Background and aims: Nucleoside and nucleobase analogues have been used for decades as cornerstone therapies for tumors treatment. Although they can act as antimetabolites, they can also inhibit essential enzymes [1] as well as interact with receptors (P1 and P2 receptors). At this time, there is a compelling need of new nucleoside analogues due to the occurrence of drug resistance. Therefore, in this study we aimed to evaluate the antiproliferative effects of novel synthetic variously-substituted nitrogenous aromatic heterocycles on a cell line (U937) of histiocytic lymphoma. Methods: U937 were cultured in RPMI1640 medium supplemented with 10% Fetal Bovine Serum and penicillin-streptomycin. The compounds (PP1, PP2, PP3, PP4, PP5 and PP6) were dissolved in acetone and tested within the range of 238-0.93 μM for the IC50 calculation. Cytotoxicity was evaluated by MTT assay and LDH release. Apoptosis and cell cycle analyses were carried out by cytofluorimetry through Annexin-V binding assay and propidium iodide staining. Variations in intracellular calcium concentration were evaluated by FURA-2. Results: Of the tested compounds, only PP1, PP5 and PP6 showed a cytotoxic effect (IC50 of 8.9, 0.86 and 8.1 μM) not accompanied by a significant release of LDH, but triggered both early and late apoptosis (p<0.01compared to vehicle) without affecting the cell cycle. Finally, the compounds did not increase the intracellular calcium, suggesting that they do not act through P2X receptors or Gq-coupled receptors. Conclusion: Our data suggest that the selected compounds specifically trigger apoptosis without acting on P2X receptors. However, the exact mechanism of action is still unknown and further studies are needed to shed light on the possible use of these novel compounds as possible therapies. References 1. Jordheim LP et al. Nat Rev Drug Discov (2013) 12, 447-464.

Antiproliferative effects of novel synthetic nucleobase analogues on U937 Histiocytic lymphoma cell line

Alessandro Trentini
Primo
Validation
;
Arianna Romani
Resources
;
Maria Cristina Manfrinato
Membro del Collaboration Group
;
Tiziana Bellini
Funding Acquisition
;
Barbara Cacciari
Penultimo
Conceptualization
;
Stefania Hanau
Ultimo
Supervision
2017

Abstract

Background and aims: Nucleoside and nucleobase analogues have been used for decades as cornerstone therapies for tumors treatment. Although they can act as antimetabolites, they can also inhibit essential enzymes [1] as well as interact with receptors (P1 and P2 receptors). At this time, there is a compelling need of new nucleoside analogues due to the occurrence of drug resistance. Therefore, in this study we aimed to evaluate the antiproliferative effects of novel synthetic variously-substituted nitrogenous aromatic heterocycles on a cell line (U937) of histiocytic lymphoma. Methods: U937 were cultured in RPMI1640 medium supplemented with 10% Fetal Bovine Serum and penicillin-streptomycin. The compounds (PP1, PP2, PP3, PP4, PP5 and PP6) were dissolved in acetone and tested within the range of 238-0.93 μM for the IC50 calculation. Cytotoxicity was evaluated by MTT assay and LDH release. Apoptosis and cell cycle analyses were carried out by cytofluorimetry through Annexin-V binding assay and propidium iodide staining. Variations in intracellular calcium concentration were evaluated by FURA-2. Results: Of the tested compounds, only PP1, PP5 and PP6 showed a cytotoxic effect (IC50 of 8.9, 0.86 and 8.1 μM) not accompanied by a significant release of LDH, but triggered both early and late apoptosis (p<0.01compared to vehicle) without affecting the cell cycle. Finally, the compounds did not increase the intracellular calcium, suggesting that they do not act through P2X receptors or Gq-coupled receptors. Conclusion: Our data suggest that the selected compounds specifically trigger apoptosis without acting on P2X receptors. However, the exact mechanism of action is still unknown and further studies are needed to shed light on the possible use of these novel compounds as possible therapies. References 1. Jordheim LP et al. Nat Rev Drug Discov (2013) 12, 447-464.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/2381159
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