Targeting DNA topoisomerases: past &amp; future

Gmeiner, William H.; Waardenburg, Robert C.A.M. van

doi:10.20517/cdr.2021.65

Cited by 4 publications

(4 citation statements)

References 10 publications

(22 reference statements)

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“…Chemicals stabilizing DNA topoisomerases in the cleavage state without the relegation phase (topoisomerase “poisons”) are commonly used in chemotherapy but may induce DNA damage in the nervous system and cause cognitive deficits in cancer patients and experimental animals (El-Agamy and others 2019; Matsos and Johnston 2019; Nguyen and Ehrlich 2020). In the context of migraine and oxidative stress, it is important that 8-oxoG and other oxidative modifications of DNA bases and intermediate of their repair are potent TOP1 poisons (reviewed in Gmeiner and van Waardenburg 2021). Moreover, neurons may be preferentially affected by such lesions due to a high number of residing mitochondria, the main source of endogenous ROS.…”

Section: Potential Of Aberrant Activity Of Dna Topoisomerases In Migr...mentioning

confidence: 99%

DNA Damage and Repair in Migraine: Oxidative Stress and Beyond

et al. 2022

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Energy generation in the brain to ameliorate energy deficit in migraine leads to oxidative stress as it is associated with reactive oxygen species (ROS) that may damage DNA and show a pronociceptive action in meninges mediated by transient receptor potential cation channel subfamily A member 1 (TRPA1). Recent studies show high levels of single-strand breaks (SSBs) at specific sites in the genome of postmitotic neurons and point at SSB repair (SSBR) as an important element of homeostasis of the central nervous system. DNA topoisomerase 1 (TOP1) is stabilized in the DNA damage-inducing state by neuronal stimulation, including cortical spreading depression. Impairment in poly (ADP-ribose) polymerase 1 (PARP-1) and X-ray repair cross complementing 1 (XRCC1), key SSBR proteins, may be linked with migraine by transient receptor potential melastatin 2 (TRPM2). TRPM2 may also mediate the involvement of migraine-related neuroinflammation with PARP-1 activated by oxidative stress–related SSBs. In conclusion, aberrant activity of SSBR evoked by compromised PARP-1 and XRCC1 may contribute to pathological phenomena in the migraine brain. Such aberrant SSBR results in the lack of repair or misrepair of SSBs induced by ROS or resulting from impaired TOP1. Therefore, components of SSBR may be considered a prospective druggable target in migraine.

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Section: Potential Of Aberrant Activity Of Dna Topoisomerases In Migr...mentioning

confidence: 99%

DNA Damage and Repair in Migraine: Oxidative Stress and Beyond

et al. 2022

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“…Human topoisomerase I expression levels are lower in healthy cells, but higher in rapidly dividing cancer cells [ 8 ]. Rapid, uncontrolled cell proliferation is a characteristic of aggressive malignancies, and these tumor cells would be reliant on topoisomerases to allow the high replication and transcription rates of DNA [ 9 ]. High TOP1 gene copy number, mRNA, and protein levels, as well as enzyme activity, are associated with unfavorable prognosis in some epithelial cancers [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

“…High TOP1 gene copy number, mRNA, and protein levels, as well as enzyme activity, are associated with unfavorable prognosis in some epithelial cancers [ 10 , 11 ]. Inhibition of topoisomerases is an important principle of anticancer treatment [ 1 , 9 ], and inhibitors of topoisomerases I and II are broadly used in the clinic. A correlation has been observed between the level of human topoisomerase I expression in cells and the sensitivity of cells to topoisomerase I inhibitors [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Current Role of Topoisomerase I Inhibitors for the Treatment of Mesenchymal Malignancies and Their Potential Future Use as Payload of Sarcoma-Specific Antibody-Drug Conjugates

Schöffski,

Wang,

Schöffski

et al. 2023

Oncol Res Treat

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Background: Topoisomerase I is an enzyme that plays a crucial part in DNA replication and transcription by the relaxation of supercoiled double-stranded DNA. Topoisomerase I inhibitors bind to the topoisomerase I cleavage complex, thereby stabilizing it and preventing the religation of the DNA strands, leading to DNA damage, cell cycle arrest, and apoptosis. Various topoisomerase I inhibitors have been evaluated in solid tumors, and irinotecan and topotecan have been approved for the treatment of epithelial malignancies. None of them have been approved for sarcoma, a diverse group of rare solid tumors with an unmet need for effective treatments. Summary: Topoisomerase I inhibitors have been evaluated in preclinical studies as single agents or in combination in solid tumors, some of which have included sarcomas where activity was observed. Clinical trials evaluating topoisomerase I inhibitors for the treatment of sarcoma have shown limited efficacy as monotherapy. In combination with other cytotoxic agents, topoisomerase I inhibitors have become part of clinical routine in selected sarcoma subtypes. Regimens such as irinotecan/vincristine/temozolomide are used in relapsed rhabdomyosarcoma, irinotecan/temozolomide and vincristine/topotecan/cyclophosphamide are commonly given in refractory Ewing sarcoma, and topotecan/carboplatin showed some activity in advanced soft tissue sarcoma. This review provides an overview of key studies with topoisomerase I inhibitors for the treatment of sarcoma. Topoisomerase I inhibitors are currently also being assessed as “payloads” for antibody-drug conjugates (ADCs), allowing for the targeting of specific antigen-expressing tumor cells and the delivery of the inhibitor directly to the tumor cells with the potential of enhancing therapeutic efficacy while minimizing systemic toxicity. Here, we also provide a brief overview on topoisomerase I-ADCs. Key Message: Topoisomerase I inhibitors are an important component of some systemic therapies for selected sarcomas and have potent cytotoxic properties and pharmacological characteristics that make them relevant candidates as payloads for the development of sarcoma-specific ADCs. ADCs are antibody-based targeted agents allowing for efficient and specific delivery of a given drug to the tumor cell. Topoisomerase I-ADCs are a novel targeted delivery approach which may have the potential to improve the therapeutic index of topoisomerase I inhibitors in the treatment of sarcoma and warrants investigation in a broad variety of mesenchymal malignancies.

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“…This region contains a variety of posttranslational modifications (PTMs) that influence TOP2A biological functions or stability (Lotz & Lamour, 2020). The hyperphosphorylation of TOP2A was linked to drug response in breast and other cancer cells (Matsumoto et al , 1997; Chikamori et al , 2003; Gmeiner & van Waardenburg, 2021). Introduction of ubiquitin is another mechanism of chemotherapy resistance, as it not only alters TOP2A biochemical activity but also depletes target levels through proteasome degradation (Guturi et al , 2016; Fielding et al , 2018).…”

Section: Introductionmentioning

confidence: 99%

O‐GlcNAcylation promotes topoisomerase IIα catalytic activity in breast cancer chemoresistance

Liu,

Yu,

Zhang

et al. 2023

EMBO Reports

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DNA topoisomerase IIa (TOP2A) plays a vital role in replication and cell division by catalytically altering DNA topology. It is a prominent target for anticancer drugs, but clinical efficacy is often compromised due to chemoresistance. In this study, we investigate the role of TOP2A O-GlcNAcylation in breast cancer cells and patient tumor tissues. Our results demonstrate that elevated TOP2A, especially its O-GlcNAcylation, promotes breast cancer malignant progression and resistance to adriamycin (Adm). O-GlcNAcylation at Ser1469 enhances TOP2A chromatin DNA binding and catalytic activity, leading to resistance to Adm in breast cancer cells and xenograft models. Mechanistically, O-GlcNAcylation-modulated interactions between TOP2A and cell cycle regulators influence downstream gene expression and contribute to breast cancer drug resistance. These results reveal a previously unrecognized mechanistic role for TOP2A O-GlcNAcylation in breast cancer chemotherapy resistance and provide support for targeting TOP2A O-GlcNAcylation in cancer therapy.

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Targeting DNA topoisomerases: past & future

Cited by 4 publications

References 10 publications

DNA Damage and Repair in Migraine: Oxidative Stress and Beyond

DNA Damage and Repair in Migraine: Oxidative Stress and Beyond

Current Role of Topoisomerase I Inhibitors for the Treatment of Mesenchymal Malignancies and Their Potential Future Use as Payload of Sarcoma-Specific Antibody-Drug Conjugates

O‐GlcNAcylation promotes topoisomerase IIα catalytic activity in breast cancer chemoresistance

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