Type

Journal Article

Authors

Peter O'Gorman
Constantine S Mitsiades
Martin Clynes
Kenneth Anderson
Paul Richardson
Jake Delmore
Steffen Klippel
Jana Jakubikova
Justine Meiller
Melissa G Ooi
and 1 others

Subjects

Microbiology

Topics
pharmacokinetics bortezomib drug effects cell line tumor drug therapy cell line biological transport coculture techniques pathology antineoplastic agents cellular microenvironment rhodamine 123 pharmacology metabolism boronic acids humans p glycoprotein pyrazines gene expression regulation fluorescent dyes genetics multiple myeloma stromal cells drug resistance neoplasm

The interaction of bortezomib with multidrug transporters: implications for therapeutic applications in advanced multiple myeloma and other neoplasias. (2012)

Abstract 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. 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. 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. 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.
Collections Ireland -> Dublin City University -> PubMed

Full list of authors on original publication

Peter O'Gorman, Constantine S Mitsiades, Martin Clynes, Kenneth Anderson, Paul Richardson, Jake Delmore, Steffen Klippel, Jana Jakubikova, Justine Meiller, Melissa G Ooi and 1 others

Experts in our system

1
Peter O'Gorman
Dublin City University
Total Publications: 15
 
2
Martin Clynes
Dublin City University
Total Publications: 209
 
3
Kenneth Anderson
Dublin City University
Total Publications: 5
 
4
Paul Richardson
Dublin City University
Total Publications: 6
 
5
Justine Meiller
Dublin City University
Total Publications: 7