Akademik Veri Yönetim Sistemi
AASLD-TASL Hepatology Connect Meeting, İzmir, Türkiye, 16 - 17 Şubat 2024, ss.32-33, (Özet Bildiri)
Background: Hepatocellular carcinoma (HCC), the liver’s primary malignancy and the third leading cause of cancer-related deaths, poses challenges for traditional chemotherapy due to resistance mechanisms. Hyperactivation of cell survival pathways inhibits success. Despite the limited gains from current targeted agents, this study explores the cytotoxic potential of newly identified vicinal diaryl isoxazole and pyrazole derivatives against HCC. Methods: After assessing the cytotoxicity through SRB-assay and RT-CES, oxidative stress, DNA damage, cellular arrest, and cell death were analyzed using flow cytometry. Changes in the transcriptome level were studied using a high-throughput multiplex gene expression analysis. Immunostaining methods evaluated senescence and oxidative stress, while western blot analysis explored cell cycle regulation, senescence, and oxidative stress pathways. In vivo, compound effectiveness in inhibiting tumor growth was tested using a tumor xenograft assay. Results: Over 60 compounds, compounds a1 and b1 displayed considerable cytotoxicity at lower concentrations against cells. In cells treated with compounds, parallel to dose- and time-dependent cell growth inhibition, vital differences were observed in the expression of the cell cycle signaling pathway and related genes in transcriptomic analyses. These compounds induced morphological alterations characteristic of senescence, including the presence of enlarged and multinucleated cells. These effects were linked to a series of biochemical events, including DNA damage associated with oxidative stress, induction of senescence, cell cycle arrest in the G2/M phase, and initiation of apoptosis. Furthermore, changes in the protein levels of G2/M cyclins, such as CDK1, Cyclin-E, and Cyclin-B, were noted post-treatment. Moreover, the administration of compounds a1 and b1 significantly reduced tumor size in nude mice. Conclusions: In conclusion, the research showed the anti-tumor properties of compounds a1 and b1, linked to the initiation of oxidative stress and mechanisms dependent on senescence. Further research is needed to explore the potential of these compounds as agents for combating HCC.
Keywords: senescence, oxidative stress, medicinal chemistry, drug discovery, hepatocellular carcinoma