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Analysis of determi...
Analysis of determinants for in vitro resistance to the small molecule deubiquitinase inhibitor b-AP15
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- Mofers, Arjan (author)
- Linköpings universitet,Avdelningen för läkemedelsforskning,Medicinska fakulteten
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- Perego, Paola (author)
- Karolinska Institutet,Molecular Pharmacology Unit, Italy
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- Selvaraju, Karthik (author)
- Linköpings universitet,Avdelningen för läkemedelsforskning,Medicinska fakulteten
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- Gatti, Laura (author)
- Fdn IRCCS Ist Neurol Carlo Besta, Dept Clin Neurosci, Cerebrovasc Unit, Milan, Italy.,Cerebrovascular Unit, Italy
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- Gullbo, Joachim (author)
- Uppsala universitet,Experimentell och klinisk onkologi,Uppsala University, Sweden
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- Linder, Stig, 1954- (author)
- Linköpings universitet,Karolinska Institutet,Avdelningen för läkemedelsforskning,Medicinska fakulteten,Karolinska Institutet, Sweden
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- D´arcy, Padraig, 1978- (author)
- Linköpings universitet,Avdelningen för läkemedelsforskning,Medicinska fakulteten
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(creator_code:org_t)
- 2019-10-22
- 2019
- English.
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In: PLOS ONE. - San Francisco, CA, United States : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 14:10
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Abstract
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- Background: b-AP15NLX1570 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-AP15NLX1570 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-AP15NLX1570.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 (similar to 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-AP15NLX1570 are cell cycle-active. The slow and incomplete development of resistance towards these compounds is an attractive feature in view of future clinical use.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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