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Open Access Highly Accessed Research article

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

Clara Guerzoni12, Stefano Amatori3, Luca Giorgi4, Maria Cristina Manara12, Lorena Landuzzi12, Pier-Luigi Lollini5, Aurora Tassoni3, Mauro Balducci3, Marco Manfrini6, Loredana Pratelli7, Massimo Serra2, Piero Picci12, Mauro Magnani8, Vieri Fusi4, Mirco Fanelli3* and Katia Scotlandi12*

Author Affiliations

1 PROMETEO Laboratory, Section of Biomolecular Therapies, RIT Department, Istituto Ortopedico Rizzoli, Bologna 40136, Italy

2 Experimental Oncology Laboratory, CRS Development of Biomolecular Therapies, IstitutoOrtopedico Rizzoli, Bologna 40136, Italy

3 Molecular Pathology Lab. “PaoLa”, Department of Biomolecular Sciences, University of Urbino “Carlo Bo”, via Arco d’Augusto, 2, 61032 Fano (PU), Italy

4 Department of Basic Sciences and Fundamentals, University of Urbino “Carlo Bo”, P.za Rinascimento, 6, 61029 Urbino (PU), Italy

5 Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy

6 Clinica Ortopedica e Traumatologica III, Istituto Ortopedico Rizzoli, Bologna 40136, Italy

7 Clinical Pathology, Istituto Ortopedico Rizzoli, Bologna 40136, Italy

8 Department of Biomolecular Sciences, University of Urbino “Carlo Bo”, via Saffi 2, 61029 Urbino (PU), Italy

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BMC Cancer 2014, 14:137  doi:10.1186/1471-2407-14-137

Published: 27 February 2014

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.

Keywords:
Sarcoma; Cancer therapy; DNA damage; Apoptosis; Macrocycles