Triphenylphosphonium derivatives disrupt metabolism and inhibit melanoma growth in vivo when delivered via a thermosensitive hydrogel

• Published in: PloS one Vol. 15; no. 12; p. e0244540
• Main Authors: Kloepping, Kyle C, Kraus, Alora S, Hedlund, Devin K, Gnade, Colette M, Wagner, Brett A, McCormick, Michael L, Fath, Melissa A, Seol, Dongrim, Lim, Tae-Hong, Buettner, Garry R, Goswami, Prabhat C, Pigge, F Christopher, Spitz, Douglas R, Schultz, Michael K
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 30.12.2020; Public Library of Science (PLoS)
• Subjects: Acetylcysteine; Adenoviruses; Animals; Antioxidants; Auranofin - administration & dosage; Auranofin - pharmacology; Biocompatibility; Biology; Biology and Life Sciences; Bone surgery; Buthionine sulfoximine; Buthionine Sulfoximine - administration & dosage; Buthionine Sulfoximine - pharmacology; Cancer therapies; Carbon; Care and treatment; Cations; Cell Line, Tumor; Cell Survival - drug effects; Cytomegalovirus; Cytotoxicity; Delayed-Action Preparations; Depletion; Derivatives; Development and progression; Disruption; Dosage and administration; Drug delivery systems; Drug resistance; Drug Synergism; Female; Free radicals; Gels (Pharmacy); Glucose; Glutathione; Growth rate; Health aspects; Humans; Hydrogels; Hydrogels - chemistry; Immunotherapy; Lipophilic; Malignancy; Medical schools; Medicine; Medicine and Health Sciences; Melanoma; Melanoma - drug therapy; Melanoma - metabolism; Metabolism; Metastases; Mice; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Molecular chains; Oncology; Organophosphorus compounds; Organophosphorus Compounds - administration & dosage; Organophosphorus Compounds - chemistry; Organophosphorus Compounds - pharmacology; Oxidation resistance; Oxidative metabolism; Oxidative stress; Oxidative Stress - drug effects; Oxygen; Penicillin; Pharmacodynamics; Phosphorylation; Physical Sciences; Physiological aspects; Reactive oxygen species; Reductases; Research and Analysis Methods; Structure-Activity Relationship; Survival; Temperature; Thioredoxin; Toxicity; Tumors; Xenograft Model Antitumor Assays; United States; United States > US; Iowa City Iowa
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0244540

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.