Analysis of determinants for in vitro resistance to the small molecule deubiquitinase inhibitor b-AP15


Autoři: Arjan Mofers aff001;  Paola Perego aff002;  Karthik Selvaraju aff001;  Laura Gatti aff003;  Joachim Gullbo aff004;  Stig Linder aff001;  Padraig D'Arcy aff001
Působiště autorů: Department of Medicine and Health, Linköping University, Linköping, Sweden aff001;  Molecular Pharmacology Unit, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy aff002;  Cerebrovascular Unit, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy aff003;  Department of Radiology, Oncology and Radiation Science, Section of Oncology, Uppsala University, Uppsala, Sweden aff004;  Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden aff005
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0223807

Souhrn

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. Limited information is available with regard to potential resistance mechanisms to b-AP15/VLX1570.

Results

We 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.

Conclusions

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.

Klíčová slova:

Cancer treatment – Cell cycle and cell division – Cell cycle inhibitors – Cell death – Drug therapy – Glutathione – Multiple myeloma – Proteasomes


Zdroje

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