Page 102 - SRPSKO DRUŠTVO ISTRAŽIVAČA RAKA

Serbian Association for Cancer Research SDIRSACR

reference gene. Statistical processing of the results was done by one-factor analysis of variance (ANOVA) with Taki's
post-hoc test.
Results: Celecoxib and silibinin exhibit a concentration-dependent increase in cytotoxicity i.e. inhibition of viability
and proliferation of A549 cells. Compared to the untreated, control group, celecoxib decreased the expression of the
gene responsible for the synthesis of the COX-2 isoenzyme (PTGS2) and the expression of the antiapoptotic BCL2 gene
(p<0.01), and increased the expression of the tumor suppressor gene TP53 and the proapoptotic BAX gene, without
statistical significance. The addition of silibinin to celecoxib showed a synergistic effect in further increasing the mRNA
levels of TP53 and BAX genes (p<0.01).
Conclusions: COX-2 is an important factor in the survival and proliferation of malignant cells. Celecoxib and silibinin
show antiproliferative and proapoptotic effects on lung cancer cells. The addition of silibinin to celecoxib offers the
potential to use lower doses of celecoxib to exert its antineoplastic effects, thereby reducing the side effects of this
selective COX-2 inhibitor.

P04

Investigation of the effect of exportin-1 gene inhibition with selinexor on glioma

Beyza Öztürk Sever , Asuman Çelebi , Timuçin Avşar 2
1
2
1 Neuroscience PhD Program, Faculty of Medicine, Bahçeşehir University, Istanbul, Turkey
2 Department of Medical Biology, Faculty of Medicine, Bahçeşehir University, Istanbul, Turkey

Keywords: drug resistance, exportin 1, glioma, temozolomide

Background: Glioblastoma (GBM) is the most common malignant brain tumor, typically treated with
surgery followed by temozolomide (TMZ) chemotherapy and radiotherapy. However, recurrence and
therapy resistance are common, highlighting the need for new treatment strategies. Exportin 1 (XPO1), a
nuclear export protein, translocates tumor suppressors, regulatory proteins, and RNA from the nucleus
to the cytoplasm. Dysregulated nuclear export contributes to tumor progression and chemoresistance.
Understanding the role of XPO1 in GBM and exploring its inhibition could offer new therapeutic opportunities.
Materials and Methods: TMZ-resistant GBM cell line LN18, standard GBM cell line U87MG, and TMZ-sensitive LN229
cell line were used as in vitro models. The selective XPO1 inhibitor Selinexor was administered alone and in combination
with TMZ. The effects on cell viability were assessed, along with mechanistic evaluations including apoptosis, cell
cycle distribution, colony formation capacity, and expression levels of genes involved in DNA repair and resistance.
Results: The combination of Selinexor and TMZ was effective in reducing cell viability across all cell lines,
with the most dramatic effect observed in the TMZ-resistant LN18 cells. Mechanistic analysis showed that
cell death in resistant cells occurred primarily through apoptosis, while TMZ-sensitive and non-resistant
lines (U87MG and LN229) exhibited G1/G0 and S cell cycle arrest. Colony formation assays revealed that
combination treatment significantly reduced the number of colonies, indicating impaired long-term proliferative
capacity. Furthermore, in TMZ resistant cells, the combination treatment downregulated genes involved in
DNA damage response (DDR), mismatch repair (MMR), and other resistance-related pathways. This suggests
that XPO1 inhibition may enhance TMZ efficacy in resistant cells by suppressing key resistance mechanisms.
Conclusions: Targeting XPO1 with Selinexor may potentiate the effect of TMZ, particularly in drug-resistant GBM
models. These findings support the combination’s potential to overcome resistance and reduce tumor recurrence,
warranting further investigation in preclinical and clinical studies.

Acknowledgments and funding: We thank our laboratory team and supervisor for their valuable contributions to this
study.

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