Antiangiogenic and antitumoral activity of LQFM126 prototype against B16F10 melanoma cells.

Abstract

Inhibition of mouse double minute 2 homolog (MDM2)-p53 interaction and reactivation of p53 signaling have been explored as effective anticancer therapeutic strategy. The potent and specific antitumor activity shown by Nutlins, first class of MDM2-p53 inhibitors discovered, has made these compounds potential antitumor candidates. To this end, we synthesized Nutlin-1 and Nutlin-2 analogs through molecular simplification and selected the compound with the most efficient antitumoral activity. Cytotoxicity of Nutlin-2 analog LQFM126 on B16F10 melanoma cells induced intense cytoplasmic vacuolization, reduction of cell size, chromatin condensation, cytoplasmic degeneration and nuclear fragmentation. LQFM126 antiproliferative effects mediated cell cycle retention in G0/G1 phase and increased the levels of cell cycle regulatory proteins p21 and p27. This Nutlin analog increased mitochondrial membrane potential, activated caspase-8, -9 and -3/7 and reduced VEGF levels in B16F10 cells. Therefore, LQFM126 promoted alterations suggestive of apoptosis, G0/G1 cell cycle arrest and suppression of angiogenesis through modulation of VEGF expression in B16F10 cells. Additionally, LQFM126 was classified as UN GHS category 4 (LD50 > 300-2000 mg/kg), suggesting it has low acute systemic toxicity. LQFM126 can be a promising prototype for anticancer therapy.

• Authors: Artur Christian Garcia da Silva, Bruna Dos Santos Rodrigues, Wanessa Machado Andrade, Thaís Rosa Marques Dos Santos, Flávio Silva de Carvalho, Germán Sanz, Boniek G Vaz, Luciano M Lião, Ricardo Menegatti, Marize Campos Valadares
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 325 Pg. 109127 (Jul 01 2020) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 32437695 (Publication Type: Journal Article)
• Copyright: Copyright © 2020. Published by Elsevier B.V.

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• Cyclin-Dependent Kinase Inhibitor p21
• Imidazoles
• Piperazines
• Pyrazoles
• Reactive Oxygen Species
• nutlin 1
• Caspases

Topics

• Angiogenesis Inhibitors (chemical synthesis, chemistry, pharmacology, therapeutic use)
• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology, therapeutic use)
• Caspases (metabolism)
• Cell Cycle (drug effects)
• Cell Death (drug effects)
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Imidazoles (chemistry)
• Melanoma, Experimental (pathology)
• Membrane Potential, Mitochondrial (drug effects)
• Mice
• Piperazines (chemistry)
• Pyrazoles (chemical synthesis, chemistry, pharmacology, therapeutic use)
• Reactive Oxygen Species (metabolism)