Antitumor effect of copper(II) complexes with nitrogen-oxygen donor ligands on glioblastoma multiforme cells in vitro

[S. A. Babić]

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Multiformni glioblastom predstavlja najčešći i najagresivniji primarni tumor centralnog nervnog sistema sa prosečnim preživljavanjem od momenta postavljanja dijagnoze 15 meseci. Standarna terapija multiformnog glioblastoma podrazumeva hirušku intervenciju, radioterapiju i hemioterapiju. Od citostatika koristi se temozolomid, neželjena dejstva ovog leka su posledica neselektivnosti, pa se može javiti supresija koštane srži, kardiotoksičnost, hepatotoksičnost, nefortoksičnost. Iz prethodno navedenih činjeica, možemo zaključiti da bi razvitak potencijalnih citostatika mogao da pomogne u efikasnijoj terapiji multiformnog glioblastoma. Cilj ovog istraživanja jeste ispitivanje antitumorskog dejstva novosintetisanih bakar(II) jedinjenja na tumorske ćelijske linije U251, HeLa i HCT116, kao i na maligo neizmenjene fibroblaste MRC-5. Sintetisana jedinjenja bakra Su1 i Cu2 su demonstrirala signifikantan antikancerski efekat na testiranim HCT116, HeLa, U251 ćelijama uz veliki stepen selektivnosti prema maligno neizmenjenim ćelijama fibroblastima. Snažan citotokični efekat dva jedinjenja bakra na ćelije multifomrnog glioblastoma je postignut indukcijom rane apoptoze, promenom odnosa Bcl2/Bax molekula. Primenjeni bakarni kompleksi dovodili su do narušavanja normalnog protoka ćelijskog ciklusa u kancerskim U251 ćelijama, što je rezultiralo značajnim smanjenjem stope njihovog preživljavanja.

Glioblastoma multiforme represents the most common and aggressive primary tumor of the central nervous system, with an average survival of 15 months from the time of diagnosis. Standard therapy for glioblastoma multiforme includes surgical intervention, radiotherapy, and chemotherapy. Among cytostatics, temozolomide is commonly used; however, the adverse effects of this drug result from its non-selectivity, which may lead to bone marrow suppression, cardiotoxicity, hepatotoxicity, and nephrotoxicity. Based on these facts, it can be concluded that the development of potential cytostatics could contribute to more effective therapy for glioblastoma multiforme. The aim of this study was to investigate the antitumor activity of newly synthesized copper(II) compounds on tumor cell lines U251, HeLa, and HCT116, as well as on nonmalignant fibroblasts MRC-5. The synthesized copper compounds Cu1 and Cu2 demonstrated a significant anticancer effect on the tested HCT116, HeLa, and U251 cells, with a high degree of selectivity toward non-malignant fibroblast cells. The strong cytotoxic effect of the two copper compounds on glioblastoma multiforme cells was achieved through the induction of early apoptosis and alteration of the Bcl2/Bax molecular ratio. The applied copper complexes also led to disruption of normal cell cycle progression in cancerous U251 cells, resulting in a significant reduction in their survival rate.

multiformni glioblastom, apoptotska ćelijska smrt, ćelijska deoba, kancerogeneza, proteini apoptoze, jedinjenja bakra

glioblastoma multiforme, apoptotic cell death, cell division, carcinogenesis, apoptosis-related proteins, copper compounds

616.831-006:546.562(043.3)

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