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Kevetrin induces apoptosis in TP53 wild­type and mutant acute myeloid leukemia cells.
Napolitano, Roberta; De Matteis, Serena; Carloni, Silvia; Bruno, Samantha; Abbati, Giulia; Capelli, Laura; Ghetti, Martina; Bochicchio, Maria Teresa; Liverani, Chiara; Mercatali, Laura; Calistri, Daniele; Cuneo, Antonio; Menon, Krishna; Musuraca, Gerardo; Martinelli, Giovanni; Simonetti, Giorgia.
Afiliação
  • Napolitano R; Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, I­47014 Meldola, Italy.
  • De Matteis S; Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, I­47014 Meldola, Italy.
  • Carloni S; Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, I­47014 Meldola, Italy.
  • Bruno S; Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna and Institute of Hematology 'L. e A. Seràgnoli', I­40138 Bologna, Italy.
  • Abbati G; Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, I­47014 Meldola, Italy.
  • Capelli L; Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, I­47014 Meldola, Italy.
  • Ghetti M; Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, I­47014 Meldola, Italy.
  • Bochicchio MT; Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, I­47014 Meldola, Italy.
  • Liverani C; Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, I­47014 Meldola, Italy.
  • Mercatali L; Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, I­47014 Meldola, Italy.
  • Calistri D; Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, I­47014 Meldola, Italy.
  • Cuneo A; Department of Medical Sciences, University of Ferrara­Arcispedale Sant'Anna, I­44124 Ferrara, Italy.
  • Menon K; Innovation Pharmaceuticals, Beverly, MA 01880, USA.
  • Musuraca G; Hematology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, I­47014 Meldola, Italy.
  • Martinelli G; Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna and Institute of Hematology 'L. e A. Seràgnoli', I­40138 Bologna, Italy.
  • Simonetti G; Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, I­47014 Meldola, Italy.
Oncol Rep ; 44(4): 1561-1573, 2020 10.
Article em En | MEDLINE | ID: mdl-32945487
ABSTRACT
Tumor protein p53 is a key regulator of several cellular pathways, including DNA repair, cell cycle and angiogenesis. Kevetrin exhibits p53­dependent as well as­independent activity in solid tumors, while its effects on leukemic cells remain unknown. The aim of the present study was to analyze the response of acute myeloid leukemia (AML) cell lines (TP53 wild­type OCI­AML3 and MOLM­13; and TP53­mutant KASUMI­1 and NOMO­1) to kevetrin at a concentration range of 85­340 µM. The cellular and molecular effects of the treatment were analyzed in terms of cell growth, viability [Annexin V­propidium iodide (PI) staining] and cell cycle alterations (PI staining). Gene expression profiling, western blotting and immunofluorescence were performed to elucidate the pathways underlying kevetrin activity. Pulsed exposure exerted no effect on the wild­type cells, but was effective on mutant cells. After continuous treatment, significant cell growth arrest and apoptosis were observed in all cell lines, with TP53­mutant models displaying a higher sensitivity and p53 induction. Kevetrin also displayed efficacy against TP53 wild­type and mutant primary AML, with a preferential cytotoxic activity against blast cells. Gene expression profiling revealed a common core transcriptional program altered by drug exposure and the downregulation of glycolysis, DNA repair and unfolded protein response signatures. These findings suggest that kevetrin may be a promising therapeutic option for patients with both wild­type and TP53­mutant AML.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia Mieloide Aguda / Proteína Supressora de Tumor p53 / Proliferação de Células / Antineoplásicos Tipo de estudo: Prognostic_studies Limite: Aged / Aged80 / Female / Humans / Male Idioma: En Revista: Oncol Rep Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia Mieloide Aguda / Proteína Supressora de Tumor p53 / Proliferação de Células / Antineoplásicos Tipo de estudo: Prognostic_studies Limite: Aged / Aged80 / Female / Humans / Male Idioma: En Revista: Oncol Rep Ano de publicação: 2020 Tipo de documento: Article