Hybrids of sclareol and 1,2,4-triazolo[1,5-a]pyrimidine inhibit P-glycoprotein function in glioblastoma cells
2022
Autori:
Stepanović, AnaStojković, Pavle
Terzić Jovanović, Nataša
Novaković, Miroslav
Opsenica, Igor M.
Pešić, Milica
Tip dokumenta:
Konferencijski prilog (Objavljena verzija)
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© 2022 by the STRATAGEM COST Action
Metapodaci
Prikaz svih podataka o dokumentuApstrakt:
Background: Natural products exhibit a wide range of biological activities and they are starting point in the drug discovery process. Sclareol (SCL) naturally occurring labdane diterpene isolated from Clary sage (Salvia sclarea L.) shows diverse biological properties such as antioxidative, antimicrobial, anti-inflammatory, and anticancer activities. It is well established that fusing two pharmacophores can lead to significant improvement in the biological potential of the molecule by modifying its physicochemical properties. We envisioned that chimeric molecules synthesized by linking triazolo[1,5-a]pyrimidine pharmacophore to SCL would have more potent anticancer activity than their parental compound – SCL. Therefore, the cytotoxic potential of a series of SCL derivatives was compared with SCL. We have also studied their potential to increase the accumulation of substrates of membrane transporter which causes resistance of cancer cells – P-glycoprotein (P-gp). Methods: Cytotoxic potential, selectivity towards cancer cells, and resistance profile of SCL and its derivatives were examined by MTT assay after 72 h exposure in human glioblastoma cells (sensitive U87 and multidrug-resistant U87-TxR) and rat microglial cells (BV-2). We also investigated the effect of SCL and its derivatives on P-gp activity in U87-TxR resistant cells by determining the level of accumulated P-gp substrates (rhodamine 123 and doxorubicin) by flow cytometry. Results: More than half of the tested SCL derivatives considerably reduced glioblastoma cell viability with a concentration of 5 μM. Tested compounds evaded the resistance of glioblastoma cells showing similar or better activity against U87-TxR cells in comparison with U87 cells. All compounds significantly increased the accumulation of rhodamine 123 pointing to the inhibition of P-gp. However, only three of them increased the accumulation of doxorubicin likewise tariquidar, a well-known third-generation P-gp inhibitor, implying that these three SCL derivatives can be valuable as chemo-sensitizing agents. Conclusion: Our results showed that SCL derivatives can be considered as modulators of P-gp activity especially pointing to several lead compounds whose detailed molecular mechanism of anticancer action should be studied.
Finansiranje / projekti:
- Ministarstvo nauke, tehnološkog razvoja i inovacija Republike Srbije, institucionalno finansiranje - 200168 (Univerzitet u Beogradu, Hemijski fakultet) (RS-MESTD-inst-2020-200168)
- Ministarstvo nauke, tehnološkog razvoja i inovacija Republike Srbije, institucionalno finansiranje - 200026 (Univerzitet u Beogradu, Institut za hemiju, tehnologiju i metalurgiju - IHTM) (RS-MESTD-inst-2020-200026)
- Ministarstvo nauke, tehnološkog razvoja i inovacija Republike Srbije, institucionalno finansiranje - 200007 (Univerzitet u Beogradu, Institut za biološka istraživanja 'Siniša Stanković') (RS-MESTD-inst-2020-200007)
U:
- Abstract Book: STRATAGEM’s 5th Annual Meeting: New Diagnostic and Therapeutic Tools against Multidrug Resistant Tumours; 2022 Jun 29 - Jul 1; Coimbra, Portugal. STRATAGEM COST Action; 2022. p. 81.