title: Induction of apoptosis in Ehrlich ascites tumour cells via p53 activation by a novel small-molecule MDM2 inhibitor - LQFM030.
abstract: OBJECTIVE
  The activation of the p53 pathway through the inhibition of MDM2 has been proposed as a novel therapeutic strategy against tumours. A series of cis-imidazoline analogues, termed nutlins, were reported to displace the recombinant p53 protein from its complex with MDM2 by binding to MDM2 in the p53 pocket, and exhibited an antitumour activity both in vitro and in vivo. Thus, the purpose of this study was to evaluate the antitumour properties of LQFM030 (2), a nutlin analogue created by employing the strategy of molecular simplification.
  
  
  METHODS
  LQFM030 (2) cytotoxicity was evaluated in Ehrlich ascites tumour (EAT) cells, p53 wild type, by the trypan blue exclusion test, and the mechanisms involved in EAT cell death were investigated by light and fluorescence microscopy, flow cytometry, real-time PCR and Western blotting.
  
  
  RESULTS
  Our results demonstrate that LQFM030 has dose-dependent antiproliferative activity and cytotoxic activity on EAT cells, induces the accumulation of p53 protein and promotes cell cycle arrest and apoptosis. p53 gene transcription was unaffected by LQFM030 (2); however, MDM2 mRNA increased and MDM2 protein decreased.
  
  
  CONCLUSIONS
  These results suggest that the small-molecule p53 activator LQFM030 (2) has the potential for further development as a novel cancer therapeutic agent.
authors.affiliation: Laboratório de Farmacologia e Toxicologia Celular, FarmaTec, Faculdade de Farmácia, Universidade Federal de Goiás, UFG, Goiânia, GO, Brazil.|Lab. de Biologia e DNA Forense da Polícia Técnico-Científica de Goiás, GO - Brazil, Universidade Federal de Goiás, UFG, Goiânia, GO, Brazil.
authors.forename: Mariana F
authors.initials: MF
authors.lastname: da Mota
authors.affiliation: Laboratório de Farmacologia e Toxicologia Celular, FarmaTec, Faculdade de Farmácia, Universidade Federal de Goiás, UFG, Goiânia, GO, Brazil.
authors.forename: Alane P
authors.initials: AP
authors.lastname: Cortez
authors.affiliation: Laboratório de Farmacologia e Toxicologia Celular, FarmaTec, Faculdade de Farmácia, Universidade Federal de Goiás, UFG, Goiânia, GO, Brazil.
authors.forename: Polyana L
authors.initials: PL
authors.lastname: Benfica
authors.affiliation: Laboratório de Farmacologia e Toxicologia Celular, FarmaTec, Faculdade de Farmácia, Universidade Federal de Goiás, UFG, Goiânia, GO, Brazil.
authors.forename: Bruna Dos S
authors.initials: Bdos S
authors.lastname: Rodrigues
authors.affiliation: Laboratório de Farmacologia e Toxicologia Celular, FarmaTec, Faculdade de Farmácia, Universidade Federal de Goiás, UFG, Goiânia, GO, Brazil.
authors.forename: Thalyta F
authors.initials: TF
authors.lastname: Castro
authors.affiliation: Departamento de Fisiologia e Farmacologia, Instituto de Ciências Biologicas, Universidade Federal de Goiás, UFG, Goiânia, GO, Brazil.
authors.forename: Larissa M
authors.initials: LM
authors.lastname: Macedo
authors.affiliation: Departamento de Fisiologia e Farmacologia, Instituto de Ciências Biologicas, Universidade Federal de Goiás, UFG, Goiânia, GO, Brazil.
authors.forename: Carlos H
authors.initials: CH
authors.lastname: Castro
authors.affiliation: Instituto de Química, Universidade Federal de Goiás, UFG, Goiânia, GO, Brazil.
authors.forename: Luciano M
authors.initials: LM
authors.lastname: Lião
authors.affiliation: Instituto de Química, Universidade Federal de Goiás, UFG, Goiânia, GO, Brazil.|Laboratório de Química Farmacêutica Medicinal (LQFM), Faculdade de Farmácia, Universidade Federal de Goiás, UFG, Goiânia, GO, Brazil.
authors.forename: Flávio S
authors.initials: FS
authors.lastname: de Carvalho
authors.affiliation: Faculdade de Ciências da Saúde, Universidade de Brasília, UNB, Brasília, DF, Brazil.
authors.forename: Luiz A S
authors.initials: LA
authors.lastname: Romeiro
authors.affiliation: Laboratório de Química Farmacêutica Medicinal (LQFM), Faculdade de Farmácia, Universidade Federal de Goiás, UFG, Goiânia, GO, Brazil.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Menegatti
authors.affiliation: Centro de Biotecnologia, Universidade Federal de Rio Grande do Sul, UFRS, Porto Alegre, RS, Brazil.
authors.forename: Hugo
authors.initials: H
authors.lastname: Verli
authors.affiliation: Centro de Biotecnologia, Universidade Federal de Rio Grande do Sul, UFRS, Porto Alegre, RS, Brazil.
authors.forename: Bianca
authors.initials: B
authors.lastname: Villavicencio
authors.affiliation: Laboratório de Farmacologia e Toxicologia Celular, FarmaTec, Faculdade de Farmácia, Universidade Federal de Goiás, UFG, Goiânia, GO, Brazil.
authors.forename: Marize C
authors.initials: MC
authors.lastname: Valadares
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy / Q000378:metabolism*; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D010880:Piperidines / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; C000618691:LQFM030; D010880:Piperidines; D011720:Pyrazoles; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2
keywords: Ehrlich ascites tumor; LQFM030; MDM2; Nutlins; p53