Inhibitory effect of iron withdrawal by chelation on the growth of human and murine mammary carcinoma and fibrosarcoma cells

Coombs, Melanie R. Power; Grant, Taryn; Greenshields, Anna L.; Arsenault, Daniel J.; Holbein, Bruce E.

doi:10.1016/j.yexmp.2015.07.008

Cited by 23 publications

(10 citation statements)

References 34 publications

(35 reference statements)

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“…Given the larger molecular size of DIBI, it seems unlikely it would be freely transportable for intracellular uptake by microorganisms while deferiprone would presumably be available intracellularly. We have also reported enhanced growth inhibition by DIBI over deferiprone for Candida albicans ( Savage et al, 2018 ) and Acinetobacter baumannii ( Ang et al, 2018 ) as well as for breast cancer cells ( Power Coombs et al, 2015 ).…”

Section: Discussionmentioning

confidence: 90%

Novel Iron-Chelator DIBI Inhibits Staphylococcus aureus Growth, Suppresses Experimental MRSA Infection in Mice and Enhances the Activities of Diverse Antibiotics in vitro

Parquet¹,

Savage²,

Allan³

et al. 2018

Front. Microbiol.

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DIBI, a purpose-designed hydroxypyridinone-containing iron-chelating antimicrobial polymer was studied for its anti-staphylococcal activities in vitro in comparison to deferiprone, the chemically related, small molecule hydroxypyridinone chelator. The sensitivities of 18 clinical isolates of Staphylococcus aureus from human, canine and bovine infections were determined. DIBI was strongly inhibitory to all isolates, displaying approximately 100-fold more inhibitory activity than deferiprone when compared on their molar iron-binding capacities. Sensitivity to DIBI was similar for both antibiotic-resistant and -sensitive isolates, including hospital- and community-acquired (United States 300) MRSA. DIBI inhibition was primarily bacteriostatic in nature at low concentration and was reversible by addition of Fe. DIBI also exhibited in vivo anti-infective activity in two distinct MRSA ATCC43300 infection and colonization models in mice. In a superficial skin wound infection model, topical application of DIBI provided a dose-dependent suppression of infection along with reduced wound inflammation. Intranasal DIBI reduced staphylococcal burden by >2 log in a MRSA nares carriage model. DIBI was also examined for its influence on antibiotic activities with a reference isolate ATCC6538, typically utilized to assess new antimicrobials. Sub-bacteriostatic concentrations of DIBI resulted in Fe-restricted growth and this physiological condition displayed increased sensitivity to GEN, CIP, and VAN. DIBI did not impair antibiotic activity but rather it enhanced overall killing. Importantly, recovery growth of survivors that typically followed an initial sub-MIC antibiotic killing phase was substantially suppressed by DIBI for each of the antibiotics examined. DIBI has promise for restricting staphylococcal infection on its own, regardless of the isolate’s animal source or antibiotic resistance profile. DIBI also has potential for use in combination with various classes of currently available antibiotics to improve their responses.

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Section: Discussionmentioning

confidence: 90%

Novel Iron-Chelator DIBI Inhibits Staphylococcus aureus Growth, Suppresses Experimental MRSA Infection in Mice and Enhances the Activities of Diverse Antibiotics in vitro

Parquet¹,

Savage²,

Allan³

et al. 2018

Front. Microbiol.

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“…According to Tsuchiya et al [ 41 ], when cellular injuries such as DNA damage or oxidative stress accumulate in proliferating cells, the cell-cycle is arrested in G1 or G2 phase before apoptosis induction. Furthermore, anti-cancer drugs inhibit cell proliferation and induce apoptosis often with a S-phase arrest [ 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

The signaling pathways by which the Fas/FasL system accelerates oocyte aging

Zhu

Lin

Zhang

et al. 2016

Aging

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Abstract:In spite of great efforts, the mechanisms for postovulatory oocyte aging are not fully understood. Although our previous work showed that the FasL/Fas signaling facilitated oocyte aging, the intra-oocyte signaling pathways are unknown. Furthermore, the mechanisms by which oxidative stress facilitates oocyte aging and the causal relationship between Ca 2+ rises and caspase-3 activation and between the cell cycle and apoptosis during oocyte aging need detailed investigations. Our aim was to address these issues by studying the intra-oocyte signaling pathways for Fas/FasL to accelerate oocyte aging. The results indicated that sFasL released by cumulus cells activated Fas on the oocyte by increasing reactive oxygen species via activating NADPH oxidase. The activated Fas triggered Ca 2+ release from the endoplasmic reticulum by activating phospholipase C-γ pathway and cytochrome c pathway. The cytoplasmic Ca 2+ rises activated calcium/calmodulin-dependent protein kinase II (CaMKII) and caspase-3. While activated CaMKII increased oocyte susceptibility to activation by inactivating maturation-promoting factor (MPF) through cyclin B degradation, the activated caspase-3 facilitated further Ca 2+ releasing that activates more caspase-3 leading to oocyte fragmentation. Furthermore, caspase-3 activation and fragmentation were prevented in oocytes with a high MPF activity, suggesting that an oocyte must be in interphase to undergo apoptosis.

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“…Chelation of iron(III) has been proposed as a cancer treatment that causes reductions in tumor growth by decreasing the bioavailability of iron(III) to the proliferating cancer cells resulting in cytostatic effects 17 – 19 , 26 – 29 . Both Myc-CaP and TRAMP-C2 exhibited significant anti-tumor response to L1 treatment that points to the drug having an effect after a short duration, over the course of weeks of tumor growth.…”

Section: Discussionmentioning

confidence: 99%

Iron deposition is associated with differential macrophage infiltration and therapeutic response to iron chelation in prostate cancer

Leftin

Zhao

Turkekul

et al. 2017

Sci Rep

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Immune cells such as macrophages are drivers and biomarkers of most cancers. Scoring macrophage infiltration in tumor tissue provides a prognostic assessment that is correlated with disease outcome and therapeutic response, but generally requires invasive biopsy. Routine detection of hemosiderin iron aggregates in macrophages in other settings histologically and in vivo by MRI suggests that similar assessments in cancer can bridge a gap in our ability to assess tumor macrophage infiltration. Quantitative histological and in vivo MRI assessments of non-heme cellular iron revealed that preclinical prostate tumor models could be differentiated according to hemosiderin iron accumulation—both in tumors and systemically. Monitoring cellular iron levels during “off-label” administration of the FDA-approved iron chelator deferiprone evidenced significant reductions in tumor size without extensive perturbation to these iron deposits. Spatial profiling of the iron-laden infiltrates further demonstrated that higher numbers of infiltrating macrophage iron deposits was associated with lower anti-tumor chelation therapy response. Imaging macrophages according to their innate iron status provides a new phenotypic window into the immune tumor landscape and reveals a prognostic biomarker associated with macrophage infiltration and therapeutic outcome.

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Inhibitory effect of iron withdrawal by chelation on the growth of human and murine mammary carcinoma and fibrosarcoma cells

Cited by 23 publications

References 34 publications

Novel Iron-Chelator DIBI Inhibits Staphylococcus aureus Growth, Suppresses Experimental MRSA Infection in Mice and Enhances the Activities of Diverse Antibiotics in vitro

Novel Iron-Chelator DIBI Inhibits Staphylococcus aureus Growth, Suppresses Experimental MRSA Infection in Mice and Enhances the Activities of Diverse Antibiotics in vitro

The signaling pathways by which the Fas/FasL system accelerates oocyte aging

Iron deposition is associated with differential macrophage infiltration and therapeutic response to iron chelation in prostate cancer

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