title: An aza-macrocycle containing maltolic side-arms (maltonis) as potential drug against human pediatric sarcomas.
abstract: BACKGROUND
  Identification of new drugs against paediatric sarcomas represents an urgent clinical need that mainly relies on public investments due to the rarity of these diseases. In this paper we evaluated the in vitro and in vivo efficacy of a new maltol derived molecule (maltonis), belonging to the family of molecules named hydroxypyrones.
  
  
  METHODS
  Maltonis was screened for its ability to induce structural alteration of DNA molecules in comparison to another maltolic molecule (malten). In vitro antitumour efficacy was tested using a panel of sarcoma cell lines, representative of Ewing sarcoma, osteosarcoma and rhabdomyosarcoma, the three most common paediatric sarcomas, and in normal human mesenchymal primary cell cultures. In vivo efficacy was tested against TC-71 Ewing sarcoma xenografts.
  
  
  RESULTS
  Maltonis, a soluble maltol-derived synthetic molecule, was able to alter the DNA structure, inhibit proliferation and induce apoptotic cell death in paediatric sarcoma cells, either sensitive or resistant to some conventional chemotherapeutic drugs, such as doxorubicin and cisplatin. In addition, maltonis was able to induce: i) p21, p15 and Gadd45a mRNA upregulation; ii) Bcl-2, survivin, CDK6 and CDK8 down-regulation; iii) formation of γ-H2AX nuclear foci; iv) cleavage of PARP and Caspase 3. Two independent in vivo experiments demonstrated the tolerability and efficacy of maltonis in the inhibition of tumour growth. Finally maltonis was not extruded by ABCB1, one of the major determinants of chemotherapy failure, nor appeared to be a substrate of the glutathione-related detoxification system.
  
  
  CONCLUSIONS
  Considering that treatment of poorly responsive patients still suffers for the paucity of agents able to revert chemoresistance, maltonis may be considered for the future development of new therapeutic approaches for refractory metastatic patients.
authors.forename: Clara
authors.initials: C
authors.lastname: Guerzoni
authors.forename: Stefano
authors.initials: S
authors.lastname: Amatori
authors.forename: Luca
authors.initials: L
authors.lastname: Giorgi
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Manara
authors.forename: Lorena
authors.initials: L
authors.lastname: Landuzzi
authors.forename: Pier-Luigi
authors.initials: PL
authors.lastname: Lollini
authors.forename: Aurora
authors.initials: A
authors.lastname: Tassoni
authors.forename: Mauro
authors.initials: M
authors.lastname: Balducci
authors.forename: Marco
authors.initials: M
authors.lastname: Manfrini
authors.forename: Loredana
authors.initials: L
authors.lastname: Pratelli
authors.forename: Massimo
authors.initials: M
authors.lastname: Serra
authors.forename: Piero
authors.initials: P
authors.lastname: Picci
authors.forename: Mauro
authors.initials: M
authors.lastname: Magnani
authors.forename: Vieri
authors.initials: V
authors.lastname: Fusi
authors.affiliation: PROMETEO Laboratory, Section of Biomolecular Therapies, RIT Department, Istituto Ortopedico Rizzoli, Bologna 40136, Italy. mirco.fanelli@uniurb.it.
authors.forename: Mirco
authors.initials: M
authors.lastname: Fanelli
authors.forename: Katia
authors.initials: K
authors.lastname: Scotlandi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D004249:DNA Damage / Q000187:drug effects; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000008:administration & dosage / Q000494:pharmacology; D064593:Heterografts; D006801:Humans; D020128:Inhibitory Concentration 50; D059630:Mesenchymal Stem Cells / Q000187:drug effects; D051379:Mice; D012509:Sarcoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology
chemical_list: C512308:1,7-dimethyl-1,4,7,10-tetraazacyclododecane; D000970:Antineoplastic Agents; D006571:Heterocyclic Compounds