Page 159 - SRPSKO DRUŠTVO ISTRAŽIVAČA RAKA

SDIRSACR Oncology Insights

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Adamantane–sclareol hybrids selectively target multidrug resistant glioblastoma cells by inducing
oxidative stress

Ema Lupšić , Marija Grozdanić , Pavle Stojković , Igor M. Opsenica , Milica Pešić , Ana Podolski-Renić 1
1
1
1
2
2
1Institute for Biological Research “Siniša Stanković” – National Institute of the Republic of Serbia, University of Belgrade, Belgrade,
Serbia
2University of Belgrade – Faculty of Chemistry, Belgrade, Serbia
Keywords: glioblastoma, innovative anticancer agents, multidrug resistance, oxidative stress, P-glycoprotein

Background: Glioblastoma is an aggressive brain malignancy characterized by a limited therapeutic response, primarily
due to multidrug resistance (MDR). One critical contributor to MDR is the activity of P-glycoprotein (P-gp), an efflux
transporter that decreases drug accumulation within cells. Inhibiting P-gp and disrupting redox homeostasis may
present viable strategies to counteract MDR. This study evaluates the in vitro biological activity of two adamantane-
sclareol hybrid compounds (1 and 2) in terms of glioblastoma cell viability, P-gp functionality, and oxidative stress.
Materials and Methods: Our experimental model comprises the human glioblastoma U87 cell line (P-gp-negative), its
drug-resistant counterpart U87-TxR (P-gp-positive), and normal human astroglial SVG p12 cells. Cytotoxicity assays for
compounds 1 and 2, alone or in combination with paclitaxel (PTX), were conducted via the MTT. Flow cytometry was
employed to assess P-gp activity, apoptosis induction, and intracellular reactive oxygen species (ROS) levels. Real-time
PCR was performed to quantify the expression of antioxidant-related genes.
Results: Compounds 1 and 2 exhibited a more pronounced growth inhibition in glioblastoma cells compared to normal
SVG p12 cells. These hybrids bypassed MDR in glioblastoma cells, illustrated by lower IC50 values in MDR U87-TxR cells
relative to sensitive U87 cells. Apoptosis rates were significantly higher in U87-TxR cells when treated with the hybrids
compared to U87 cells. Furthermore, both compounds enhanced the intracellular accumulation of the P-gp substrate,
rhodamine 123, indicating their P-gp inhibitory effects. The combination of PTX with compounds 1 and 2 demonstrated
predominantly synergistic interactions. Notably, both hybrids increased intracellular ROS levels, especially in U87-TxR
cells. This oxidative stress response was also followed by upregulation of antioxidant-related genes in both glioblastoma
lines.
Conclusions: The adamantane-sclareol hybrids exhibit selective cytotoxicity against glioblastoma cells, with a marked
effect on MDR glioblastoma cells, as confirmed by MTT assay. This selective cytotoxicity was also confirmed by enhanced
apoptosis induction and disruption of the redox balance, indicating a phenomenon known as collateral sensitivity.
Additionally, both hybrids inhibited P-gp activity and displayed synergistic interactions with PTX, underscoring their
therapeutic potential in the treatment of glioblastoma.

Acknowledgments and funding: This research was supported by the Science Fund of the Republic of Serbia, grant No.
7005, Development of nature-inspired photoresponsive anticancer agents – sclareol and artemisinin derivatives in
cancer multidrug-resistance models: a foundation of theranostic approach – PhotoSCLART.

P70

The effects of novel diclofenac-based carborane-substituted prodrug on colon cancer cell lines and
mouse-derived organoids

Vuk Gordić , Christoph Selg , Tamara Krajnović , Antonio Buzharevski , Sanja Mijatović , Evamarie Hey-Hawkins ,
2
1
2
1
3
1
Danijela Maksimović-Ivanić 1
1Department of Immunology, Institute for Biological Research “Siniša Stanković” – National Institute of the Republic of Serbia,
University of Belgrade, Belgrade, Serbia
2Department of Chemistry and Mineralogy, Institute of Bioanalytical Chemistry, Leipzig University, Leipzig, Germany
3Department of Chemistry and Mineralogy, Institute of Inorganic Chemistry, Leipzig University, Leipzig, Germany
Keywords: carboranes, colon cancer, diclofenac, drug repurposing, non-steroidal anti-inflammatory drug (NSAID),
organoids

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