mice (5 weeks n=20/group), were fed with a chow diet (C) and a diet with 40% calories of fat (HFD) throughout the experiment. At 16 weeks, the development of MS was confirmed by biochemical and morphological parameters. The Mrp2 and P-gpactivitieswere evaluated using the in vitro model of everted intestinal sacs.Once the MS features were settled, mice werechallenged s.c. with triple negative M-406 mammary adenocarcinoma (day 0); when the tumor was palpable, mice were distributed into 4 groups (n=8/group):GI: C no treatment, GII:C+Cy (30 mg/kg/day in drinking water), GIII: HFD no treatment and GIV: HFD+Cy. Efflux of Mrp2 substrate DNP-SG decreased 64% in HFD respect to C (P