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.
Highlights
Previous reports have demonstrated that melanoma cells maintain sustained mitochondrial oxidative phosphorylation in the presence of glycolysis [1,2,3,4,5]
In order to develop an understanding of the effect of changes to TPP-aliphatic side-chain length on melanoma cell viability, MTT cell viability assays were performed in A375 (Fig 2A) and MeWo (Fig 2B) cells treated with TPP derivatives (0.5 μM) for different incubation periods
These results suggest that the decreased melanoma cell viability could be attributed to TPP targeting of melanoma cell mitochondria and subsequent decrease in mitochondrial activity
Summary
Previous reports have demonstrated that melanoma cells maintain sustained (or increased) mitochondrial oxidative phosphorylation in the presence of glycolysis [1,2,3,4,5]. The pharmacodynamics of tumor drug accumulation showed that cancer-selective growth-inhibitory levels of TPP drug accumulation in vivo could be most effectively achieved using a novel, locally administered, thermosensitive-hydrogel delivery system These findings suggest that the disruption of mitochondrial metabolism using hydrogel-delivered TPP derivatives can be selectively cytotoxic to melanoma cells in vivo while minimizing off-target effects in non-malignant cells and highlights the potential for a TPP-hydrogel delivery system for melanoma therapy. This approach has potential in particular in the context of localized treatment of disseminated disease (e.g., brain and lymph node mets) in the adjuvant setting
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