title: The interaction of bortezomib with multidrug transporters: implications for therapeutic applications in advanced multiple myeloma and other neoplasias.
abstract: OBJECTIVE
  Bortezomib is an important agent in multiple myeloma treatment, but resistance in cell lines and patients has been described. The main mechanisms of resistance described in cancer fall into one of two categories, pharmacokinetic resistance (PK), e.g. over expression of drug efflux pumps and pharmacodynamic resistance, e.g. apoptosis resistance or altered survival pathways, where the agent reaches an appropriate concentration, but this fails to propagate an appropriate cell death response. Of the known pump mechanisms, P-glycoprotein (P-gp) is the best studied and considered to be the most important in contributing to general PK drug resistance. Resistance to bortezomib is multifactorial and there are conflicting indications that cellular overexpression of P-gp may contribute to resistance agent. Hence, better characterization of the interactions of this drug with classical resistance mechanisms should identify improved treatment applications.
  
  
  METHODS
  Cell lines with different P-gp expression levels were used to determine the relationship between bortezomib and P-gp. Coculture system with stromal cells was used to determine the effect of the local microenvironment on the bortezomib-elacridar combination. To further assess P-gp function, intracellular accumulation of P-gp probe rhodamine-123 was utilised.
  
  
  RESULTS
  In the present study, we show that bortezomib is a substrate for P-gp, but not for the other drug efflux transporters. Bortezomib activity is affected by P-gp expression and conversely, the expression of P-gp affect bortezomib's ability to act as a P-gp substrate. The local microenvironment did not alter the cellular response to bortezomib. We also demonstrate that bortezomib directly affects the expression and function of P-gp.
  
  
  CONCLUSIONS
  Our findings strongly support a role for P-gp in bortezomib resistance and, therefore, suggest that combination of a P-gp inhibitor and bortezomib in P-gp positive myeloma would be a reasonable treatment combination to extend efficacy of this important drug.
authors.affiliation: School of Nursing and Human Sciences, Dublin City University, Dublin 9, Ireland.
authors.forename: Robert
authors.initials: R
authors.lastname: O'Connor
authors.forename: Melissa G
authors.initials: MG
authors.lastname: Ooi
authors.forename: Justine
authors.initials: J
authors.lastname: Meiller
authors.forename: Jana
authors.initials: J
authors.lastname: Jakubikova
authors.forename: Steffen
authors.initials: S
authors.lastname: Klippel
authors.forename: Jake
authors.initials: J
authors.lastname: Delmore
authors.forename: Paul
authors.initials: P
authors.lastname: Richardson
authors.forename: Kenneth
authors.initials: K
authors.lastname: Anderson
authors.forename: Martin
authors.initials: M
authors.lastname: Clynes
authors.forename: Constantine S
authors.initials: CS
authors.lastname: Mitsiades
authors.forename: Peter
authors.initials: P
authors.lastname: O'Gorman
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001692:Biological Transport; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002460:Cell Line; D045744:Cell Line, Tumor; D060833:Cellular Microenvironment; D018920:Coculture Techniques; D019008:Drug Resistance, Neoplasm; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D011719:Pyrazines / Q000494:pharmacology*; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D017154:Stromal Cells / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001897:Boronic Acids; D005456:Fluorescent Dyes; D011719:Pyrazines; D020112:Rhodamine 123; D000069286:Bortezomib