Elevated labile iron in castration–resistant prostate cancer is targetable with ferrous iron–activatable antiandrogen therapy

Gonciarz, Ryan L.; Sakhamuri, Sasank; Hooshdaran, Nima; Kumar, G. Vijaya; Kim, Hyun-Jung; Evans, Michael J.; Renslo, Adam R.

doi:10.1016/j.ejmech.2023.115110

Cited by 3 publications

(4 citation statements)

References 48 publications

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“…While previous reports for hydrogen peroxide or enzyme activity detection appended a reactive trigger directly onto the fluorophore phenol ( 50 – 53 ), direct conjugation of a TRX moiety onto this site would yield an unstable carbonate prone to hydrolysis within biological settings. To overcome this issue, we employed a (N,N’-dimethyl)ethylenediamine linker separating the TRX trigger and dye ( 15 , 37 ), used previously to cage and release phenolic reporters ( 37 , 54 , 55 ). Upon reaction with Fe(II), the TRX endoperoxide is reduced to a cyclohexanone intermediate, which undergoes spontaneous β-elimination ( 33 ) to release an extended amine linker that then undergoes a self-immolative cyclization to uncage the free phenol of the fluorescein payload.…”

Section: Resultsmentioning

confidence: 99%

“…We developed a robust synthesis of IG1-FM in six sequential steps from the known ( 15 , 37 ) enantiopure TRX intermediate 1 , storing and handling the material as the HCl salt to prevent premature self-immolation of the extended linker moiety ( Scheme 2 ). We found that activation of the terminal amine 1 for coupling was best achieved via inverse addition of triethylamine to a reaction mixture containing a large excess of phosgene (~33 equiv.…”

Section: Resultsmentioning

confidence: 99%

“…At the same time, misregulation of iron-dependent redox activity can lead to the generation of harmful reactive oxygen species (ROS) through Fenton chemistry ( 5 ), which can induce oxidative stress and ultimately promote a unique cell death pathway, termed ferroptosis, via aberrant peroxidation of polyunsaturated fatty acids ( 6 – 9 ). Indeed, oxidative stress induced by prolonged misregulation of iron has been linked to cancer ( 10 – 15 ), cardiovascular disorders ( 16 ), neurodegenerative disorders ( 17 – 19 ), and aging ( 20 ). The importance of iron in biology and medicine motivates the development of chemical tools that can effectively monitor this nutrient under different physiological and pathological states.…”

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confidence: 99%

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A tandem activity-based sensing and labeling strategy reveals antioxidant response element regulation of labile iron pools

Pezacki,

Gonciarz,

Okamura

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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Iron is an essential element for life owing to its ability to participate in a diverse array of oxidation–reduction reactions. However, misregulation of iron-dependent redox cycling can also produce oxidative stress, contributing to cell growth, proliferation, and death pathways underlying aging, cancer, neurodegeneration, and metabolic diseases. Fluorescent probes that selectively monitor loosely bound Fe(II) ions, termed the labile iron pool, are potentially powerful tools for studies of this metal nutrient; however, the dynamic spatiotemporal nature and potent fluorescence quenching capacity of these bioavailable metal stores pose challenges for their detection. Here, we report a tandem activity-based sensing and labeling strategy that enables imaging of labile iron pools in live cells through enhancement in cellular retention. Iron green-1 fluoromethyl (IG1-FM) reacts selectively with Fe(II) using an endoperoxide trigger to release a quinone methide dye for subsequent attachment to proximal biological nucleophiles, providing a permanent fluorescent stain at sites of elevated labile iron. IG1-FM imaging reveals that degradation of the major iron storage protein ferritin through ferritinophagy expands the labile iron pool, while activation of nuclear factor-erythroid 2-related factor 2 (NRF2) antioxidant response elements (AREs) depletes it. We further show that lung cancer cells with heightened NRF2 activation, and thus lower basal labile iron, have reduced viability when treated with an iron chelator. By connecting labile iron pools and NRF2-ARE activity to a druggable metal-dependent vulnerability in cancer, this work provides a starting point for broader investigations into the roles of transition metal and antioxidant signaling pathways in health and disease.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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A tandem activity-based sensing and labeling strategy reveals antioxidant response element regulation of labile iron pools

Pezacki,

Gonciarz,

Okamura

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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“…While antiandrogen therapies have made significant progress, PCa diagnosed at an advanced stage is almost always fatal. It is evident that novel treatment strategies are required, as evidenced by a 3% annual increase in incidence of PCa, 50% of which is due to advanced-stage disease [5]. Developing antiandrogens that are both safe and effective at advanced stages of the disease remains a major challenge in the present day.…”

Section: Introductionmentioning

confidence: 99%

Assessing the Potential of Small Peptides for Altering Expression Levels of the Iron-Regulatory Genes FTH1 and TFRC and Enhancing Androgen Receptor Inhibitor Activity in In Vitro Prostate Cancer Models

Currie,

Bjerknes,

Myklebust

et al. 2023

IJMS

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Recent research highlights the key role of iron dyshomeostasis in the pathogenesis of prostate cancer (PCa). PCa cells are heavily dependent on bioavailable iron, which frequently results in the reprogramming of iron uptake and storage pathways. Although advanced-stage PCa is currently incurable, bioactive peptides capable of modulating key iron-regulatory genes may constitute a means of exploiting a metabolic adaptation necessary for tumor growth. Recent annual increases in PCa incidence have been reported, highlighting the urgent need for novel treatments. We examined the ability of LNCaP, PC3, VCaP, and VCaP-EnzR cells to form colonies in the presence of androgen receptor inhibitors (ARI) and a series of iron-gene modulating oligopeptides (FT-001-FT-008). The viability of colonies following treatment was determined with clonogenic assays, and the expression levels of FTH1 (ferritin heavy chain 1) and TFRC (transferrin receptor) were determined with quantitative polymerase chain reaction (PCR). Peptides and ARIs combined significantly reduced PCa cell growth across all phenotypes, of which two peptides were the most effective. Colony growth suppression generally correlated with the magnitude of concurrent increases in FTH1 and decreases in TFRC expression for all cells. The results of this study provide preliminary insight into a novel approach at targeting iron dysmetabolism and sensitizing PCa cells to established cancer treatments.

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In vivo bioluminescence imaging of labile iron in xenograft models and liver using FeAL-1, an iron-activatable form of D-luciferin

Gonciarz,

Jiang,

Tram

et al. 2023

Cell Chemical Biology

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Elevated labile iron in castration–resistant prostate cancer is targetable with ferrous iron–activatable antiandrogen therapy

Cited by 3 publications

References 48 publications

A tandem activity-based sensing and labeling strategy reveals antioxidant response element regulation of labile iron pools

A tandem activity-based sensing and labeling strategy reveals antioxidant response element regulation of labile iron pools

Assessing the Potential of Small Peptides for Altering Expression Levels of the Iron-Regulatory Genes FTH1 and TFRC and Enhancing Androgen Receptor Inhibitor Activity in In Vitro Prostate Cancer Models

In vivo bioluminescence imaging of labile iron in xenograft models and liver using FeAL-1, an iron-activatable form of D-luciferin

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