Journal article
Triphenylphosphonium derivatives disrupt metabolism and inhibit melanoma growth in vivo when delivered via a thermosensitive hydrogel
PloS one, Vol.15(12), pp.e0244540-e0244540
2020
DOI: 10.1371/journal.pone.0244540
PMCID: PMC7773266
PMID: 33378390
Abstract
Despite dramatic improvements in outcomes arising from the introduction of targeted therapies and immunotherapies, metastatic melanoma is a highly resistant form of cancer with 5 year survival rates of <35%. Drug resistance is frequently reported to be associated with changes in oxidative metabolism that lead to malignancy that is non-responsive to current treatments. The current report demonstrates that triphenylphosphonium(TPP)-based lipophilic cations can be utilized to induce cytotoxicity in pre-clinical models of malignant melanoma by disrupting mitochondrial metabolism. In vitro experiments demonstrated that TPP-derivatives modified with aliphatic side chains accumulated in melanoma cell mitochondria; disrupted mitochondrial metabolism; led to increases in steady-state levels of reactive oxygen species; decreased total glutathione; increased the fraction of glutathione disulfide; and caused cell killing by a thiol-dependent process that could be rescued by N-acetylcysteine. Furthermore, TPP-derivative-induced melanoma toxicity was enhanced by glutathione depletion (using buthionine sulfoximine) as well as inhibition of thioredoxin reductase (using auranofin). In addition, there was a structure-activity relationship between the aliphatic side-chain length of TPP-derivatives (5-16 carbons), where longer carbon chains increased melanoma cell metabolic disruption and cell killing. In vivo bio-distribution experiments showed that intratumoral administration of a C14-TPP-derivative (12-carbon aliphatic chain), using a slow-release thermosensitive hydrogel as a delivery vehicle, localized the drug at the melanoma tumor site. There, it was observed to persist and decrease the growth rate of melanoma tumors. These results demonstrate that TPP-derivatives selectively induce thiol-dependent metabolic oxidative stress and cell killing in malignant melanoma and support the hypothesis that a hydrogel-based TPP-derivative delivery system could represent a therapeutic drug-delivery strategy for melanoma.
Details
- Title: Subtitle
- Triphenylphosphonium derivatives disrupt metabolism and inhibit melanoma growth in vivo when delivered via a thermosensitive hydrogel
- Creators
- Kyle C Kloepping - University of IowaAlora S Kraus - University of IowaDevin K Hedlund - University of IowaColette M Gnade - University of IowaBrett A Wagner - University of IowaMichael L McCormick - University of IowaMelissa A Fath - University of IowaDongrim Seol - University of IowaTae-Hong Lim - University of IowaGarry R Buettner - University of IowaPrabhat C Goswami - University of IowaF Christopher Pigge - University of IowaDouglas R Spitz - University of IowaMichael K Schultz - University of Iowa
- Resource Type
- Journal article
- Publication Details
- PloS one, Vol.15(12), pp.e0244540-e0244540
- DOI
- 10.1371/journal.pone.0244540
- PMID
- 33378390
- PMCID
- PMC7773266
- NLM abbreviation
- PLoS One
- ISSN
- 1932-6203
- eISSN
- 1932-6203
- Grant note
- T32 CA078586 / NCI NIH HHS P01 CA217797 / NCI NIH HHS R01 CA182804 / NCI NIH HHS R50 CA243693 / NCI NIH HHS T32 GM008365 / NIGMS NIH HHS P30 CA086862 / NCI NIH HHS K25 CA172218 / NCI NIH HHS
- Language
- English
- Date published
- 2020
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Radiology; Orthodontics; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Pathology; Orthopedics and Rehabilitation; Radiation Oncology; Obstetrics and Gynecology; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Chemistry
- Record Identifier
- 9984197134202771
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