Targeting actin inhibits repair of doxorubicin-induced DNA damage: a novel therapeutic approach for combination therapy

Lisa Pfitzer,Christina Moser,Rebecca Smith,Ernst Wagner,Florian Foerster,Olga V Kalinina,Angelika M Vollmar,Florian Gegenfurtner,Stefan Zahler,Anja Arner,Johanna Busse,Themistoklis Zisis,Rolf Müller,Gyula Timinszky,Carina Atzberger,Rebekka Kubisch-Dohmen

doi:10.1038/s41419-019-1546-9

Abstract

Severe side effects often restrict clinical application of the widely used chemotherapeutic drug doxorubicin. In order to decrease required substance concentrations, new concepts for successful combination therapy are needed. Since doxorubicin causes DNA damage, combination with compounds that modulate DNA repair could be a promising strategy. Very recently, a role of nuclear actin for DNA damage repair has been proposed, making actin a potential target for cancer therapy in combination with DNA-damaging therapeutics. This is of special interest, since actin-binding compounds have not yet found their way into clinics. We find that low-dose combination treatment of doxorubicin with the actin polymerizer chondramide B (ChB) synergistically inhibits tumor growth in vivo. On the cellular level we demonstrate that actin binders inhibit distinctive double strand break (DSB) repair pathways. Actin manipulation impairs the recruitment of replication factor A (RPA) to the site of damage, a process crucial for homologous recombination. In addition, actin binders reduce autophosphorylation of DNA-dependent protein kinase (DNA-PK) during nonhomologous end joining. Our findings substantiate a direct involvement of actin in nuclear DSB repair pathways, and propose actin as a therapeutic target for combination therapy with DNA-damaging agents such as doxorubicin.

Highlights

The anthracycline doxorubicin (Doxo) is widely used for therapy of a broad range of cancer types
The aim of our study was to investigate whether this mechanism can be modulated by actin-binding compounds, and whether such compounds might be feasible for combination therapy with DNA-damaging drugs like Doxo
(see figure on previous page) Fig. 6 Recruitment of replication factor A (RPA)-2 is inhibited upon actin manipulation. a Simplified flow chart of RPA-mediated repair. b HeLa cells were treated with the indicated substances for 2 h, followed by incubation in DMEM ± actin substances

Summary

Introduction

The anthracycline doxorubicin (Doxo) is widely used for therapy of a broad range of cancer types. Doxo is still an indispensable part of cancer therapy. To. One mode of action of Doxo is to stabilize the topoisomerase II complex during DNA replication, which induces DNA double strand breaks (DSB) and promotes apoptosis[3,4]. One mode of action of Doxo is to stabilize the topoisomerase II complex during DNA replication, which induces DNA double strand breaks (DSB) and promotes apoptosis[3,4] Cells respond to such DNA damage by starting various repair mechanisms. Targeting specific proteins involved in these DNA repair pathways (repair factors) has been suggested as a promising approach for cancer therapy. DSBs can be repaired by different repair pathways, depending on the functional context of the cell.

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Conclusion