Delivery of doxorubicin across the blood-brain barrier by ondansetron pretreatment: a study in vitro and in vivo

Cancer Lett. 2014 Oct 28;353(2):242-7. doi: 10.1016/j.canlet.2014.07.018. Epub 2014 Jul 29.

Abstract

Doxorubicin (Dox) has got a limited efficacy in the treatment of central nervous system tumors because of its poor penetration through blood-brain barrier mediated by MDR efflux transporters. We investigated the possibility that ondansetron (Ond) enhances Dox cytotoxicity in cell lines interfering with P-glycoprotein and increases Dox concentration in rat brain tissues. The MDR phenotype was studied using human hepatocellular carcinoma cell line PLC/PRF/5 (P5 and P1(0.5) clones), two subclones of NIH 3T3 cells (PSI-2 and PN1A) and two glioblastoma cell lines (A172, U87MG). Rats were pretreated with Ond before injection of Dox. Quantitative analysis of Dox was performed by mass spectrometry. Our in vitro experiments demonstrated that Ond at 10 µg/ml is not toxic to all cell lines. However, Ond reverses the MDR phenotype in P1(0.5) and PN1A cell lines. In addition, we showed that pretreatment with Ond increases Dox concentration in rat brain tissues, without increasing acute heart and renal toxicity.

Keywords: Blood–brain barrier; Brain tumors; Doxorubicin; Multidrug resistance; Ondansetron.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • Antibiotics, Antineoplastic / pharmacokinetics*
  • Blood-Brain Barrier / metabolism*
  • Brain Neoplasms / drug therapy*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Doxorubicin / pharmacokinetics*
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm
  • Humans
  • Lipid Peroxidation
  • Male
  • Mice
  • NIH 3T3 Cells
  • Ondansetron / pharmacology*
  • Rats
  • Rats, Wistar
  • Tissue Distribution

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antibiotics, Antineoplastic
  • Ondansetron
  • Doxorubicin