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

• Doxorubicin penetration through blood–brain barrier mediated by MDR efflux pumps.
• Impact of ondansetron pretreatment on doxorubicin delivery in preclinical models.
• Ondansetron reverses MDR phenotype in cancer cells, sensitizing them to doxorubicin.
• Ondansetron pretreatment allows an accumulation of doxorubicin within the rat brain.

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.