Evading multidrug resistance in glioblastoma with natural compound sclareol and its novel derivatives
2023
Autori:
Lupšić, EmaStepanović, Ana
Stojković, Pavle
Terzić-Jpvanović, Nataša
Novaković, Miroslav
Nedialkov, Paraskev
Trendafilova, Antoaneta
Opsenica, Igor M.
Pešić, Milica
Ostala autorstva
Selma, KanazirSavić, Danijela
Tip dokumenta:
Konferencijski prilog (Objavljena verzija)
,
© 2023 by Serbian Neuroscience Society and associates.
Metapodaci
Prikaz svih podataka o dokumentuApstrakt:
Background: Glioblastoma is a highly aggressive and resistant brain tumor. P-glycoprotein
(P-gp) constitutes the blood-brain barrier and is expressed on the cell membrane of multidrugresistant (MDR) glioblastoma cells. Our objective was to investigate the anti-glioblastoma
effects of sclareol (SCL), a natural diterpene alcohol, and its two derivatives (11c and 12l).
Methods: Our cellular model included human glioblastoma U87 cell line without P-gp
expression, its MDR counterpart U87-TxR with P-gp expression, and normal lung fibroblasts
MRC-5. Cytotoxic effects were examined by MTT. P-gp function, cell cycle disturbance,
time-dependent cell death induction, the level of reactive oxygen and nitrogen species, and
changes in the mitochondrial membrane potential were studied by flow cytometry. Results:
SCL and its derivatives evaded the MDR in glioblastoma cells, showing lower IC50 values in
U87-TxR than in U87, referred to as collateral sensitivity. Both derivatives were more potent
than SCL, while 12l was active in the nanomolar range. 11c and 12l displayed greater
selectivity towards glioblastoma cells compared to SCL. All compounds significantly
disturbed the cell cycle and induced cell death: SCL - late apoptosis and necrosis, 11c - only
early apoptosis, and 12l - early and late apoptosis. SCL and its derivatives acted as
antioxidants, while 11c and 12l decreased mitochondrial membrane potential. Conclusion:
SCL derivatives were more potent than SCL. The observed collateral sensitivity in
glioblastoma cells can be explained by oxidative stress modulation because although resistant
due to P-gp expression, U87-TxR cells are more susceptible to changes in oxidative status
than U87 cells.
Ključne reči:
MDR; Glioblastoma; SclareolFinansiranje / projekti:
- 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:
- Kanazir S, Savić D, editors. Book of abstracts: 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia. Belgrade: Serbian Neuroscience Society; 2023. p. 72.