Bortezomib, carfilzomib and ixazomib do not mediate relevant transporter-based drug-drug interactions

Abstract

Abstract. In order to optimize the clinical application of an increasing number of proteasome inhibitors, investigations into the differences between their respective pharmacodynamic and pharmacokinetic profiles, including their ability to act as a perpetrator in drug-drug interactions, are warranted. Therefore, in the present in vitro study, it was investigated whether bortezomib, carfilzomib and ixazomib are able to alter the expression, and/or the activity, of specific drug transporters generally relevant for pharmacokinetic drug-drug interactions. Through induction experiments, the current study demonstrated that the aforementioned three proteasome inhibitors do not induce mRNA expression of the transporter genes ATP binding cassette (ABC)B1, C1, C2 and G2 in the LS180 cell line, which was used as a model for systemic induction. By contrast, in certain myeloma cell lines, ixazomib provoked minor alterations in individual transporter gene expression. None of the proteasome inhibitors tested relevantly inhibited drug transporters within the range of physiological plasma concentrations. Taken together, transporter-based drug-drug interactions are unlikely to be a primary concern in the clinical application of the tested compounds.

BaxΔ2 sensitizes colorectal cancer cells to proteasome inhibitor-induced cell death

“…Alteration of cellular proteostasis by inhibition of the 26S proteasome has proven to be effective for targeting cancer cells. Unlike conventional chemotherapeutic drugs, proteasome inhibitors specifically target the 20S core particle of the 26S proteasome without affecting drug transporters [ 1 , 2 ]. These inhibitors can cause apoptosis, mainly through protein accumulation-mediated cellular stress or proteotoxicity [ 1 , 3 , 4 ].…”

“…Several proteasome inhibitors have been approved by the FDA or are undergoing clinical and pre-clinical studies for cancer therapy [ 5 – 10 ]. The primary applications of proteasome inhibitors in cancer therapy are for the treatment of multiple myeloma or mantle cell lymphoma [ 2 , 3 , 11 , 12 ]. To date, no proteasome inhibitor has been approved for the treatment of solid tumors.…”

“…However, MG132 is not FDA approved for clinical use due to its non-specific cytotoxicity. Bortezomib, the most common and first FDA approved proteasome inhibitor used for the treatment of multiple myeloma, belongs to the boronate class of proteasome inhibitors, and induces reversible inhibition [ 1 , 2 , 12 ]. While bortezomib is only approved to treat of multiple myeloma and mantle cell lymphoma, multiple studies have shown that the use of bortezomib in concert with other chemotherapeutics can significantly increase cell death in solid tumors [ 8 – 10 , 15 , 16 ].…”

“…While bortezomib is only approved to treat of multiple myeloma and mantle cell lymphoma, multiple studies have shown that the use of bortezomib in concert with other chemotherapeutics can significantly increase cell death in solid tumors [ 8 – 10 , 15 , 16 ]. Ixazomib is another reversible boronate proteasome inhibitor, which recently gained clinical approval for treatment of multiple myeloma, and has also shown the ability to inhibit proliferation and induce apoptosis in solid tumors [ 2 , 3 , 5 , 12 ]. On the other hand, carfilzomib, is a potent irreversible proteasome inhibitor approved for treatment of multiple myeloma, especially in patients who didn’t respond well to previous treatment with bortezomib [ 2 , 3 , 7 , 12 ].…”

“…Ixazomib is another reversible boronate proteasome inhibitor, which recently gained clinical approval for treatment of multiple myeloma, and has also shown the ability to inhibit proliferation and induce apoptosis in solid tumors [ 2 , 3 , 5 , 12 ]. On the other hand, carfilzomib, is a potent irreversible proteasome inhibitor approved for treatment of multiple myeloma, especially in patients who didn’t respond well to previous treatment with bortezomib [ 2 , 3 , 7 , 12 ]. Recent research has shown that carfilzomib can also suppress cell proliferation and promote apoptosis in solid tumors when used in combination with other chemotherapeutics [ 7 , 17 , 18 ].…”