Dimethylsphingosine and miltefosine induce apoptosis in lung adenocarcinoma A549 cells in a synergistic manner. (1st September 2019)

• Record Type: Journal Article
• Authors: Uzunova, Veselina; Tzoneva, Rumiana; Stoyanova, Tihomira; Pankov, Roumen; Skrobanska, Ralica; Georgiev, Georgi; Maslenkova, Liliana; Tsonchev, Zlatan; Momchilova, Albena
• Is Part Of: Chemico-biological interactions. Volume 310(2019)
• Publication Date: 2019-09-01
• Subjects: Dimethylsphingosine -- Miltefosine -- Lung cancer -- Apoptosis -- Synergy; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2019.108731
• Languages: English
• ISSNs: 0009-2797

Abstract

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. Highlights: Dimethylsphingosine and miltefosine act in synergy to induce apoptosis in A549 lung cancer cells. Miltefosine reduces the pro-survival factor sphingosine-1-phosphate in A549 cells. Combined treatment with miltefosine and dimethylsphingosine is more cytotoxic to cancer cells compared to normal cells. Miltefosine modulates the level of sphingosine-1-phosphate indirectly by inhibition of protein kinase C.