Anti-Melanoma Activities of Artemisone and Prenylated Amino-Artemisinins in Combination With Known Anticancer Drugs

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 prooxidant 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.

Intracellular Accumulation of Novel and Clinically Used TB Drugs Potentiates Intracellular Synergy

“…This study supports the use of the combination of PhX1/WHN296, or indeed more lipophilic artemisinin derivatives ( 29 ), in further studies given the large degree of both in vitro and in vivo accumulation and efficacy in the in vitro intracellular assays. The model, combining two-dimensional synergy, mass spectrometry, and efficacy evaluation, provides a novel approach to understanding synergistic efficacy and accumulation within the infected macrophage.…”

“…In this study, we evaluated the intracellular accumulations and efficacies as well as potential synergizing activities of the phenoxazine derivative PhX1 ( M. tuberculosis MIC 90 0.19 μM [ 28 ]), the prenylated artemisinin derivative WHN296 (MIC 90 18 μM [ 29 ]), the isoniazid-based semicarbazone DPINH (MIC 90 0.36 μM [ 30 ]), and the decoquinate derivative RMB041 (MIC 90 1.61 μM [ 31 ]), as presented in Figure 1 . Clofazimine, which structurally resembles the phenoxazine PhX1, was included as a comparator drug.…”

Transdermal delivery of artemisinins for treatment of pre-clinical cerebral malaria

“…Transdermal drug delivery avoids complications related to parenteral injections (contamination, technical difficulty related to repeated intravenous injections) as well as oral treatment (gastrointestinal side effects, first pass metabolism, coma and vomiting) and compliance ( Shen et al, 2015 ). Topical or transcutaneous treatment by spraying artemisinins in various formulations has been suggested for elevating allergy symptoms, anesthetic purposes, wounds healing, and skin cancer ( Härtel et al, 2018 ; Li et al, 2012 ; Nnamani et al, 2014 ; Wong et al, 2020 ). Other transdermal methods of applying artemisinins (and other drugs) were suggested to treat malaria, mostly with limited success (see Introduction).…”

“…Similar results were found using ART encapsulated in solid lipid nanoparticles that also reached the stratum corneum of human skin ( Dwivedi et al, 2016 ). These last two methods might be more useful for the treatment of skin lesions or melanoma/skin cancer ( Wong et al, 2020 ). Other surfactant-based nanodispersions were unable to deliver ART into the skin ( van Zyl et al, 2019 ).…”

Synthesis and biological evaluation of novel artemisone–piperazine–tetronamide hybrids

“…The combination of artemisinin-type drugs with anticancer drugs can enhance the activity of the anticancer drugs in vitro or in vivo. 9,10,17,18 Given the therapeutic properties of tetronamides and the lack of artemisone-piperazine-tetronamide hybrids reported in the literature, we designed and synthesised a series of hybrid tetronamide derivatives possessing an artemisone-piperazine moiety (12a-f, Scheme 4) to evaluate their in vitro cytotoxicity and compare with VCR and ARA. Then we also research the effects of iron ions (Fe 2+ ) on cytotoxic activity.…”