Abstract
PurposeAs a continuation of our search for anticancer agents, we have synthesized a new acridine-retrotuftsin analog HClx9-[Arg(NO2)-Pro-Lys-Thr-OCH3]-1-nitroacridine (named ART) and have evaluated its activity against melanoma and neuroblastoma lines. Both tumors develop from cells (melanocytes, neurons) of neuroectodermal origin, and both are tumors with high heterogeneity and unsatisfactory susceptibility to chemotherapies. Thus, we analyzed the action of ART on pairs of biological forms of melanoma (amelanotic and melanotic) and neuroblastoma (dopaminergic and cholinergic) with regard to proliferation, mechanism of cell death, and effect on the activity of tricarboxylic acid cycle (TAC) enzymes.MethodsThe cytotoxicity of ART was evaluated by XTT and trypan blue tests. Cell death was estimated by plasma membrane structure changes (phosphatidylserine and calreticulin externalization), caspase activation, presence of ROS (reactive oxygen species), activity of tricarboxylic acid cycle enzymes (pyruvate dehydrogenase complex, aconitase, and isocitrate dehydrogenase), NAD level, and ATP level.ResultsART influences the biological forms of melanoma and neuroblastoma in different ways. Amelanotic (Ab) melanoma (with the inhibited melanogenesis, higher malignancy) and SHSY5Y neuroblastoma (with cholinergic DC cells) were especially sensitive to ART action. The Ab melanoma cells died through apoptosis, while, with SH-SY5Y-DC neuroblastoma, the number of cells decreased but not as a result of apoptosis. With Ab melanoma and SH-SY5Y-DC cells, a diminished activity of TAC enzymes was noticed, along with ATP/NAD depletion.ConclusionOur data show that the biological forms of certain tumors responded in different ways to the action of ART. As a combination of retrotuftsin and acridine, the compound can be an inducer of apoptotic cell death of melanoma, especially the amelanotic form. Although the mechanism of the interrelationships between energy metabolism and cell death is not fully understood, interference of ART with TAC enzymes could encourage the further investigation of its anticancer action.
Highlights
The acridine family includes a wide range of tricyclic molecules with various biological activities, such as anticancer, antiinflammatory, antimicrobial, antiparasitic, antiviral, and fungicidal activities (Gensicka-Kowalewska et al 2017; Kukowska 2017)
ART was cytotoxic against melanoma and neuroblastoma cells in a dose-dependent manner, but different biological forms of both tumors responded in different ways when the dose increased over 20 μM (Fig. 2a)
The more sensitive type was amelanotic Ab melanoma, which after just 48 h incubation with 50 μM of ART had over 30% of cells with inhibited mitochondrial activity (Fig. 2a) and 60% stained with trypan blue dye (TB+; Fig. 3a)
Summary
The acridine family includes a wide range of tricyclic molecules with various biological activities, such as anticancer, antiinflammatory, antimicrobial, antiparasitic, antiviral, and fungicidal activities (Gensicka-Kowalewska et al 2017; Kukowska 2017). Acridines influence many biological processes, e.g., proliferation, pH homeostasis, and secretion of neurotransmitters These compounds intercalate between base pairs in the double-stranded DNA structure (Kitchen et al 1985; Pommier et al 1987), influence activity of the topoisomerases that control the chromatin structure (Ferguson and Denny 1991) and affect the activity of telomerases and cyclin-dependent kinases One way of constructing new derivatives is by binding acridine compounds with other biologically active elements, e.g., muramyl dipeptide (MDP), tuftsin, peptide nucleic acids (PNA), or antiinflammatory drugs such as ibuprofen, (S)-naproxen, acetylsalicylic acid (Gensicka-Kowalewska et al 2017; Kukowska 2017), and mycophenolic acid (MPA) (Cholewinski et al 2016)
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