Page 166 - SRPSKO DRUŠTVO ISTRAŽIVAČA RAKA

Serbian Association for Cancer Research SDIRSACR

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Two novel pyrimidine-artesunate hybrids overcome multidrug-resistance in non-small cell lung
carcinoma through collateral sensitivity

Milica Pajović1, Ana Podolski-Renić1, Ema Lupšić1, Ljiljana Koračak2, Vladimir Ajdačić2, Milica Selaković2, Miroslav
Novakovic3, Igor M. Opsenica4, Milica Pešić1

1Institute for Biological Research “Siniša Stanković” – National Institute of the Republic of Serbia, University of Belgrade, Bulevar
despota Stefana 142, 11108 Belgrade, Republic of Serbia
2Innovative Centre, Faculty of Chemistry, Ltd., Studentski trg 12 – 16, 11158 Belgrade, Republic of Serbia
3Institute of Chemistry, Technology and Metallurgy, National Institute of the Republic of Serbia, University of Belgrade, Njegoševa
12, 11000 Belgrade, Republic of Serbia
4Faculty of Chemistry, University of Belgrade, Studentski trg 12 – 16, 11158 Belgrade, Republic of Serbia

Keywords: artesunate, collateral sensitivity, multidrug-resistance, non-small cell lung carcinoma, P-glycoprotein,
pyrimidine

Background: Two novel hybrid compounds (1 and 2) based on artemisinin and pyrimidine were tested for their
anticancer activity against non-small cell lung carcinoma (NSCLC), specifically targeting multidrug-resistance mediated
by P-glycoprotein (P-gp).
Materials and Methods: We used the human NSCLC cell line NCI-H460 (without P-gp expression), its multidrug-
resistant counterpart NCI-H460/R (with P-gp expression), and the normal human lung fibroblast cell line MRC-5. Cell
viability after treatment with 1 and 2, alone or in combination with the P-gp inhibitors dexverapamil (Dex-Ver) and
tariquidar (TQ), was assessed using the MTT assay. Accumulation of the rhodamine 123 (Rho 123), a P-gp substrate,
was analyzed by flow cytometry.
Results: Compounds 1 and 2 exhibited enhanced cytotoxicity towards resistant NCI-H460/R cells, indicating collateral
sensitivity. Both compounds also showed significant selectivity for cancer cells. Flow cytometry analysis revealed
that 1 and 2 effectively inhibited P-gp activity, as evidenced by the increased accumulation of Rho 123. Simultaneous
treatment of 1 and 2 with P-gp inhibitors indicated that the type of P-gp inhibition matters. The substrate inhibitor Dex-
Ver lowered cytotoxicity of 1 and 2, while the non-substrate inhibitor TQ, increased it. Flow cytometry also showed that
co-treatment with Dex-Ver further increased Rho 123 levels, indicating additive inhibition. However, when combined
with TQ, Rho 123 accumulation was comparable to that of TQ alone, suggesting that P-gp was already maximally
inhibited and the compounds made no further contribution.
Conclusions: The study demonstrates that pyrimidine-artesunate hybrids selectively target MDR cancer cells,
emphasising their potential to overcome drug resistance in cancer treatment.

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.

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Investigating the In Vitro Cytotoxicity of Novel Pyrido-dipyrimidine Compounds

Nađa Grozdanić1, Maja Petrović1, Milica Marković2, Tatjana Stanojković2, Lazar Milović3, Nenad Janković3

1Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia
2University of Belgrade – Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia
3University of Kragujevac, Institute for Information Technologies, Jovana Cvijića bb, 34000 Kragujevac, Serbia

Keywords: Apoptosis, Caspases, Cytotoxicity

Background: Pyrido-dipyrimidine compounds have gained substantial attention in medicinal chemistry due to their
potential as anticancer agents. These compounds are known to inhibit essential pathways involved in tumor growth
and proliferation, positioning them as promising therapeutic candidates. The present study investigates the in vitro

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