title: Ricolinostat (ACY-1215) induced inhibition of aggresome formation accelerates carfilzomib-induced multiple myeloma cell death.
abstract: Proteasome inhibition induces the accumulation of aggregated misfolded/ubiquitinated proteins in the aggresome; conversely, histone deacetylase 6 (HDAC6) inhibition blocks aggresome formation. Although this rationale has been the basis of proteasome inhibitor (PI) and HDAC6 inhibitor combination studies, the role of disruption of aggresome formation by HDAC6 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 HDAC6 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.
authors.affiliation: Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Mishima
authors.forename: Loredana
authors.initials: L
authors.lastname: Santo
authors.forename: Homare
authors.initials: H
authors.lastname: Eda
authors.forename: Diana
authors.initials: D
authors.lastname: Cirstea
authors.forename: Neeharika
authors.initials: N
authors.lastname: Nemani
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Yee
authors.forename: Elizabeth
authors.initials: E
authors.lastname: O'Donnell
authors.forename: Martin Karl
authors.initials: MK
authors.lastname: Selig
authors.forename: Steven N
authors.initials: SN
authors.lastname: Quayle
authors.forename: Shirin
authors.initials: S
authors.lastname: Arastu-Kapur
authors.forename: Christopher
authors.initials: C
authors.lastname: Kirk
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Boise
authors.forename: Simon S
authors.initials: SS
authors.lastname: Jones
authors.forename: Noopur
authors.initials: N
authors.lastname: Raje
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004357:Drug Synergism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005260:Female; D064593:Heterografts; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051379:Mice; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology*; D010588:Phagosomes / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D011743:Pyrimidines; C524865:carfilzomib; C572255:ricolinostat
keywords: HDAC6 inhibitor; aggresome; carfilzomib; multiple myeloma; proteasome inhibitor