Novel bexarotene derivatives: Synthesis and cytotoxicity evaluation for glioma cells in 2D and 3D in vitro models.

Autor: Gretskaya NM; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Str. 16/10, 117997, Moscow, Russia., Gamisonia AM; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Str. 16/10, 117997, Moscow, Russia; National Medical Research Center of Obstetrics, Gynaecology and Perinatology Named After Academician V.I. Kulakov, academician Oparina str. 4, 117997, Moscow, Russia., Dudina PV; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Str. 16/10, 117997, Moscow, Russia., Zakharov SS; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Str. 16/10, 117997, Moscow, Russia., Sherstyanykh G; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Str. 16/10, 117997, Moscow, Russia., Akasov R; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Str. 16/10, 117997, Moscow, Russia; Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Trubetskaya Str. 8-2, 119991, Moscow, Russia; Federal Scientific Research Center, Crystallography and Photonic, Russian Academy of Sciences, Leninsky Prosp., 59, 119333, Moscow, Russia., Burov S; J.S.Co. Cytomed, 199004, Saint-Petersburg, Russia., Serkov IV; Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432, Chernogolovka, Severniy Pr., 1, Russia., Akimov MG; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Str. 16/10, 117997, Moscow, Russia. Electronic address: akimovmike@gmail.com., Bezuglov VV; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Str. 16/10, 117997, Moscow, Russia., Markvicheva E; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Str. 16/10, 117997, Moscow, Russia.
Jazyk: angličtina
Zdroj: European journal of pharmacology [Eur J Pharmacol] 2020 Sep 15; Vol. 883, pp. 173346. Date of Electronic Publication: 2020 Jul 11.
DOI: 10.1016/j.ejphar.2020.173346
Abstrakt: Glioblastoma (GBM) is an aggressive and lethal form of brain cancer with a high invasion capacity and a lack of effective chemotherapeutics. Retinoid bexarotene (BXR) inhibits the neurospheroidal colony formation and migration of primary glioblastoma cells but has side effects. To enhance the BXR glioblastoma selectivity and cytotoxicity, we chemically modified it at the carboxyl group with either nitroethanolamine (NEA) bearing a NO-donating group (a well-known bioactivity enhancer; BXR-NEA) or with a dopamine (DA) moiety (to represent the highly toxic for various tumor cells N-acyldopamine family; BXR-DA). These two novel compounds were tested in the 2D (monolayer culture) and 3D (multicellular tumor spheroids) in vitro models. Both BXR-DA and BXR-NEA were found to be more toxic for rat C6 and human U-87MG glioma cells than the initial BXR. After 24 h incubation of the cells (monolayer culture) with the drugs, the IC 50 values were in the range of 28-42, and 122-152 μM for BXR derivatives and BXR, respectively. The cell death occurred via apoptosis according to the annexin staining and caspase activation. The tumor spheroids demonstrated higher resistance to the treatment compared to that one of the monolayer cultures. BXR-DA and BXR-NEA were more specific against tumor cells than the parental drug, in particular the selectivity index was 1.8-2.7 vs. 1.3-1.5, respectively. Moreover, they inhibited cell migration more effectively than parental BXR according to a scratch assay. Cell spreading from the tumor spheroids was also inhibited. Thus, the obtained BXR derivatives could be promising for glioblastoma treatment.
(Copyright © 2020 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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