An article published this year in “JOURNAL OF HEMATOLOGY & ONCOLOGY”
using our Cell Cycle Analysis (PI
/ RNASE)
and our FITC-conjugated
Annexin-V, by our customers from University Hospital of Salamanca (IBSAL) &
Cancer Research Center (IBMCC-CSIC-USAL), Salamanca, Spain, in the analysis of
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. Congrats and Thanks.
Summary:
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 (IC50 1.6–4.8 μM) 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 α-tubulin and histone
hyperacetylation) and a DNA-damaging effect (shown by an increase in γH2AX);
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 γH2AX 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.
Reference:
Product link:
CELL CYCLE ANALYSIS (PI / RNASE): http://www.immunostep.com/solutions-buffers-chemicals/3870-pi-rnase-solution.html
FITC Annexin V Apoptosis Detection
Kit with PI: http://www.immunostep.com/apoptosis-tools/3727-anxvkf-100t.html
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