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Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2022

Open Access 01-12-2022 | Multiple Myeloma | Research

Exploiting DNA Ligase III addiction of multiple myeloma by flavonoid Rhamnetin

Authors: Daniele Caracciolo, Giada Juli, Caterina Riillo, Adriana Coricello, Francesca Vasile, Sara Pollastri, Roberta Rocca, Francesca Scionti, Nicoletta Polerà, Katia Grillone, Mariamena Arbitrio, Nicoletta Staropoli, Basilio Caparello, Domenico Britti, Giovanni Loprete, Giosuè Costa, Maria Teresa Di Martino, Stefano Alcaro, Pierosandro Tagliaferri, Pierfrancesco Tassone

Published in: Journal of Translational Medicine | Issue 1/2022

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Abstract

Background

DNA ligases are crucial for DNA repair and cell replication since they catalyze the final steps in which DNA breaks are joined. DNA Ligase III (LIG3) exerts a pivotal role in Alternative-Non-Homologous End Joining Repair (Alt-NHEJ), an error-prone DNA repair pathway often up-regulated in genomically unstable cancer, such as Multiple Myeloma (MM). Based on the three-dimensional (3D) LIG3 structure, we performed a computational screening to identify LIG3-targeting natural compounds as potential candidates to counteract Alt-NHEJ activity in MM.

Methods

Virtual screening was conducted by interrogating the Phenol Explorer database. Validation of binding to LIG3 recombinant protein was performed by Saturation Transfer Difference (STD)—nuclear magnetic resonance (NMR) experiments. Cell viability was analyzed by Cell Titer-Glo assay; apoptosis was evaluated by flow cytometric analysis following Annexin V-7AAD staining. Alt-NHEJ repair modulation was evaluated using plasmid re-joining assay and Cytoscan HD. DNA Damage Response protein levels were analyzed by Western blot of whole and fractionated protein extracts and immunofluorescence analysis. The mitochondrial DNA (mtDNA) copy number was determined by qPCR. In vivo activity was evaluated in NOD-SCID mice subcutaneously engrafted with MM cells.

Results

Here, we provide evidence that a natural flavonoid Rhamnetin (RHM), selected by a computational approach, counteracts LIG3 activity and killed Alt-NHEJ-dependent MM cells. Indeed, Nuclear Magnetic Resonance (NMR) showed binding of RHM to LIG3 protein and functional experiments revealed that RHM interferes with LIG3-driven nuclear and mitochondrial DNA repair, leading to significant anti-MM activity in vitro and in vivo.

Conclusion

Taken together, our findings provide proof of concept that RHM targets LIG3 addiction in MM and may represent therefore a novel promising anti-tumor natural agent to be investigated in an early clinical setting.
Appendix
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Metadata
Title
Exploiting DNA Ligase III addiction of multiple myeloma by flavonoid Rhamnetin
Authors
Daniele Caracciolo
Giada Juli
Caterina Riillo
Adriana Coricello
Francesca Vasile
Sara Pollastri
Roberta Rocca
Francesca Scionti
Nicoletta Polerà
Katia Grillone
Mariamena Arbitrio
Nicoletta Staropoli
Basilio Caparello
Domenico Britti
Giovanni Loprete
Giosuè Costa
Maria Teresa Di Martino
Stefano Alcaro
Pierosandro Tagliaferri
Pierfrancesco Tassone
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2022
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-022-03705-z

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