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

PLoS One. 2020 Dec 30;15(12):e0244540. doi: 10.1371/journal.pone.0244540. eCollection 2020.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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