In vitro биолошка евалуација аналога di-tert-бутилфенола на бази p-карборана
In vitro biological evaluation of p-carborane-based di-tert-butylphenol analogs
2023
Authors:
Jelača, SanjaBraun, Sebastian
Mijatović, Sanja
Hey-Hawkins, Evamarie
Maksimović-Ivanić, Danijela
Contributors
Arsenijević, NebojšaDocument Type:
Conference object (Published version)
,
© 2023 by the Serbian Society for Immunology, Molecular Oncology and Regenerative Medicine, Kragujevac, Serbia
Metadata
Show full item recordAbstract:
Targeting inflammatory mediators, such as cyclooxygenase-2 (COX) and 5-lipoxygenase
(5-LO), may be a promising strategy for the treatment of cancer. To improve the selectivity,
a carborane moiety was incorporated into known dual COX-2/5-LO inhibitors. In the
present study, we have evaluated the antitumor activity of di-tert-butylphenol derivatives
(R-830, KME-4, E-5110, and S-2474) and their respective p-carborane analogs (R-830-Cb,
KME-4-Cb, E-5110-Cb, and S-2474-Cb) on a panel of human cancer cell lines (A375, A549,
HCT116, HT-29, and MDA-MB-231). Treatment with di-tert-butylphenol derivatives decreased
the viability of all cancer cells in a dose-dependent manner after 72 h. At the same
time, incorporation of a p-carborane moiety resulted in diminished cytotoxic potential for
all tested carborane analogs, except R-830-Cb. Thus, for further investigation of the potential
mechanism of action, R-830 and its p-carborane analog R-830-Cb were selected. Differently
to R-830, its carborane counterpart did not affect the viability of primary peritoneal exudate
cells, indicating that incorporation of the carborane cage improved selectivity toward
the malignant phenotype. Tumor cell viability decrease triggered by R-830-Cb was followed
by a loss of dividing potential, while a certain percentage of HCT116 cells was subjected
to caspase-dependent programmed cell death. In parallel, fluorescent microscopy revealed
the presence of numerous cells with abnormally shaped nuclei and condensed chromatin.
Furthermore, abolishment of the autophagy using autophagy inhibitors 3-methyladenine
(3-MA) and chloroquine, revealed a cytoprotective role of this process, compromising the
activity of the drug. All observed effects were accompanied by reduced production of reactive
oxygen and nitrogen species (ROS/RNS) indicating a disturbed redox status of the cells
in response to the treatment. Taken together, carborane-based analog R-830-Cb is a promising
candidate for further assessment of the antitumor effect in vivo.
Keywords:
carboranes; cyclooxygenase-2; 5-lipoxygenase; cancer; apoptosisFunding / projects:
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200007 (University of Belgrade, Institute for Biological Research 'Siniša Stanković') (RS-MESTD-inst-2020-200007)
In:
- Arsenijević N, editor. Abstract Book: The second Serbian Molecular Medicine Congress; 2023 Oct 6-8; Foča, Bosnia and Herzegovina. Kragujevac: Serbian Society for Immunology, Molecular Oncology and Regenerative Medicine; 2023. p. 79-80.