A chemical probe for BAG1 targets androgen receptor-positive prostate cancer through oxidative stress signaling pathway

Kuznik, Nane C.; Solozobova, Valeria; Lee, Irene I.; Jung, Nicole; Yang, Linxiao; Nienhaus, Karin; Ntim, Emmanuel Amankwah; Rottenberg, Jaice T.; Muhle‐Goll, Claudia; Kumar, Ashish; Peravali, Ravindra; Gräßle, Simone; Gourain, Victor; Deville, Célia; Cato, Laura; Neeb, Antje; Dilger, M.; Clausbruch, Christina Alexandra Cramer von; Weiss, Carsten; Kieffer, Bruno; Nienhaus, G. Ulrich; Brown, Myles; Bräse, Stefan; Cato, Andrew C. B.

doi:10.1016/j.isci.2022.104175

Cited by 9 publications

(7 citation statements)

References 80 publications

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“…This is an important consideration for Thio-2, or any novel compound thought to directly impact AR and/or AR signaling. It is now critically important that Thio-2 derivatives, such as A4B17, that are reported to disrupt the BAG-1L:AR NTD interaction, suppress AR signaling, and inhibit prostate cancer model growth are subjected to a rigorous interrogation to validate these findings (26, 27).…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…More recently, due to concerns regarding Thio-2 specificity, A4B17 has been developed (26). Similar to Thio-2, A4B17 disrupts the BAG-1L:AR NTD interaction and suppresses AR target gene expression demonstrating efficacy in pre-clinical prostate cancer models (27). Taken together, these data support targeting the BAG domain of BAG-1L as an attractive therapeutic strategy to overcome persistent AR signaling in CRPC.…”

Section: Introductionmentioning

confidence: 99%

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Targeting the BAG-1 family of co-chaperones in lethal prostate cancer

Neeb¹,

Figueiredo²,

Bogdan³

et al. 2022

Preprint

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Therapies that abrogate persistent androgen receptor (AR) signaling in castration resistant prostate cancer (CRPC) remain an unmet clinical need. The N-terminal domain (NTD) of the AR drives transcriptional activity in CRPC but is intrinsically disordered and remains a challenging therapeutic target. Therefore, inhibiting critical co-chaperones, such as BAG-1L, is an attractive alternative strategy. We performed druggability analyses demonstrating the BAG domain to be a challenging drug target. Thio-2, a tool compound, has been reported to bind the BAG domain of BAG-1L and inhibit BAG-1L-mediated AR transactivation. However, despite these data, the mechanism of action of Thio-2 is poorly understood and the BAG domain which is present in all BAG-1 isoforms has not been validated as a therapeutic target. Herein, we demonstrate growth inhibiting activity of Thio-2 in CRPC cell lines and patient derived models with decreased AR genomic binding and AR signaling independent of BAG-1 isoform function. Furthermore, genomic abrogation of BAG-1 isoforms did not recapitulate the described Thio-2 phenotype, and NMR studies suggest that Thio-2 may bind the AR NTD, uncovering a potential alternative mechanism of action, although in the context of low compound solubility. Furthermore, BAG-1 isoform knockout mice are viable and fertile, in contrast to previous studies, and when crossed with prostate cancer mouse models, BAG-1 deletion does not significantly impact prostate cancer development and growth. Overall, these data demonstrate that Thio-2 inhibits AR signaling and growth in CRPC independent of BAG-1 isoforms, and unlike previous studies of the activated AR, therapeutic targeting of the BAG domain requires further validation before being considered a therapeutic strategy for the treatment of CRPC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeting the BAG-1 family of co-chaperones in lethal prostate cancer

Neeb¹,

Figueiredo²,

Bogdan³

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Accordingly, SOD mimetics were proposed with therapeutic effects on prostate cancer cells by reducing oxidative stress and suppressing AR expression [ 117 ]. Also, small molecules such as A4B17 have been implicated as promising AR-positive prostate cancer therapeutics by suppressing AR target genes involved in oxidative stress and metabolism [ 118 ]. These results collectively suggested the feasibility of antioxidant agents in the treatment of hormone-associated (castration-resistant or AR-positive) prostate cancers.…”

Section: Receptors Associated With Redox Imbalancementioning

confidence: 99%

“…Importantly, the sensitivity of cancer cells to redox modulation differs significantly. Taking prostate cancers as an example, while AR-independent prostate cancer cells are sensitive to CAP-induced ROS elevation [ 141 ], antioxidant treatment is feasible in AR-positive or castration-resistant prostate cancers [ 118 ]. These evidences suggest that although the dose-dependent feature of CAP largely improves its flexibility in cancer treatment that may prevent malignant cells from developing drug resistance, it also creates complexity in determining the optimal dose for a particular patient.…”

Section: Cold Atmospheric Plasma As An Emerging Redox-modulating Tool...mentioning

confidence: 99%

Receptor-Mediated Redox Imbalance: An Emerging Clinical Avenue against Aggressive Cancers

2022

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Cancer cells are more vulnerable to abnormal redox fluctuations due to their imbalanced antioxidant system, where cell surface receptors sense stress and trigger intracellular signal relay. As canonical targets of many targeted therapies, cell receptors sensitize the cells to specific drugs. On the other hand, cell target mutations are commonly associated with drug resistance. Thus, exploring effective therapeutics targeting diverse cell receptors may open new clinical avenues against aggressive cancers. This paper uses focused case studies to reveal the intrinsic relationship between the cell receptors of different categories and the primary cancer hallmarks that are associated with the responses to external or internal redox perturbations. Cold atmospheric plasma (CAP) is examined as a promising redox modulation medium and highly selective anti-cancer therapeutic modality featuring dynamically varying receptor targets and minimized drug resistance against aggressive cancers.

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Optimizing CRISPR/Cas9 precision: Mitigating off-target effects for safe integration with photodynamic and stem cell therapies in cancer treatment

Merlin,

Abrahamse

2024

Biomedicine & Pharmacotherapy

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A chemical probe for BAG1 targets androgen receptor-positive prostate cancer through oxidative stress signaling pathway

Cited by 9 publications

References 80 publications

Targeting the BAG-1 family of co-chaperones in lethal prostate cancer

Targeting the BAG-1 family of co-chaperones in lethal prostate cancer

Receptor-Mediated Redox Imbalance: An Emerging Clinical Avenue against Aggressive Cancers

Optimizing CRISPR/Cas9 precision: Mitigating off-target effects for safe integration with photodynamic and stem cell therapies in cancer treatment

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