Journal article
Augmentation of intracellular iron using iron sucrose enhances the toxicity of pharmacological ascorbate in colon cancer cells
Redox biology, Vol.14, pp.82-87
04/2018
DOI: 10.1016/j.redox.2017.08.017
PMCID: PMC5591450
PMID: 28886484
Abstract
Pharmacological doses (> 1mM) of ascorbate (a.k.a., vitamin C) have been shown to selectively kill cancer cells through a mechanism that is dependent on the generation of H O at doses that are safely achievable in humans using intravenous administration. The process by which ascorbate oxidizes to form H O is thought to be mediated catalytically by redox active metal ions such as iron (Fe). Because intravenous iron sucrose is often administered to colon cancer patients to help mitigate anemia, the current study assessed the ability of pharmacological ascorbate to kill colon cancer cells in the presence and absence of iron sucrose. In vitro survival assays showed that 10mM ascorbate exposure (2h) clonogenically inactivated 40-80% of exponentially growing colon cancer cell lines (HCT116 and HT29). When the H O scavenging enzyme, catalase, was added to the media, or conditionally over-expressed using a doxycycline inducible vector, the toxicity of pharmacological ascorbate was significantly blunted. When colon cancer cells were treated in the presence or absence of 250µM iron sucrose, then rinsed, and treated with 10mM ascorbate, the cells demonstrated increased levels of labile iron that resulted in significantly increased clonogenic cell killing, compared to pharmacological ascorbate alone. Interestingly, when colon cancer cells were treated with iron sucrose for 1h and then 10mM ascorbate was added to the media in the continued presence of iron sucrose, there was no enhancement of toxicity despite similar increases in intracellular labile iron. The combination of iron chelators, deferoxamine and diethylenetriaminepentaacetic acid, significantly inhibited the toxicity of either ascorbate alone or ascorbate following iron sucrose. These observations support the hypothesis that increasing intracellular labile iron pools, using iron sucrose, can be used to increase the toxicity of pharmacological ascorbate in human colon cancer cells by a mechanism involving increased generation of H O .
Details
- Title: Subtitle
- Augmentation of intracellular iron using iron sucrose enhances the toxicity of pharmacological ascorbate in colon cancer cells
- Creators
- Kristin E Brandt - University of IowaKelly C Falls - University of IowaJoshua D Schoenfeld - University of IowaSamuel N Rodman - University of IowaZhimin Gu - University of IowaFenghuang Zhan - University of Iowa, Internal MedicineJoseph J Cullen - University of Iowa, SurgeryBrett A Wagner - University of Iowa, Radiation Research LaboratoryGarry R Buettner - University of Iowa, Radiation OncologyBryan G Allen - University of Iowa, Radiation OncologyDaniel J Berg - University of Iowa, Internal MedicineDouglas R Spitz - University of Iowa, Radiation OncologyMelissa A Fath - University of Iowa, Radiation Research Laboratory
- Resource Type
- Journal article
- Publication Details
- Redox biology, Vol.14, pp.82-87
- Publisher
- Elsevier; Netherlands
- DOI
- 10.1016/j.redox.2017.08.017
- PMID
- 28886484
- PMCID
- PMC5591450
- ISSN
- 2213-2317
- eISSN
- 2213-2317
- Copyright
- © 2020 Elsevier B.V. or its licensors or contributors. ScienceDirect ® is a registered trademark of Elsevier B.V.
- Grant note
- Funding: The authors would like to thank the Radiation and Free Radical Research Core in the Holden Comprehensive Cancer Center and Dr.Michael McCormick for technical assistance with the catalase assays.The authors would like to thank Dr. Dawn Quelle for reagents and assistants in making the Lentivirus. The authors would like to thank the Flow Cytometry Core in the Holden Comprehensive Cancer Center for assistance with the Calcein assays. This work was supported by National Institute of Health, United States grants R01CA182804,R01CA133114, R01 CA169046, R01CA184051 P30CA086862,T35HL007485-34 F30CA213817 and 5T32GM007337 as well as the Carver Research Program of Excellence in Redox Biology and Medicine and the Carver College of Medicine medical student summer research program. P30 ES005605 / NIEHS NIH HHS F30 CA213817 / NCI NIH HHS T35 HL007485 / NHLBI NIH HHS T32 GM007337 / NIGMS NIH HHS R01 CA184051 / NCI NIH HHS R01 CA182804 / NCI NIH HHS R01 CA133114 / NCI NIH HHS P30 CA086862 / NCI NIH HHS R01 CA169046 / NCI NIH HHS Conflicts of Interest: None Reported. Corrigendum: The authors regret the exclusion of funding source: institutional research grant #IRG – 77-004-34. The authors would like to apologise for any inconvenience caused. (January 2020)
- Language
- English
- Date published
- 04/2018
- Academic Unit
- Radiation Oncology; Radiation Research Laboratory
- Record Identifier
- 9983763598802771
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