{"doi":"10.1371/journal.pone.0244540","title":"Triphenylphosphonium derivatives disrupt metabolism and inhibit melanoma growth in vivo when delivered via a thermosensitive hydrogel","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.","journal":"PLoS ONE","year":2020,"id":73119,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9554,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":386400,"name":"Alora S. Kraus","orcid":null,"position":1,"is_corresponding":false},{"id":386401,"name":"Devin K. Hedlund","orcid":null,"position":2,"is_corresponding":false},{"id":385115,"name":"Colette Gnade","orcid":"0000-0002-9163-7458","position":3,"is_corresponding":false},{"id":297600,"name":"Brett A. Wagner","orcid":"0000-0002-0094-7259","position":4,"is_corresponding":false},{"id":357059,"name":"Michael L. McCormick","orcid":"0000-0002-7403-7186","position":5,"is_corresponding":false},{"id":385116,"name":"Melissa A. Fath","orcid":"0000-0002-7272-2120","position":6,"is_corresponding":false},{"id":385117,"name":"Dongrim Seol","orcid":"0000-0003-0383-3756","position":7,"is_corresponding":false},{"id":386402,"name":"Tae‐Hong Lim","orcid":null,"position":8,"is_corresponding":false},{"id":297603,"name":"Garry R. Buettner","orcid":"0000-0002-5594-1903","position":9,"is_corresponding":false},{"id":385118,"name":"Prabhat C. Goswami","orcid":"0000-0002-5700-2096","position":10,"is_corresponding":false},{"id":385119,"name":"F. Christopher Pigge","orcid":"0000-0003-2700-7141","position":11,"is_corresponding":false},{"id":297605,"name":"Douglas R. Spitz","orcid":"0000-0002-1254-8765","position":12,"is_corresponding":false},{"id":326422,"name":"Michael K. Schultz","orcid":"0000-0002-4554-2212","position":13,"is_corresponding":false},{"id":386399,"name":"Kyle C. Kloepping","orcid":null,"position":0,"is_corresponding":true}],"reference_count":83,"raw_metadata":null,"created_at":"2026-07-18T21:45:32.034078Z","pmid":"33378390","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}