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10.1186/s13045-017-0495-y http://scihub22266oqcxt.onion/10.1186/s13045-017-0495-y C5477689!5477689 !28633670     free     free     free Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=28633670 &cmd=llinks): Failed to open stream: HTTP request failed! 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Preclinical anti-myeloma activity of EDO-S101, a new bendamustine-derived molecule with added HDACi activity, through potent DNA damage induction and impairment of DNA repair |pdf=|usr=}}{{28633670 }} gab.com Text Preclinical anti-myeloma activity of EDO-S101, a new bendamustine-derived molecule with added HDACi activity, through potent DNA damage induction and impairment of DNA repair JO: J Hematol Oncol http://www.kidney.de/pget.php?&tw=1&pmid=28633670 #FOAvip BACKGROUND: Despite recent advances in the treatment of multiple myeloma (MM), the prognosis of most patients remains poor, and resistance to traditional and new drugs frequently occurs. EDO-S101 is a novel therapeutic agent conceived as the fusion of a histone deacetylase inhibitor radical to bendamustine, with the aim of potentiating its alkylating activity. METHODS: The efficacy of EDO-S101 was evaluated in vitro, ex vivo and in vivo, alone, and in combination with standard anti-myeloma agents. The underlying mechanisms of action were also evaluated on MM cell lines, patient samples, and different murine models. RESULTS: EDO-S101 displayed potent activity in vitro in MM cell lines (IC(50) 1.6-4.8 ?M) and ex vivo in cells isolated from MM patients, which was higher than that of bendamustine and independent of the p53 status and previous melphalan resistance. This activity was confirmed in vivo, in a CB17-SCID murine plasmacytoma model and in de novo Vk*MYC mice, leading to a significant survival improvement in both models. In addition, EDO-S101 was the only drug with single-agent activity in the multidrug resistant Vk12653 murine model. Attending to its mechanism of action, the molecule showed both, a HDACi effect (demonstrated by ?-tubulin and histone hyperacetylation) and a DNA-damaging effect (shown by an increase in ?H2AX); the latter being again clearly more potent than that of bendamustine. Using a reporter plasmid integrated into the genome of some MM cell lines, we demonstrate that, apart from inducing a potent DNA damage, EDO-S101 specifically inhibited the double strand break repair by the homologous recombination pathway. Moreover, EDO-S101 treatment reduced the recruitment of repair proteins such as RAD51 to DNA-damage sites identified as ?H2AX foci. Finally, EDO-S101 preclinically synergized with bortezomib, both in vitro and in vivo. CONCLUSION: These findings provide rationale for the clinical investigation of EDO-S101 in MM, either as a single agent or in combination with other anti-MM drugs, particularly proteasome inhibitors. Twit Text FOAVip Preclinical anti-myeloma activity of EDO-S101, a new bendamustine-derived molecule with added HDACi activity, through potent DNA damage induction and impairment of DNA repair ????J Hematol Oncol http://www.kidney.de/pget.php?&tw=1&pmid=28633670 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=28633670 #FOAvip English Wikipedia <ref>{{Cite pmid|28633670 }}</ref> Preclinical anti-myeloma activity of EDO-S101, a new bendamustine-derived molecule with added HDACi activity, through potent DNA damage induction and impairment of DNA repair #MMPMID28633670 López-Iglesias AA ; Herrero AB ; Chesi M ; San-Segundo L ; González-Méndez L ; Hernández-García S ; Misiewicz-Krzeminska I ; Quwaider D ; Martín-Sánchez M ; Primo D ; Paíno T ; Bergsagel PL ; Mehrling T ; González-Díaz M ; San-Miguel JF ; Mateos MV ; Gutiérrez NC ; Garayoa M ; Ocio EM J Hematol Oncol 2017[Jun]; 10 (1 ): 127 PMID28633670 show ga BACKGROUND: Despite recent advances in the treatment of multiple myeloma (MM), the prognosis of most patients remains poor, and resistance to traditional and new drugs frequently occurs. EDO-S101 is a novel therapeutic agent conceived as the fusion of a histone deacetylase inhibitor radical to bendamustine, with the aim of potentiating its alkylating activity. METHODS: The efficacy of EDO-S101 was evaluated in vitro, ex vivo and in vivo, alone, and in combination with standard anti-myeloma agents. The underlying mechanisms of action were also evaluated on MM cell lines, patient samples, and different murine models. RESULTS: EDO-S101 displayed potent activity in vitro in MM cell lines (IC(50) 1.6-4.8 ?M) and ex vivo in cells isolated from MM patients, which was higher than that of bendamustine and independent of the p53 status and previous melphalan resistance. This activity was confirmed in vivo, in a CB17-SCID murine plasmacytoma model and in de novo Vk*MYC mice, leading to a significant survival improvement in both models. In addition, EDO-S101 was the only drug with single-agent activity in the multidrug resistant Vk12653 murine model. Attending to its mechanism of action, the molecule showed both, a HDACi effect (demonstrated by ?-tubulin and histone hyperacetylation) and a DNA-damaging effect (shown by an increase in ?H2AX); the latter being again clearly more potent than that of bendamustine. Using a reporter plasmid integrated into the genome of some MM cell lines, we demonstrate that, apart from inducing a potent DNA damage, EDO-S101 specifically inhibited the double strand break repair by the homologous recombination pathway. Moreover, EDO-S101 treatment reduced the recruitment of repair proteins such as RAD51 to DNA-damage sites identified as ?H2AX foci. Finally, EDO-S101 preclinically synergized with bortezomib, both in vitro and in vivo. CONCLUSION: These findings provide rationale for the clinical investigation of EDO-S101 in MM, either as a single agent or in combination with other anti-MM drugs, particularly proteasome inhibitors. |Animals [MESH] |Antineoplastic Agents/chemistry/pharmacology/*therapeutic use [MESH] |Apoptosis/drug effects [MESH] |Bendamustine Hydrochloride/analogs & derivatives/pharmacology/therapeutic use [MESH] |Benzimidazoles/chemistry/pharmacology/*therapeutic use [MESH] |Cell Cycle Checkpoints/drug effects [MESH] |Cell Line, Tumor [MESH] |DNA Damage/*drug effects [MESH] |DNA Repair/*drug effects [MESH] |Histone Deacetylase Inhibitors/chemistry/pharmacology/*therapeutic use [MESH] |Humans [MESH] |Membrane Potential, Mitochondrial/drug effects [MESH] |Mice [MESH] |Mice, SCID [MESH] |Mitochondria/drug effects/genetics/metabolism/pathology [MESH]Preclinical anti-myeloma activity of EDO-S101, a new bendamustine-deri(epmc).pdf DeepDyve Pubget Overpricing