Abstract
Backgroundb-AP15/VLX1570 are small molecule inhibitors of the ubiquitin specific peptidase 14 (USP14) and ubiquitin carboxyl-terminal hydrolase 5 (UCHL5) deubiquitinases (DUBs) of the 19S proteasome. b-AP15/VLX1570 have been shown to be cytotoxic to cells resistant to bortezomib, raising the possibility that this class of drugs can be used as a second-line therapy for treatment-resistant multiple myeloma. Limited information is available with regard to potential resistance mechanisms to b-AP15/VLX1570.ResultsWe found that b-AP15-induced cell death is cell-cycle dependent and that non-cycling tumor cells may evade b-AP15-induced cell death. Such non-cycling cells may re-enter the proliferative state to form colonies of drug-sensitive cells. Long-term selection of cells with b-AP15 resulted in limited drug resistance (~2-fold) that could be reversed by buthionine sulphoximine, implying altered glutathione (GSH) metabolism as a resistance mechanism. In contrast, drug uptake and overexpression of drug efflux transporters were found not to be associated with b-AP15 resistance.ConclusionsThe proteasome DUB inhibitors b-AP15/VLX1570 are cell cycle-active. The slow and incomplete development of resistance towards these compounds is an attractive feature in view of future clinical use.
Highlights
Background b-AP15/VLX1570 are small molecule inhibitors of the ubiquitin specific peptidase 14 (USP14) and ubiquitin carboxyl-terminal hydrolase 5 (UCHL5) deubiquitinases (DUBs) of the 19S proteasome. b-AP15/VLX1570 have been shown to be cytotoxic to cells resistant to bortezomib, raising the possibility that this class of drugs can be used as a second-line therapy for treatment-resistant multiple myeloma
Ixazomib (MLN9708), the first oral proteasome inhibitor approved by fluorescein diacetate (FDA), preferentially inhibits the chymotrypsin-like activity of the β5 subunit to bortezomib
We previously reported that attempts to derive b-AP15 resistant multiple myeloma cell lines by selection were unsuccessful [34]
Summary
The proteasome DUB inhibitors b-AP15/VLX1570 are cell cycle-active. The slow and incomplete development of resistance towards these compounds is an attractive feature in view of future clinical use.
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