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Dimethylsphingosine and miltefosine induce apoptosis in lung adenocarcinoma A549 cells in a synergistic manner.

Authors
  • Uzunova, Veselina1
  • Tzoneva, Rumiana1
  • Stoyanova, Tihomira1
  • Pankov, Roumen2
  • Skrobanska, Ralica2
  • Georgiev, Georgi2
  • Maslenkova, Liliana1
  • Tsonchev, Zlatan3
  • Momchilova, Albena4
  • 1 Department of Lipid-Protein Interactions, Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Acad. G. Bonchev str. bl 21, 1113, Sofia, Bulgaria. , (Bulgaria)
  • 2 Department of Cytology, Histology and Embryology, Biological Faculty, Sofia University, 8, Dragan Tzankov str, 1164, Sofia, Bulgaria. , (Bulgaria)
  • 3 Department of Neurology, ISUL Hospital Tsaritsa Yoanna, 8 Bialo more str, 1527, Sofia, Bulgaria. , (Bulgaria)
  • 4 Department of Lipid-Protein Interactions, Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Acad. G. Bonchev str. bl 21, 1113, Sofia, Bulgaria. Electronic address: [email protected] , (Bulgaria)
Type
Published Article
Journal
Chemico-biological interactions
Publication Date
Sep 01, 2019
Volume
310
Pages
108731–108731
Identifiers
DOI: 10.1016/j.cbi.2019.108731
PMID: 31265827
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Lung cancer is one of the most common and lethal types of oncological diseases. Despite the advanced therapeutic approaches, the prognosis for lung cancer still remains poor. Apparently, there is an imperative need for more efficient therapeutic strategies. In this work we report that concurrent treatment of human adenocarcinoma A549 cells with specific concentrations of two antitumor agents, the sphingosine kinase 1 inhibitor N, N dimethylsphingosine (DMS) and the alkylphosphocholine miltefosine, induced synergistic cytotoxic effect, which was confirmed by calculation of the combination index. The simultaneous action of these agents, induced significant decrease of A549 cell number, as well as pronounced morphological alterations. Combined drugs caused substantial apoptotic events, and significant reduction of the pro-survival marker sphingosine- 1-phosphate (S1P), when compared to the individual treatments with each of the anticancer drugs alone. Miltefosine is known to affect the synthesis of choline-containing phospholipids, including sphingomyelin, but we report for the first time that it also reduces S1P. Here we suggest a putative mechanism underlying the effect of miltefosine on sphingosine kinase 1, involving miltefosine-induced inhibition of protein kinase C. In conclusion, our findings provide a possibility for treatment of lung cancer cells with lower concentrations of the two antitumor drugs, DMS and miltefosine, which is favorable, regarding their potential cytotoxicity to normal cells. Copyright © 2019 Elsevier B.V. All rights reserved.

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