Effective Radiosensitization of Bladder Cancer Cells by Pharmacological Inhibition of DNA-PK and ATR

Chughtai, Ahmed Ali; Pannhausen, Julia; Dinger, Pia; Wirtz, Julia; Knüchel, Ruth; Gaisa, Nadine T.; Eble, Michael J.; Rose, Michael

doi:10.3390/biomedicines10061277

Cited by 7 publications

(4 citation statements)

References 50 publications

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“…Colony formation was determined as previously described [ 35 ] with slight modifications: Cells were plated into six‐well plates (EJ28: 75 × 10 2 cells per well; SCaBER: 1 × 10 3 cells per well; J82: 1 × 10 3 cells per well) in triplicate and cultured in growth medium with G418 for 10 days. After cultivation (37 °C, 5% CO 2 ), the colonies were stained in 0.05% crystal violet solution (10% formaldehyde, 80% methanol).…”

Section: Methodsmentioning

confidence: 99%

Dual role of GRHL3 in bladder carcinogenesis depending on histological subtypes

Lammert,

Pannhausen,

Noetzel

et al. 2024

Molecular Oncology

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The effect of grainyhead‐like transcription factor 3 (GRHL3) on cancer development depends on the cancer subtypes as shown in tumor entities such as colorectal or oral squamous cell carcinomas. Here, we analyzed the subtype‐specific role of GRHL3 in bladder carcinogenesis, comparing common urothelial carcinoma (UC) with squamous bladder cancer (sq‐BLCA). We examined GRHL3 mRNA and protein expression in cohorts of patient samples, its prognostic role and its functional impact on tumorigeneses in different molecular and histopathological subtypes of bladder cancer. We showed for GRHL3 a reverse expression in squamous and urothelial bladder cancer subtypes. Stably GRHL3‐overexpressing EJ28, J82, and SCaBER in vitro models revealed a tumor‐suppressive function in squamous and an oncogenic role in the urothelial cancer cells affecting cell and colony growth, and migratory and invasive capacities. Transcriptomic profiling demonstrated highly subtype‐specific GRHL3‐regulated expression networks coined by the enrichment of genes involved in integrin‐mediated pathways. In SCaBER, loss of ras homolog family member A (RHOA) GTPase activity was demonstrated to be associated with co‐regulation of eukaryotic translation initiation factor 4E family member 3 (EIF4E3), a potential tumor suppressor gene. Thus, our data provide for the first time a detailed insight into the role of the transcription factor GRHL3 in different histopathological subtypes of bladder cancer.

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Section: Methodsmentioning

confidence: 99%

Dual role of GRHL3 in bladder carcinogenesis depending on histological subtypes

Lammert,

Pannhausen,

Noetzel

et al. 2024

Molecular Oncology

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“…These kinds of inhibitors were shown to be effective, especially in the treatment of head and neck squamous cell carcinoma, in combination with other therapies such as surgery, RT, and chemotherapy [176]. They also specifically target DDR pathways and impair DSB repair processes, exhibiting significant radiosensitizing effects [177]. CHK1 is also related to as many as thirty-eight compounds, according to DrugBank, the majority of which are investigational or experimental.…”

Section: Targeting Essential Phosphorylation Factors For Regulating Ddrmentioning

confidence: 99%

Drug Discovery Targeting Post-Translational Modifications in Response to DNA Damages Induced by Space Radiation

Xie

Zhou

2023

IJMS

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DNA damage in astronauts induced by cosmic radiation poses a major barrier to human space exploration. Cellular responses and repair of the most lethal DNA double-strand breaks (DSBs) are crucial for genomic integrity and cell survival. Post-translational modifications (PTMs), including phosphorylation, ubiquitylation, and SUMOylation, are among the regulatory factors modulating a delicate balance and choice between predominant DSB repair pathways, such as non-homologous end joining (NHEJ) and homologous recombination (HR). In this review, we focused on the engagement of proteins in the DNA damage response (DDR) modulated by phosphorylation and ubiquitylation, including ATM, DNA-PKcs, CtIP, MDM2, and ubiquitin ligases. The involvement and function of acetylation, methylation, PARylation, and their essential proteins were also investigated, providing a repository of candidate targets for DDR regulators. However, there is a lack of radioprotectors in spite of their consideration in the discovery of radiosensitizers. We proposed new perspectives for the research and development of future agents against space radiation by the systematic integration and utilization of evolutionary strategies, including multi-omics analyses, rational computing methods, drug repositioning, and combinations of drugs and targets, which may facilitate the use of radioprotectors in practical applications in human space exploration to combat fatal radiation hazards.

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“…In mammals, c-NHEJ is the main repair pathway for DSB processing and operates with fast kinetics and efficiency, throughout the cell cycle [ 42 , 139 , 140 , 141 ]. Inhibition of c-NHEJ is shown to confer marked radiosensitivity in a wide range of cells [ 142 , 143 , 144 ]. We recently reported that at low doses of IR, c-NHEJ is partly suppressed by mechanisms that remain to be characterized, giving thus way to HR [ 131 , 145 , 146 ].…”

Section: Shift Of Balance To Error-prone Dsb Repair Pathways Is Likel...mentioning

confidence: 99%

BMN673 Is a PARP Inhibitor with Unique Radiosensitizing Properties: Mechanisms and Potential in Radiation Therapy

Soni

Lin

Mladenov

et al. 2022

Cancers

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BMN673 is a relatively new PARP inhibitor (PARPi) that exhibits superior efficacy in vitro compared to olaparib and other clinically relevant PARPi. BMN673, similar to most clinical PARPi, inhibits the catalytic activities of PARP-1 and PARP-2 and shows impressive anticancer potential as monotherapy in several pre-clinical and clinical studies. Tumor resistance to PARPi poses a significant challenge in the clinic. Thus, combining PARPi with other treatment modalities, such as radiotherapy (RT), is being actively pursued to overcome such resistance. However, the modest to intermediate radiosensitization exerted by olaparib, rucaparib, and veliparib, limits the rationale and the scope of such combinations. The recently reported strong radiosensitizing potential of BMN673 forecasts a paradigm shift on this front. Evidence accumulates that BMN673 may radiosensitize via unique mechanisms causing profound shifts in the balance among DNA double-strand break (DSB) repair pathways. According to one of the emerging models, BMN673 strongly inhibits classical non-homologous end-joining (c-NHEJ) and increases reciprocally and profoundly DSB end-resection, enhancing error-prone DSB processing that robustly potentiates cell killing. In this review, we outline and summarize the work that helped to formulate this model of BMN673 action on DSB repair, analyze the causes of radiosensitization and discuss its potential as a radiosensitizer in the clinic. Finally, we highlight strategies for combining BMN673 with other inhibitors of DNA damage response for further improvements.

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Effective Radiosensitization of Bladder Cancer Cells by Pharmacological Inhibition of DNA-PK and ATR

Cited by 7 publications

References 50 publications

Dual role of GRHL3 in bladder carcinogenesis depending on histological subtypes

Dual role of GRHL3 in bladder carcinogenesis depending on histological subtypes

Drug Discovery Targeting Post-Translational Modifications in Response to DNA Damages Induced by Space Radiation

BMN673 Is a PARP Inhibitor with Unique Radiosensitizing Properties: Mechanisms and Potential in Radiation Therapy

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