Digitalni repozitorijum
Univerziteta u Beogradu
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Rescuing hamster fibrosarcoma growth by stimulation of different prooncogenic signaling pathways relative to repurposed anticancer drug mechanisms
Popović, Kosta J.
Poša, Mihalj
Miljković, Dejan
Čapo, Ivan
Popović, Jovan K.
Dolićanin, Zana
Popović, Dušica J.
Lalošević, Dušan
Abstract: Many drugs registered for various non-oncological indications influence tumor metabolic processes, signaling pathways, enzymes, proteins, tumor receptors and genes that regulate proliferation, neoangiogenesis, apoptosis and necroptosis, without affecting these activities in healthy cells. The aim: Detecting underlying anticancer mechanism of metformin in two-drug combinations with other repurposed drugs (2-Deoxy-D-glucose, deoxycholic acid, caffeine, itraconazole or disulfiram) by rescuing BHK-21/C13 hamster fibrosarcoma growth with glucose, vitamin C, nitroglycerin or mebendazole. Methods: The anticancer mechanisms of examined drug combinations, <50% LD50 (equivalent to usual human dose), were determined by rescuing fibrosarcoma growth with addition of aforementioned agents in treatment. Immunohistochemical markers (Ki-67, PCNA, CD34, CD31, GLUT1, iNOS, COX4, Cytochrome C) in control and experimental groups were assessed 19 days after BHK-21/C13 tumor inoculation. Tumors were excised, measured and blood collected. Biophysical, pathohistological, toxicological, hematological, biochemical and statistical analyses were performed. Results: Only addition of NF-kB stimulator mebendazole to effective two-drug combinations containing metformin rescued cancer growth, indicating that this pathway may be responsible for antitumor action. Conclusion: NF-kB signaling pathway downregulation plays an essential role among anticancer mechanisms of investigated metformin combinations in hamster fibrosarcoma treatment.
engleski
2023
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Keywords : fibrosarcoma; hamster; repurposed drugs; anticancer mechanism.