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Targeting actin inhibits repair of doxorubicin-induced DNA damage: a novel therapeutic approach for combination therapy.
Pfitzer, Lisa Moser, Christina Gegenfurtner, Florian Arner, Anja Foerster, Florian Atzberger, Carina Zisis, Themistoklis Kubisch-Dohmen, Rebekka Busse, Johanna Smith, Rebecca
Pfitzer, Lisa
Moser, Christina
Gegenfurtner, Florian
Arner, Anja
Foerster, Florian
Atzberger, Carina
Zisis, Themistoklis
Kubisch-Dohmen, Rebekka
Busse, Johanna
Smith, Rebecca
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2019-04-03
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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.
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Cell Death Dis. 2019 Apr 3;10(4):302. doi: 10.1038/s41419-019-1546-9.
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en
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2041-4889
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Attribution-NonCommercial-ShareAlike 4.0 International