Imatinib mesilate (STI-571, Gleevec(TM)), an inhibitior of bcr-abl tyrosine kinases (TK) which was primarily designed to treat chronic myeloid leukaemia, is also an inhibitor of c-kit receptor TK, and is currently the drug of choice for the therapy of metastatic gastrointestinal stromal tumors (GISTs), which frequently express constitutively activated forms of the c-kit-receptor. Despite the fact that the majority of patients receiving imatinib respond to treatment, early relapse and drug resistance occur in a large percentage of them [1]. The present study is focused on the ability of a new histone deacetylase (HDAC) inhibitor, 9-hydroxystearic acid (9-HSA) [2] to enhance the cytotoxicity of imatinib in imatinib-resistant cell lines. We chose as cellular model HT29, a colon adenocarcinoma cell line expressing the c-kit receptor and which is p53 mutated. Our results demonstrated that HT-29 exposed for 24 hr to a high dose (50 M) of imatinib and maintained in drug-free medium for up to 7 days, developed resistance characterized by loss of apoptotic response to the drug. Pretreating resistant cell line (IR-HT-29) with 9-HSA led to a growth-inhibitory and apoptotic effect of imatinib similar to that in imatinib-sensitive HT-29 cell line. More precisely, 9-HSA treatment is able per se to trigger apoptosis and subsequent imatinib treatment amplifies the process. In order to understand the mechanisms of this effect, we analyzed the degree of acetylation, methylation and phosphorylation of histones in IR-HT-29, and in 9-HSA treated IR-HT-29. Previous studies from our laboratory showed that diacetyl-dimethyl H4 content increased in a highly specific manner in 9-HSA treated HT-29. The results presented in this work clearly show that histone code in IR-HT-29 was completely changed with respect to control sensitive HT-29, and that 9-HSA treatment induced not only the increase of the diacetyl-dimethyl H4 content, but also several modification on H3-1 histone. In conclusion our data indicate that the use of HDAC inhibitor 9-HSA may be a powerful strategy to enhance cytotoxic effects of imatinib in resistant cell lines. BIBLIOGRAFIA 1. Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002; 347:472-80 2. Calonghi N, Cappadone C, Pagnotta E, Boga C, Bertucci C, Fiori J, et al. Histone deacetylase 1: a target of 9-hydroxystearic acid in the inhibition of cell growth in human colon cancer. J Lipid Res 2005; 46:1596-1603

9-HSA INDUCES APOPTOSIS AND INCREASES SENSITIVITY TO IMATINIB IN IMATINIB RESISTANT COLON CANCER CELLS

PAGNOTTA, ELEONORA;CALONGHI, NATALIA;PAROLIN, CAROLA ELEONORA;MANGANO, CHIARA;BOGA, CARLA;SANTUCCI, MARIA ALESSANDRA;MASOTTI, LANFRANCO
2006

Abstract

Imatinib mesilate (STI-571, Gleevec(TM)), an inhibitior of bcr-abl tyrosine kinases (TK) which was primarily designed to treat chronic myeloid leukaemia, is also an inhibitor of c-kit receptor TK, and is currently the drug of choice for the therapy of metastatic gastrointestinal stromal tumors (GISTs), which frequently express constitutively activated forms of the c-kit-receptor. Despite the fact that the majority of patients receiving imatinib respond to treatment, early relapse and drug resistance occur in a large percentage of them [1]. The present study is focused on the ability of a new histone deacetylase (HDAC) inhibitor, 9-hydroxystearic acid (9-HSA) [2] to enhance the cytotoxicity of imatinib in imatinib-resistant cell lines. We chose as cellular model HT29, a colon adenocarcinoma cell line expressing the c-kit receptor and which is p53 mutated. Our results demonstrated that HT-29 exposed for 24 hr to a high dose (50 M) of imatinib and maintained in drug-free medium for up to 7 days, developed resistance characterized by loss of apoptotic response to the drug. Pretreating resistant cell line (IR-HT-29) with 9-HSA led to a growth-inhibitory and apoptotic effect of imatinib similar to that in imatinib-sensitive HT-29 cell line. More precisely, 9-HSA treatment is able per se to trigger apoptosis and subsequent imatinib treatment amplifies the process. In order to understand the mechanisms of this effect, we analyzed the degree of acetylation, methylation and phosphorylation of histones in IR-HT-29, and in 9-HSA treated IR-HT-29. Previous studies from our laboratory showed that diacetyl-dimethyl H4 content increased in a highly specific manner in 9-HSA treated HT-29. The results presented in this work clearly show that histone code in IR-HT-29 was completely changed with respect to control sensitive HT-29, and that 9-HSA treatment induced not only the increase of the diacetyl-dimethyl H4 content, but also several modification on H3-1 histone. In conclusion our data indicate that the use of HDAC inhibitor 9-HSA may be a powerful strategy to enhance cytotoxic effects of imatinib in resistant cell lines. BIBLIOGRAFIA 1. Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002; 347:472-80 2. Calonghi N, Cappadone C, Pagnotta E, Boga C, Bertucci C, Fiori J, et al. Histone deacetylase 1: a target of 9-hydroxystearic acid in the inhibition of cell growth in human colon cancer. J Lipid Res 2005; 46:1596-1603
CNB9
85
85
Pagnotta E.; Calonghi N.; Parolin C.; Mangano C.; Nuccitelli A.; Boga C.; Santucci M.A.; Masotti L.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/38877
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