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

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.

Basic fibroblast growth factor promotes doxorubicin resistance in chondrosarcoma cells by affecting XRCC5 expression

“…Therefore, enhancement in DNA repair activity of cancer cells would confer resistance to Dox . Recent studies have indicated that the sensitivity of Dox treatment can be improved by inhibiting the DSB repair pathways, showing leads for novel combination therapies . Note that, bFGF signaling has previously been shown to increase DNA‐PK activity and is critical for DNA repair …”

“…38,49,50 Recent studies have indicated that the sensitivity of Dox treatment can be improved by inhibiting the DSB repair pathways, showing leads for novel combination therapies. [51][52][53][54] Note that, bFGF signaling has previously been shown to increase DNA-PK activity and is critical for DNA repair. 36,37,55 There are two main pathways for DSB repair in eukaryotic cells:…”

RHOAming Through the Nucleotide Excision Repair Pathway as a Mechanism of Cellular Response Against the Effects of UV Radiation

“…Disruption of the actin network also impairs the transport of actin-dependent proteins and organelles, affecting the transport of proteins/complexes involved in DNA damage response and repair, as well as those involved in chromatin remodeling. It was demonstrated recently that actin dynamics is crucial to RPA recruitment to DSB sites after Doxorubicin treatments (Pfitzer et al, 2019). Additionally, the overexpression of Cofilin-1, a downstream component of RhoA pathway, impairs both actin polymerization and DSB repair leading to increased radiosensitivity (Chang et al, 2015).…”

The Emerging Roles of ATP-Dependent Chromatin Remodeling Complexes in Pancreatic Cancer

“…Signals from the extracellular matrix (ECM) decreased nuclear-actin export, resulting in accumulation of nuclear actin and activation of growth-related transcription and malignant progression of breast cancer [273]. Nuclear actin could be a potential therapeutic target, as doxorubicin treatment resulted in nuclear actin aggregates and affected the recruitment of nuclear DNA-damage repair factors [274].…”