Abstract
The most frequently occurring cancers are those of the skin, with melanoma being the leading cause of death due to skin cancer. Breakthroughs in chemotherapy have been achieved in certain cases, though only marginal advances have been made in treatment of metastatic melanoma. Strategies aimed at inducing redox dysregulation by use of reactive oxygen species (ROS) inducers present a promising approach to cancer chemotherapy. Here we use a rational combination of an oxidant drug combined with a redox or pro-oxidant drug to optimize the cytotoxic effect. Thus we demonstrate for the first time enhanced activity of the amino-artemisinin artemisone and novel prenylated piperazine derivatives derived from dihydroartemisinin as the oxidant component, and elesclomol-Cu(II) as the redox component, against human malignant melanoma cells A375 in vitro. The combinations caused a dose dependent decrease in cell numbers and increase in apoptosis. The results indicate that oxidant-redox drug combinations have considerable potential and warrant further investigation.
Highlights
The body organ in which neoplasms occur most frequently is the skin, with over one million skin cancer cases recorded annually (Simões et al, 2015)
The quantitative colorimetric MTT assay was used to determine in vitro cell viability with A375 and HaCat cells. These were exposed to the artemisinin derivatives and combinations of these compounds with each of elesclomol-Cu(II) 1-Cu, sulfasalazine 8 and etoposide 9 for 24 h
Of special note is the combination of geranylpiperazine-DHA 6 with elesclomol-Cu(II) 1-Cu that led to a >255 fold increase in toxicity toward melanoma cells based on the IC50 values
Summary
The body organ in which neoplasms occur most frequently is the skin, with over one million skin cancer cases recorded annually (Simões et al, 2015). Skin cancers are classified into two main groups based on the cell of origin and clinical behavior, firstly nonmelanoma skin cancers (NMSC) mainly originating in the keratinocytes, and secondly cutaneous malignant melanoma skin cancers, originating in the melanocytes (Simões et al, 2015; Gálvez et al, 2018; Que et al, 2018). Malignant melanoma is the most severe form of skin cancer, and are notably intractable to current treatment modalities; the average survival rate is 6–10 months after diagnosis. Metastatic melanoma cells tend to disseminate to multiple organs including brain, bone, liver and lungs, rendering treatment strategies decidedly more challenging than in the case of NMSCs that often remain at the site of origin (Gálvez et al, 2018; Keung and Gershenwald, 2018). Surgery remains the standard treatment for melanoma where the bulk of the
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