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

• Published in: Cancer chemotherapy and pharmacology 2013-05, Vol.71 (5), p.1357-1368
• Main Authors: O’Connor, Robert, Ooi, Melissa G., Meiller, Justine, Jakubikova, Jana, Klippel, Steffen, Delmore, Jake, Richardson, Paul, Anderson, Kenneth, Clynes, Martin, Mitsiades, Constantine S., O’Gorman, Peter
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents - pharmacology; ATP-Binding Cassette, Sub-Family B, Member 1 - drug effects; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biological and medical sciences; Biological Transport; Boronic Acids - pharmacology; Bortezomib; Cancer Research; Cell Line; Cell Line, Tumor; Cellular Microenvironment; Coculture Techniques; Drug Resistance, Neoplasm; Fluorescent Dyes - pharmacokinetics; Gene Expression Regulation - drug effects; Hematologic and hematopoietic diseases; Humans; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunopathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Medicine; Medicine & Public Health; Multiple Myeloma - drug therapy; Multiple Myeloma - pathology; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Oncology; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pyrazines - pharmacology; Rhodamine 123 - pharmacokinetics; Stromal Cells - metabolism; Tumors
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-013-2136-7

Purpose 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.