Novel anthranilamide-pyrazolo[1,5-a]pyrimidine conjugates modulate the expression of p53-MYCN associated micro RNAs in neuroblastoma cells and cause cell cycle arrest and apoptosis.

Abstract

It has previously been shown that anthranilamide-pyrazolo[1,5-a]pyrimidine conjugates activate p53 and cause apoptosis in cervical cancer cells such as HeLa and SiHa. Here we establish the role of these conjugates in activating p53 pathway by phosphorylation at Ser15, 20 and 46 residues and downregulate key oncogenic proteins such as MYCN and Mdm2 in IMR-32 neuroblastoma cells. Compounds decreased the proliferation rate of neuroblastoma cells such as IMR-32, Neuro-2a, SK-N-SH. Compound treatment resulted in G2/M cell cycle arrest. The expression of p53 dependent genes such as p21, Bax, caspases was increased with concomitant decrease of the survival proteins as well as anti-apoptotic proteins such as Akt1, E2F1 and Bcl2. In addition the expression of important microRNAs such as miR-34a, c, miR-200b, miR-107, miR-542-5p and miR-605 were significantly increased that eventually lead to the activation of apoptotic pathway. Our data revealed that conjugates of this nature cause cell cycle arrest and apoptosis in IMR-32 cells [MYCN (+) with intact wild-type p53] by activating p53 signalling and provides a lead for the development of anti-cancer therapeutics.

• Authors: M Janaki Ramaiah, Sreerangam N C V L Pushpavalli, A Lavanya, Kaustav Bhadra, V Haritha, Nibedita Patel, Jaki R Tamboli, Ahmed Kamal, Utpal Bhadra, Manika Pal-Bhadra
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 23 Issue 20 Pg. 5699-706 (Oct 15 2013) ISSN: 1464-3405 [Electronic] England
• PMID: 23992861 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Cyclin-Dependent Kinase Inhibitor p21
• MYCN protein, human
• MicroRNAs
• N-Myc Proto-Oncogene Protein
• Nuclear Proteins
• Oncogene Proteins
• Purines
• Pyrazoles
• Pyrimidines
• Tumor Suppressor Protein p53
• bcl-2-Associated X Protein
• ortho-Aminobenzoates
• pyrazolo(1,5-a)pyrimidine
• Roscovitine
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2
• anthranilamide

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, toxicity)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cyclin-Dependent Kinase Inhibitor p21 (genetics, metabolism)
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Gene Expression Regulation, Neoplastic
• HeLa Cells
• Humans
• M Phase Cell Cycle Checkpoints (drug effects)
• MicroRNAs (metabolism)
• N-Myc Proto-Oncogene Protein
• Neuroblastoma (metabolism, pathology)
• Nuclear Proteins (antagonists & inhibitors, genetics, metabolism)
• Oncogene Proteins (antagonists & inhibitors, genetics, metabolism)
• Proto-Oncogene Proteins c-mdm2 (antagonists & inhibitors, genetics, metabolism)
• Purines (chemistry, toxicity)
• Pyrazoles (chemistry)
• Pyrimidines (chemistry)
• Roscovitine
• Tumor Suppressor Protein p53 (antagonists & inhibitors, genetics, metabolism)
• bcl-2-Associated X Protein (genetics, metabolism)
• ortho-Aminobenzoates (chemistry)