The Selective Acetamidine-Based iNOS Inhibitor CM544 Reduces Glioma Cell Proliferation by Enhancing PARP-1 Cleavage In Vitro.

Abstract

Gliomas are the most aggressive adult primary brain tumors. Expression of inducible Nitric Oxide Synthase has been reported as a hallmark of chemoresistance in gliomas and several studies have reported that inhibition of inducible Nitric Oxide Synthase could be related to a decreased proliferation of glioma cells. The present work was to analyze the molecular effects of the acetamidine derivative compound 39 (formally CM544, N-(3-{[(1-iminioethyl)amino]methyl}benzyl) prolinamide dihydrochloride), a newly synthetized iNOS inhibitor, in a C6 rat glioma cell model. There is evidence of CM544 selective binding to the iNOS, an event that triggers the accumulation of ROS/RNS, the expression of Nrf-2 and the phosphorylation of MAPKs after 3 h of treatment. In the long run, CM544 leads to the dephosphorylation of p38 and to a massive cleavage of PARP-1, confirming the block of C6 rat glioma cell proliferation in the G1/S checkpoint and the occurrence of necrotic cell death.

• Authors: Marialucia Gallorini, Cristina Maccallini, Alessandra Ammazzalorso, Pasquale Amoia, Barbara De Filippis, Marialuigia Fantacuzzi, Letizia Giampietro, Amelia Cataldi, Rosa Amoroso
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 20 Issue 3 (Jan 24 2019) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 30678338 (Publication Type: Journal Article)

Chemical References

• Amidines
• Antineoplastic Agents
• CM544
• Enzyme Inhibitors
• Proline
• Nitric Oxide Synthase Type II
• Parp1 protein, rat
• Poly (ADP-Ribose) Polymerase-1
• p38 Mitogen-Activated Protein Kinases

Topics

• Amidines (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Brain Neoplasms (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Enzyme Inhibitors (pharmacology)
• Glioma (metabolism)
• Nitric Oxide Synthase Type II (antagonists & inhibitors)
• Poly (ADP-Ribose) Polymerase-1 (metabolism)
• Proline (analogs & derivatives, pharmacology)
• Proteolysis
• Rats
• p38 Mitogen-Activated Protein Kinases (metabolism)