title: Preclinical evaluation of a novel SIRT1 modulator SRT1720 in multiple myeloma cells.
abstract: SIRT1 belongs to the silent information regulator 2 (Sir2) protein family of enzymes and functions as a NAD(+) -dependent class III histone deacetylase. Here, we examined the anti-multiple myeloma (MM) activity of a novel oral agent, SRT1720, which targets SIRT1. Treatment of MM cells with SRT1720 inhibited growth and induced apoptosis in MM cells resistant to conventional and bortezomib therapies without significantly affecting the viability of normal cells. Mechanistic studies showed that anti-MM activity of SRT1720 is associated with: (i) activation of caspase-8, caspase-9, caspase-3, poly(ADP) ribose polymerase; (ii) increase in reactive oxygen species; (iii) induction of phosphorylated ataxia telangiectasia mutated/checkpoint kinase 2 signalling; (iv) decrease in vascular endothelial growth factor-induced migration of MM cells and associated angiogenesis; and (v) inhibition of nuclear factor-κB. Blockade of ATM attenuated SRT1720-induced MM cell death. In animal tumour model studies, SRT1720 inhibited MM tumour growth. Finally, SRT1720 enhanced the cytotoxic activity of bortezomib or dexamethasone. Our preclinical studies provide the rationale for novel therapeutics targeting SIRT1 in MM.
authors.affiliation: The LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA. Dharminder_Chauhan@dfci.harvard.edu
authors.forename: Dharminder
authors.initials: D
authors.lastname: Chauhan
authors.forename: Madhavi
authors.initials: M
authors.lastname: Bandi
authors.forename: Ajita V
authors.initials: AV
authors.lastname: Singh
authors.forename: Arghya
authors.initials: A
authors.lastname: Ray
authors.forename: Noopur
authors.initials: N
authors.lastname: Raje
authors.forename: Paul
authors.initials: P
authors.lastname: Richardson
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000008:administration & dosage; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011719:Pyrazines / Q000008:administration & dosage; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays
chemical_list: D001897:Boronic Acids; D006576:Heterocyclic Compounds, 4 or More Rings; D011719:Pyrazines; C525422:SRT1720; D000069286:Bortezomib; D003907:Dexamethasone