Anticancer activity of novel vicinal diaryl isoxazole compounds in hepatocellular carcinoma

Date

2022-02-04

Author

Sinoplu, Esra
Akhan Güzelcan, Ece
Turanlı, Sümeyye
Lengerli, Deniz
Çalışkan, Burcu
Banoğlu, Erden
Atalay, Rengül

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Background and Aims Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and 2nd lethal cancer in the world. The global burden of HCC is expected to increase in the next decade due to the increase in obesity and related fatty liver disease cases in the world. Because of hyperactivation of many critical cell survival signaling pathways, HCC is highly resistant for conventional chemotherapies and targeted agents extend the patient’s survival for only six months. It is crucial to design and develop novel therapeutics against HCC. Here, we investigated the possible cytotoxic bioactivities of novel vicinal diaryl isoxazole compound on HCC. Method: Bioactivities of compounds were identified with NCI-SRB assay and RT-CES analysis. PI staining was performed for cell cycle using flow cytometry. Apoptotic cells were detected through both fluorescence microscopy and by flow cytometry. Changes in transcriptome level was controlled by multiplexed analysis of PanCancer panel for 770 cancer genes. Western blot analysis was done to assess the protein level of cell cycle and apoptosis related signaling pathways. In vivo tumour xenograft assay was performed to test the anti-cancer activity of the potent compounds. Results: Among all 48 compounds tested two of them (1a and 1b) showed very promising cytotoxic activities and were selected to be further biological testing against HCC cell lines. Both 1a and 1b compounds were identified as significant anti-cancer agents upon liver cancer cells with lower cytotoxic doses (<3 mikro molar). Time-and dose-dependent growth inhibition upon treatment with 1a and 1b was observed due to cell cycle arrest in S and G2/M phases and apoptosis.The cell cycle pathway and related genes were the most differentiated pathway and genes by analysis of cancer panel. The expressions of S and G2/M cyclins were also changed in protein level with treatment. Furthermore, upon treatment with both 1a and 1b, the tumour size decreased in nude mice significantly. Conclusion: Altogether, the anti-tumour effects of the compound 1a and 1b approve that these small molecules can be considered as eventual anti-cancer agents for liver cancer. This study was supported by a Research Grant from TUBİTAK (#215S015).

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https://easl.eu/wp-content/uploads/2022/02/LCS-2022-Abstract-book-final.pdf
https://hdl.handle.net/11511/106430

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