title: Hydrogen sulphide-releasing diclofenac derivatives inhibit breast cancer-induced osteoclastogenesis in vitro and prevent osteolysis ex vivo.
abstract: OBJECTIVE
  Hydrogen sulphide (H(2)S) and prostaglandins are both involved in inflammation, cancer and bone turnover, and non-steroidal anti-inflammatory drugs (NSAIDs) and H(2)S donors exhibit anti-inflammatory and anti-tumour properties. H(2)S-releasing diclofenac (S-DCF) derivatives are a novel class of NSAIDs combining the properties of a H(2)S donor with those of a conventional NSAID.
  
  
  METHODS
  We studied the effects of the S-DCF derivatives ACS15 and ACS32 on osteoclast and osteoblast differentiation and activity in vitro, human and mouse breast cancer cells support for osteoclast formation and signalling in vitro, and osteolysis ex vivo.
  
  
  RESULTS
  The S-diclofenac derivatives ACS15 and ACS32 inhibited the increase in osteoclast formation induced by human MDA-MB-231 and MCF-7 and mouse 4T1 breast cancer cells without affecting breast cancer cell viability. Conditioned media from human MDA-MB-231 cells enhanced IκB phosphorylation and osteoclast formation and these effects were significantly inhibited following treatment by ACS15 and ACS32, whereas the parent compound diclofenac had no effects. ACS15 and ACS32 inhibited receptor activator of NFκB ligand-induced osteoclast formation and resorption, and caused caspase-3 activation and apoptosis in mature osteoclasts via a mechanism dependent on IKK/NFκB inhibition. In calvaria organ culture, human MDA-MB-231 cells caused osteolysis, and this effect was completely prevented following treatment with ACS15 and ACS32.
  
  
  CONCLUSIONS
  S-diclofenac derivatives inhibit osteoclast formation and activity, suppress breast cancer cell support for osteoclastogenesis and prevent osteolysis. This suggests that H(2)S-releasing diclofenac derivatives exhibit anti-resorptive properties, which might be of clinical value in the treatment of osteolytic bone disease.
authors.affiliation: The Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UKEdinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UKGalapagos SASU, Romainville, FranceDepartment of Pharmaceutical Sciences 'P. Pratesi', Università degli Studi di Milano, Milan, ItalyCTG Pharma S.r.l., Milan, Italy.
authors.forename: J
authors.initials: J
authors.lastname: Frantzias
authors.affiliation: The Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UKEdinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UKGalapagos SASU, Romainville, FranceDepartment of Pharmaceutical Sciences 'P. Pratesi', Università degli Studi di Milano, Milan, ItalyCTG Pharma S.r.l., Milan, Italy.
authors.forename: J G
authors.initials: JG
authors.lastname: Logan
authors.affiliation: The Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UKEdinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UKGalapagos SASU, Romainville, FranceDepartment of Pharmaceutical Sciences 'P. Pratesi', Università degli Studi di Milano, Milan, ItalyCTG Pharma S.r.l., Milan, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Mollat
authors.affiliation: The Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UKEdinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UKGalapagos SASU, Romainville, FranceDepartment of Pharmaceutical Sciences 'P. Pratesi', Università degli Studi di Milano, Milan, ItalyCTG Pharma S.r.l., Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Sparatore
authors.affiliation: The Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UKEdinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UKGalapagos SASU, Romainville, FranceDepartment of Pharmaceutical Sciences 'P. Pratesi', Università degli Studi di Milano, Milan, ItalyCTG Pharma S.r.l., Milan, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Del Soldato
authors.affiliation: The Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UKEdinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UKGalapagos SASU, Romainville, FranceDepartment of Pharmaceutical Sciences 'P. Pratesi', Università degli Studi di Milano, Milan, ItalyCTG Pharma S.r.l., Milan, Italy.
authors.forename: S H
authors.initials: SH
authors.lastname: Ralston
authors.affiliation: The Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UKEdinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UKGalapagos SASU, Romainville, FranceDepartment of Pharmaceutical Sciences 'P. Pratesi', Università degli Studi di Milano, Milan, ItalyCTG Pharma S.r.l., Milan, Italy.
authors.forename: A I
authors.initials: AI
authors.lastname: Idris
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004008:Diclofenac / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006801:Humans; D006862:Hydrogen Sulfide; D051550:I-kappa B Kinase / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D010014:Osteolysis / Q000517:prevention & control*; D013450:Sulfones / Q000494:pharmacology*; D013871:Thiones / Q000494:pharmacology*
chemical_list: C573319:(3-(2,6-dichloro-phenylamino)phenyl)acetic acid 2-methanesulphonylsulphanyl ethyl ester; C573318:2-((2,6-dichlorophenyl)amino) benzeneacetic acid 4-(3-thioxo-3H-1,2-dithiol-5-yl) phenyl ester; C520611:2-((2,6-dichlorophenyl)amino)benzeneacetic acid 4-(3H-1,2-dithiol-3-thione-5-yl)phenyl ester; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016328:NF-kappa B; D013450:Sulfones; D013871:Thiones; D004008:Diclofenac; D051550:I-kappa B Kinase; D006862:Hydrogen Sulfide