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Ricolinostat ( ACY ‐1215) induced inhibition of aggresome formation accelerates carfilzomib‐induced multiple myeloma cell death
Author(s) -
Mishima Yuko,
Santo Loredana,
Eda Homare,
Cirstea Diana,
Nemani Neeharika,
Yee Andrew J.,
O'Donnell Elizabeth,
Selig Martin Karl,
Quayle Steven N.,
ArastuKapur Shirin,
Kirk Christopher,
Boise Lawrence H.,
Jones Simon S.,
Raje Noopur
Publication year - 2015
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.13315
Subject(s) - aggresome , carfilzomib , proteasome inhibitor , apoptosis , autophagy , bortezomib , proteasome , ubiquitin , microbiology and biotechnology , histone deacetylase , cancer research , chemistry , programmed cell death , biology , multiple myeloma , histone , biochemistry , immunology , gene
Summary Proteasome inhibition induces the accumulation of aggregated misfolded/ubiquitinated proteins in the aggresome; conversely, histone deacetylase 6 ( HDAC 6) inhibition blocks aggresome formation. Although this rationale has been the basis of proteasome inhibitor ( PI ) and HDAC 6 inhibitor combination studies, the role of disruption of aggresome formation by HDAC 6 inhibition has not yet been studied in multiple myeloma ( MM ). The present study aimed to evaluate the impact of carfilzomib ( CFZ ) in combination with a selective HDAC 6 inhibitor (ricolinostat) in MM cells with respect to the aggresome‐proteolysis pathway. We observed that combination treatment of CFZ with ricolinostat triggered synergistic anti‐ MM effects, even in bortezomib‐resistant cells. Immunofluorescent staining showed that CFZ increased the accumulation of ubiquitinated proteins and protein aggregates in the cytoplasm, as well as the engulfment of aggregated ubiquitinated proteins by autophagosomes, which was blocked by ricolinostat. Electron microscopy imaging showed increased autophagy triggered by CFZ , which was inhibited by the addition of ACY ‐1215. Finally, an in vivo mouse xenograft study confirmed a decrease in tumour volume, associated with apoptosis, following treatment with CFZ in combination with ricolinostat. Our results suggest that ricolinostat inhibits aggresome formation, caused by CFZ ‐induced inhibition of the proteasome pathway, resulting in enhanced apoptosis in MM cells.