The interaction of bortezomib with multidrug transporters: implications for therapeutic applications in advanced multiple myeloma and other neoplasias
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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.
KeywordsP-glycoprotein MDR protein Bortezomib Elacridar Co-culture
Conflict of interest
Dr. Kenneth Anderson disclosed the following relevant financial relationships: Served as a consultant for Celgene Corporation, Millennium Pharmaceuticals, Inc., Onyx Pharmaceuticals, Inc., Sanofi and Gilead. Stock Ownership in Oncopep and Acetylon Pharmaceuticals; Dr. Paul Richardson disclosed the following relevant financial relationships: Served as a consultant for Millennium Pharmaceuticals, Inc., and Johnson & Johnson Pharmaceutical Research & Development, LLC; Dr. Constantine Mitsiades disclosed the following relevant financial relationships: Received funding for clinical research from Amgen Inc., AVEO Pharma, Genzyme Corporation, Johnson & Johnson Pharmaceutical Research & Development, LLC. Served as a consultant or received honoraria from Bristol-Myers Squibb company, Millennium Pharmaceuticals, Inc., Celgene Corporation, Centocor Research & Development, Inc, Merck & Co., Inc., Novartis Pharmaceuticals Corporation; Dr. Steffen Klippel disclosed the following relevant financial relationships: Stock Ownership in Novartis Pharmaceuticals. The other authors have no disclosures.
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