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 language | English |
|---|---|
| Article number | 137 |
| Journal | BMC Cancer |
| Volume | 14 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Feb 27 2014 |
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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 journal › Article
}
TY - JOUR
T1 - An aza-macrocycle containing maltolic side-arms (maltonis) as potential drug against human pediatric sarcomas
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
PY - 2014/2/27
Y1 - 2014/2/27
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.
AB - 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.
KW - Apoptosis
KW - Cancer therapy
KW - DNA damage
KW - Macrocycles
KW - Sarcoma
UR - http://www.scopus.com/inward/record.url?scp=84895459931&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84895459931&partnerID=8YFLogxK
U2 - 10.1186/1471-2407-14-137
DO - 10.1186/1471-2407-14-137
M3 - Article
C2 - 24575739
AN - SCOPUS:84895459931
VL - 14
JO - BMC Cancer
JF - BMC Cancer
SN - 1471-2407
IS - 1
M1 - 137
ER -