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

Toxicol Appl Pharmacol. 2024 Nov:492:117130. doi: 10.1016/j.taap.2024.117130. Epub 2024 Oct 18.

Abstract

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.

Keywords: ABC Transporters; Cancer; High-Fat Diet; Metronomic Chemotherapy; Obesity.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism
  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Administration, Metronomic*
  • Animals
  • Antineoplastic Agents, Alkylating / toxicity
  • Cyclophosphamide* / toxicity
  • Diet, High-Fat
  • Female
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology
  • Male
  • Mammary Neoplasms, Experimental / chemically induced
  • Mammary Neoplasms, Experimental / drug therapy
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Mice, Obese
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins / genetics
  • Multidrug Resistance-Associated Proteins / metabolism
  • Obesity* / metabolism

Substances

  • Cyclophosphamide
  • Multidrug Resistance-Associated Protein 2
  • Antineoplastic Agents, Alkylating
  • Multidrug Resistance-Associated Proteins
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP-Binding Cassette Transporters