Constanza Cortés1,2, Sara C Kozma2, Albert Tauler1,2, Santiago Ambrosio3. 1. Departament de Bioquímica i Biologia Molecular, Facultat de Farmàcia, Universitat de Barcelona, 08028, Barcelona, Catalunya, Spain. 2. Laboratory of Cancer Metabolism, IDIBELL, Hospital Duran i Reynals, L'Hospitalet de Llobregat, Catalunya, 08907, Spain. 3. Unitat de Bioquímica, Dep. Ciències Fisiològiques II, Facultat de Medicina, Campus Universitari de Bellvitge - IDIBELL, Universitat de Barcelona, L'Hospitalet de Llobregat, Catalunya, 08907, Spain. sambrosio@ub.edu.
Abstract
BACKGROUND: In the past, the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) has been shown to induce apoptosis in several human tumor types, including neuroblastomas. Amplification and over-expression of the MYCN oncogene is a diagnostic hallmark and a poor prognostic indicator in high-risk neuroblastomas. Here, we studied the relationship between MYCN amplification and over-expression and the anti-tumor effect of SAHA to assess whether this drug may serve as a treatment option for high-risk neuroblastomas. METHODS: Different human neuroblastoma cell lines, over-expressing or not over-expressing MYCN, were used in this study. Targeted knockdown and exogenous over-expression of MYCN were employed to examine correlations between MYCN expression levels and SAHA responses. After various time periods and concentration exposures to the drug, cell viability was measured by MTS assay, and variations in MYCN mRNA and protein levels were assessed by qPCR and Western blotting, respectively. RESULTS: We found that SAHA decreased cell viability in all cell lines tested through apoptosis induction, and that SAHA had a stronger effect on cell lines carrying an amplified MYCN gene. A decrease in MYCN mRNA and protein levels was observed in the SAHA treated cell lines. Subsequent silencing and exogenous over-expression of MYCN changed the proliferation rate of the cells, but did not have any significant impact on the effect of SAHA on the viability of the cells. We also found that SAHA blocked the expression of MYCN and, by doing so, reduced the effects mediated by this protein. CONCLUSIONS: Our results suggest that SAHA may be used as a single-drug treatment option for neuroblastomas with an amplified MYCN gene, and as an adjuvant treatment option for all neuroblastomas.
BACKGROUND: In the past, the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) has been shown to induce apoptosis in several humantumor types, including neuroblastomas. Amplification and over-expression of the MYCN oncogene is a diagnostic hallmark and a poor prognostic indicator in high-risk neuroblastomas. Here, we studied the relationship between MYCN amplification and over-expression and the anti-tumor effect of SAHA to assess whether this drug may serve as a treatment option for high-risk neuroblastomas. METHODS: Different humanneuroblastoma cell lines, over-expressing or not over-expressing MYCN, were used in this study. Targeted knockdown and exogenous over-expression of MYCN were employed to examine correlations between MYCN expression levels and SAHA responses. After various time periods and concentration exposures to the drug, cell viability was measured by MTS assay, and variations in MYCN mRNA and protein levels were assessed by qPCR and Western blotting, respectively. RESULTS: We found that SAHA decreased cell viability in all cell lines tested through apoptosis induction, and that SAHA had a stronger effect on cell lines carrying an amplified MYCN gene. A decrease in MYCN mRNA and protein levels was observed in the SAHA treated cell lines. Subsequent silencing and exogenous over-expression of MYCN changed the proliferation rate of the cells, but did not have any significant impact on the effect of SAHA on the viability of the cells. We also found that SAHA blocked the expression of MYCN and, by doing so, reduced the effects mediated by this protein. CONCLUSIONS: Our results suggest that SAHA may be used as a single-drug treatment option for neuroblastomas with an amplified MYCN gene, and as an adjuvant treatment option for all neuroblastomas.
Authors: U Galderisi; G Di Bernardo; M Cipollaro; G Peluso; A Cascino; R Cotrufo; M A Melone Journal: J Cell Biochem Date: 1999-04-01 Impact factor: 4.429
Authors: Scott R Frank; Tiziana Parisi; Stefan Taubert; Paula Fernandez; Miriam Fuchs; Ho-Man Chan; David M Livingston; Bruno Amati Journal: EMBO Rep Date: 2003-06 Impact factor: 8.807
Authors: Adela Canete; Mary Gerrard; Hervé Rubie; Victoria Castel; Andrea Di Cataldo; Caroline Munzer; Ruth Ladenstein; Bénédicte Brichard; José D Bermúdez; Jerôme Couturier; Bruno de Bernardi; Andrew J Pearson; Jean Michon Journal: J Clin Oncol Date: 2009-01-26 Impact factor: 44.544
Authors: Rebecca Cotterman; Victor X Jin; Sheryl R Krig; Jessica M Lemen; Alice Wey; Peggy J Farnham; Paul S Knoepfler Journal: Cancer Res Date: 2008-12-01 Impact factor: 12.701
Authors: Jane Carr; Emma Bell; Andrew D J Pearson; Ursula R Kees; Helen Beris; John Lunec; Deborah A Tweddle Journal: Cancer Res Date: 2006-02-15 Impact factor: 12.701
Authors: Shana Claeys; Geertrui Denecker; Kaat Durinck; Bieke Decaesteker; Liselot M Mus; Siebe Loontiens; Suzanne Vanhauwaert; Kristina Althoff; Caroline Wigerup; Daniel Bexell; Emmy Dolman; Kai-Oliver Henrich; Lea Wehrmann; Ellen M Westerhout; Jean-Baptiste Demoulin; Candy Kumps; Tom Van Maerken; Genevieve Laureys; Christophe Van Neste; Bram De Wilde; Olivier De Wever; Frank Westermann; Rogier Versteeg; Jan J Molenaar; Sven Påhlman; Johannes H Schulte; Katleen De Preter; Frank Speleman Journal: Oncogene Date: 2018-12-11 Impact factor: 9.867
Authors: Roberto Ciaccio; Piergiuseppe De Rosa; Sara Aloisi; Marta Viggiano; Leonardo Cimadom; Suleman Khan Zadran; Giovanni Perini; Giorgio Milazzo Journal: Int J Mol Sci Date: 2021-11-28 Impact factor: 5.923