An aza-macrocycle containing maltolic side-arms (maltonis) as potential drug against human pediatric sarcomas

Clara Guerzoni, Stefano Amatori, Luca Giorgi, Maria C. Manara, Lorena Landuzzi, Pier Luigi Lollini, Aurora Tassoni, Mauro Balducci, Marco Manfrini, Loredana Pratelli, Massimo Serra, Piero Picci, Mauro Magnani, Vieri Fusi, Mirco Fanelli, Katia Scotlandi

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number137
JournalBMC Cancer
Volume14
Issue number1
DOIs
Publication statusPublished - Feb 27 2014

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Sarcoma
Pediatrics
Pharmaceutical Preparations
Ewing's Sarcoma
Aptitude
Primary Cell Culture
Rhabdomyosarcoma
DNA
Osteosarcoma
1,7-dimethyl-1,4,7,10-tetraazacyclododecane
Heterografts
Caspase 3
Doxorubicin
Cisplatin
Glutathione
Cell Death
Up-Regulation
Down-Regulation
Drug Therapy
Cell Line

Keywords

  • Apoptosis
  • Cancer therapy
  • DNA damage
  • Macrocycles
  • Sarcoma

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Genetics
  • Medicine(all)

Cite this

An aza-macrocycle containing maltolic side-arms (maltonis) as potential drug against human pediatric sarcomas. / Guerzoni, Clara; Amatori, Stefano; Giorgi, Luca; Manara, Maria C.; Landuzzi, Lorena; Lollini, Pier Luigi; Tassoni, Aurora; Balducci, Mauro; Manfrini, Marco; Pratelli, Loredana; Serra, Massimo; Picci, Piero; Magnani, Mauro; Fusi, Vieri; Fanelli, Mirco; Scotlandi, Katia.

In: BMC Cancer, Vol. 14, No. 1, 137, 27.02.2014.

Research output: Contribution to journalArticle

Guerzoni, C, Amatori, S, Giorgi, L, Manara, MC, Landuzzi, L, Lollini, PL, Tassoni, A, Balducci, M, Manfrini, M, Pratelli, L, Serra, M, Picci, P, Magnani, M, Fusi, V, Fanelli, M & Scotlandi, K 2014, 'An aza-macrocycle containing maltolic side-arms (maltonis) as potential drug against human pediatric sarcomas', BMC Cancer, vol. 14, no. 1, 137. https://doi.org/10.1186/1471-2407-14-137
Guerzoni, Clara ; Amatori, Stefano ; Giorgi, Luca ; Manara, Maria C. ; Landuzzi, Lorena ; Lollini, Pier Luigi ; Tassoni, Aurora ; Balducci, Mauro ; Manfrini, Marco ; Pratelli, Loredana ; Serra, Massimo ; Picci, Piero ; Magnani, Mauro ; Fusi, Vieri ; Fanelli, Mirco ; Scotlandi, Katia. / An aza-macrocycle containing maltolic side-arms (maltonis) as potential drug against human pediatric sarcomas. In: BMC Cancer. 2014 ; Vol. 14, No. 1.
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AU - Guerzoni, Clara

AU - Amatori, Stefano

AU - Giorgi, Luca

AU - Manara, Maria C.

AU - Landuzzi, Lorena

AU - Lollini, Pier Luigi

AU - Tassoni, Aurora

AU - Balducci, Mauro

AU - Manfrini, Marco

AU - Pratelli, Loredana

AU - Serra, Massimo

AU - Picci, Piero

AU - Magnani, Mauro

AU - Fusi, Vieri

AU - Fanelli, Mirco

AU - Scotlandi, Katia

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N2 - 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.

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KW - DNA damage

KW - Macrocycles

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