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.

• Authors: Kyle C Kloepping, Alora S Kraus, Devin K Hedlund, Colette M Gnade, Brett A Wagner, Michael L McCormick, Melissa A Fath, Dongrim Seol, Tae-Hong Lim, Garry R Buettner, Prabhat C Goswami, F Christopher Pigge, Douglas R Spitz, Michael K Schultz
• Journal: PloS one (PLoS One) Vol. 15 Issue 12 Pg. e0244540 ( 2020) ISSN: 1932-6203 [Electronic] United States
• PMID: 33378390 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Delayed-Action Preparations
• Hydrogels
• Organophosphorus Compounds
• Auranofin
• Buthionine Sulfoximine

Topics

• Animals
• Auranofin (administration & dosage, pharmacology)
• Buthionine Sulfoximine (administration & dosage, pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Delayed-Action Preparations
• Drug Synergism
• Female
• Humans
• Hydrogels (chemistry)
• Melanoma (drug therapy, metabolism)
• Mice
• Mitochondria (drug effects, metabolism)
• Organophosphorus Compounds (administration & dosage, chemistry, pharmacology)
• Oxidative Stress (drug effects)
• Structure-Activity Relationship
• Temperature
• Xenograft Model Antitumor Assays