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01.12.2017 | Research | Ausgabe 1/2017 Open Access

Journal of Hematology & Oncology 1/2017

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

Zeitschrift:
Journal of Hematology & Oncology > Ausgabe 1/2017
Autoren:
Ana-Alicia López-Iglesias, Ana B. Herrero, Marta Chesi, Laura San-Segundo, Lorena González-Méndez, Susana Hernández-García, Irena Misiewicz-Krzeminska, Dalia Quwaider, Montserrat Martín-Sánchez, Daniel Primo, Teresa Paíno, P. Leif Bergsagel, Thomas Mehrling, Marcos González-Díaz, Jesús F. San-Miguel, María-Victoria Mateos, Norma C. Gutiérrez, Mercedes Garayoa, Enrique M. Ocio
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​s13045-017-0495-y) contains supplementary material, which is available to authorized users.

Abstract

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.

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Zusatzmaterial
Additional file 1: Figure S1. U266, RPMI-8226, and their derivatives, U266-LR7 and RPMI-LR5 partially resistant to melphalan, were incubated with increasing doses of EDO-S101, and cell viability was analyzed by MTT metabolization. Figure S2. EDO-S101 toxicity, on PCs and B lymphocytes derived from bone marrow samples from 3 MM patients, was evaluated after 48 h of incubation by flow cytometry. Figure S3. EDO-S101 dose response (48 h) of different proteins implicated in DNA damage repair in U266 cell line. Figure S4. Dose response (48 h) of different proteins implicated in DNA damage repair and HDAC inhibitory effect after treatment with EDO-S101 of MM1S in the presence or absence of stromal components of the bone marrow microenvironment. MM1S was incubated with EDO-S101 alone, in co-culture with the human stromal cell line hMSC-TERT, and in co-culture with bone marrow mesenchymal stromal cells from a patient with MM (pBMSC). In all cases, the alkylating and the HDACi effect of EDO-S101 were preserved. Figure S5. Different MM cell lines were incubated with 1 and 2.5 μM EDO-S101 for 48 h. After propidium iodide staining, the cell cycle profile was analyzed by flow cytometry. Calculation of percentages of cells at each phase did not consider cells at G0. Figure S6. Bcl-2 family proteins studied by Western blot after treatment of MM1S with the indicated doses of EDO-S101 for 48 h. Figure S7. Toxicity profile of mice bearing a subcutaneus plasmacytoma and treated with the indicated drug. The EDO-S101 group showed a reversible 10–20% loss of body weight. Each point represents the mean ± SD. Figure S8. The combination of EDO-S101 plus bortezomib was also able to improve the effect of single treatments in RPMI-8266, JJN3, and U266 cell lines. Figure S9. Toxicity profile of mice bearing a subcutaneus plasmacytoma and treated with the indicated drugs. The EDO-S101 + Bortezomib group showed a reversible 10–20% loss of body weight. Each point represents the mean ± SD. (PPTX 348 kb)
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