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Journal of Cancer Research and Clinical Oncology

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Open Access 01-01-2019 | Original Article – Cancer Research

Novel therapeutic compound acridine–retrotuftsin action on biological forms of melanoma and neuroblastoma

Authors: Miroslawa Cichorek, Anna Ronowska, Monika Gensicka-Kowalewska, Milena Deptula, Iwona Pelikant-Malecka, Krystyna Dzierzbicka

Published in: Journal of Cancer Research and Clinical Oncology | Issue 1/2019

Abstract

Purpose

As 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.

Methods

The 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.

Results

ART 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.

Conclusion

Our 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.

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Title: Novel therapeutic compound acridine–retrotuftsin action on biological forms of melanoma and neuroblastoma
Authors: Miroslawa Cichorek
Anna Ronowska
Monika Gensicka-Kowalewska
Milena Deptula
Iwona Pelikant-Malecka
Krystyna Dzierzbicka
Publication date: 01-01-2019
Publisher: Springer Berlin Heidelberg
Published in: Journal of Cancer Research and Clinical Oncology / Issue 1/2019
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-018-2776-4

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