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The Intersection of DNA Damage Response and Ferroptosis-A Rationale for Combination Therapeutics.

ABSTRACT: Ferroptosis is a novel form of iron-dependent cell death characterized by lipid peroxidation. While the importance and disease relevance of ferroptosis are gaining recognition, much remains unknown about its interaction with other biological processes and pathways. Recently, several studies have identified intricate and complicated interplay between ferroptosis, ionizing radiation (IR), ATM (ataxia-telangiectasia mutated)/ATR (ATM and Rad3-related), and tumor suppressor p53, which signifies the participation of the DNA damage response (DDR) in iron-related cell death. DDR is an evolutionarily conserved response triggered by various DNA insults to attenuate proliferation, enable DNA repairs, and dispose of cells with damaged DNA to maintain genome integrity. Deficiency in proper DDR in many genetic disorders or tumors also highlights the importance of this pathway. In this review, we will focus on the biological crosstalk between DDR and ferroptosis, which is mediated mostly via noncanonical mechanisms. For clinical applications, we also discuss the potential of combining ionizing radiation and ferroptosis-inducers for synergistic effects. At last, various ATM/ATR inhibitors under clinical development may protect ferroptosis and treat many ferroptosis-related diseases to prevent cell death, delay disease progression, and improve clinical outcomes.

SUBMITTER: Chen PH

PROVIDER: S-EPMC7464484 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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The Intersection of DNA Damage Response and Ferroptosis-A Rationale for Combination Therapeutics.

Chen Po-Han PH Tseng Watson Hua-Sheng WH Chi Jen-Tsan JT

Biology 20200723 8

Ferroptosis is a novel form of iron-dependent cell death characterized by lipid peroxidation. While the importance and disease relevance of ferroptosis are gaining recognition, much remains unknown about its interaction with other biological processes and pathways. Recently, several studies have identified intricate and complicated interplay between ferroptosis, ionizing radiation (IR), ATM (ataxia-telangiectasia mutated)/ATR (ATM and Rad3-related), and tumor suppressor p53, which signifies the ...[more]

PMID: 32718025

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Project description:Maintenance of genomic stability is a critical determinant of cell survival and is necessary for growth and progression of malignant cells. Interstrand crosslinking (ICL) agents, including platinum-based agents, are first-line chemotherapy treatment for many solid human cancers. In malignant cells, ICL triggers the DNA damage response (DDR). When the damage burden is high and lesions cannot be repaired, malignant cells are unable to divide and ultimately undergo cell death either through mitotic catastrophe or apoptosis. The activities of ICL agents, in particular platinum-based therapies, establish a "molecular landscape," i.e., a pattern of DNA damage that can potentially be further exploited therapeutically with DDR-targeting agents. If the molecular landscape created by platinum-based agents could be better defined at the molecular level, a systematic, mechanistic rationale(s) could be developed for the use of DDR-targeting therapies in combination/maintenance protocols for specific, clinically advanced malignancies. New therapeutic drugs such as poly(ADP-ribose) polymerase (PARP) inhibitors are examples of DDR-targeting therapies that could potentially increase the DNA damage and replication stress imposed by platinum-based agents in tumor cells and provide therapeutic benefit for patients with advanced malignancies. Recent studies have shown that the use of PARP inhibitors together with platinum-based agents is a promising therapy strategy for ovarian cancer patients with "BRCAness", i.e., a phenotypic characteristic of tumors that not only can involve loss-of-function mutations in either BRCA1 or BRCA2, but also encompasses the molecular features of BRCA-mutant tumors. On the basis of these promising results, additional mechanism-based studies focused on the use of various DDR-targeting therapies in combination with platinum-based agents should be considered. This review discusses, in general, (1) ICL agents, primarily platinum-based agents, that establish a molecular landscape that can be further exploited therapeutically; (2) multiple points of potential intervention after ICL agent-induced crosslinking that further predispose to cell death and can be incorporated into a systematic, therapeutic rationale for combination/ maintenance therapy using DDR-targeting agents; and (3) available agents that can be considered for use in combination/maintenance clinical protocols with platinum-based agents for patients with advanced malignancies.

Project description:While hyperthermia has been shown to be an effective adjuvant anti-tumor treatment to radiotherapy, we still do not completely understand effects thermoradiotherapy on tumor phenotype or how these effects vary among different tumors. Here, we performed gene expression analysis in 22 spontaneous canine sarcomas before and after the first hyperthermia treatment that was administered as an adjuvant to radiotherapy. Diffusion weighted MRI (DWI) was done prior to the treatment course and at the end of therapy. Using supervised analysis, we identified significant correlation of DWI with several genes involved in VEGF signaling, telomerase, Wnt pathways and fatty acid synthesis. When the change of gene expression caused by treatment was examined, we found that thermoradiotherapy led to the induction of well known cycle regulators p21 and mdm2 and reduced cellular proliferation in most treated tumors. We also identified two tumor subtypes with dramatic differences in the gene expression response and treatment response at the end of therapy. In the subtype with strong expression and increase in DWI, the mRNA level of hsp70, POT1 and centrosomal proteins was significantly higher. In the other subtype with modest response to hyperthermia, levels of CD31, vWF and transferrin was noted to be significantly higher. It is also possible to build a predictive model based on the pre-treatment gene expression to predict the likely treatment response of the tumors. The differential expression between the two tumor subtypes was used to interrogate connectivity map and identify linkages to an HDAC inhibitor and geldanamycin, an HSP90 inhibitor. Both HDAC inhibitors and hsp90 inhibitor geldanamycin are shown to synergerize with thermoradiotherapy in reducing cell survival in clonogenic assays. Taken together, the gene expression studies of hyperthermia-treated spontaneous canine tumors shed mechanistic insights into the heterogeneity of thermoradiotherapy response and identified pathway-targeting compounds with synergistic potential to enhance its therapeutic benefits. To our knowledge, this is one of the first successful attempts to link genomic and functional imaging changes together. This is the first demonstration of using such associations to understand the connection between cellular and physiologic responses to treatment. gene expression analysis in 22 spontaneous canine sarcomas before and after the first hyperthermia treatment that was administered as an adjuvant to radiotherapy.

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The Intersection of DNA Damage Response and Ferroptosis-A Rationale for Combination Therapeutics.

Publications

The Intersection of DNA Damage Response and Ferroptosis-A Rationale for Combination Therapeutics.

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