Details

Autor(en) / Beteiligte

• Barranco, María Manuela
• Zecchinati, Felipe
• Perdomo, Virginia Gabriela
• Habib, Martín José
• Rico, María José
• Rozados, Viviana Rosa
• Salazar, Mario
• Fusini, Matías Ezequiel
• Scharovsky, Olga Graciela
• Villanueva, Silvina Stella Maris
• Mainetti, Leandro Ernesto
• García, Fabiana

Titel

Intestinal ABC transporters: Influence on the metronomic cyclophosphamide-induced toxic effect in an obese mouse mammary cancer model

Ist Teil von

• Toxicology and applied pharmacology, 2024-10, Vol.492, p.117130, Article 117130

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2024

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Metronomic chemotherapy (MCT) is a cancer therapeutic approach characterized by low dose drug chronic administration and limited or null toxicity. Obesity-induced metabolic alterations worsen cancer prognosis and influence the intestinal biochemical barrier, altering the Multidrug resistance-associated protein 2 (Mrp2) and Multidrug resistance protein-1 (Mdr-1), efflux pumps that transport chemotherapeutic drugs. Obesity and cancer are frequent co-morbidities; thus, our aim was to evaluate the effectiveness and toxicity of MCT with cyclophosphamide (Cy) in obese mice with metabolic alterations bearing a mammary adenocarcinoma. Simultaneously, the expression and activities of intestinal Mrp2 and Mdr-1 were assessed. CBi male mice, were fed with chow diet (C) or diet with 40 % of fat (HFD). After 16 weeks, metabolic alterations were confirmed by biochemical and morphological parameters. At that time-point, HFD group showed decreased expressions of Mrp2 mRNA (53 %) as well as Mdr-1a and Mdr-1b (42 % and 59 %, respectively), compared to C (P < 0.05). This result correlated with decreased intestinal Mrp2 and Mdr-1 efflux activities (64 % and 45 %, respectively), compared to C (P < 0.05). Ultimately, mice were challenged with M-406 mammary adenocarcinoma; when the tumor was palpable, mice were distributed into 4 groups. The % inhibition of tumor growth with Cy (30 mg/kg/day) in C + Cy was higher than that of HFD + Cy (P = 0.052). Besides, it was observed a 21 % diminution in body weight and leukopenia in the HFD + Cy group. Conclusion: Obesity-induced metabolic alterations impair intestinal Mrp2 and Mdr-1 functions, bringing about increments in Cy absorption, leading to toxicity; in addition, the antitumor effectiveness of MCT decreased in obese animals. •High-fat diet develops obesity and its associated metabolic alterations in CBi mice.•High-fat diet downregulates Mrp2 and Mdr-1 diminishing its barrier function.•Impairment of intestinal Mrp2 and Mdr-1 could have an impact on drug bioavailability.•Altered barrier function increments cyclophosphamide absorption leading to toxicity.•Metronomic chemotherapy with cyclophosphamide is less efficient in obese CBi mice.