Growth inhibition and toxicity assessments of cis-3,4-diaryl-α-methylene-γ-butyrolactams in cultured human renal cancer cells and zebrafish embryos

• Published in: Biochimica et biophysica acta. General subjects Vol. 1869; no. 3; p. 130761
• Main Authors: Lee, Adam Shih-Yuan, Lin, Ta-Hsien, Liu, Yen-Yu, Wang, Yun-Hsin, Cheng, Shu-Chun, Li, Tao-Sheng, Sun, Chiao-Yin, Chen, Yau-Hung
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2025
• Subjects: Animals; Animals, Genetically Modified; Antineoplastic Agents - pharmacology; Butyrolactams; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; cell death; Cell Line, Tumor; cell lines; Cell Proliferation - drug effects; Danio rerio; Embryo, Nonmammalian - drug effects; flow cytometry; fluorescence; genetically modified organisms; growth retardation; HEK293 Cells; Humans; kidney neoplasms; Kidney Neoplasms - drug therapy; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; kidneys; neoplasm cells; Renal cell carcinoma; TOR Serine-Threonine Kinases - metabolism; toxicity; Tumor Suppressor Protein p53 - metabolism; Western blotting; Zebrafish; Zebrafish - embryology; Renal cell carcinoma; Zebrafish; Butyrolactams
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2025.130761

This study aimed to compare and evaluate the growth inhibition effects of eight previously synthesized compounds, cis-3,4-diaryl-α-methylene-γ-butyrolactams (compounds 1–8), on two human renal carcinoma cell (RCC) lines: CRL-1932 (rapid growth) and HTB-44 (slow growth). MTT assays and flow cytometry were conducted, revealing that compounds 5 and 6 had the potential to induce cell death in the slow-growing RCC cells (HTB-44), while compound 8 demonstrated effectiveness in both RCC lines (HTB-44 and CRL-1932). Additionally, a non-transformed HEK293 cell line and a transgenic zebrafish with a green fluorescent kidney Tg(wt1b:egfp) were used to assess the toxicities of compounds 5, 6, and 8. The findings suggested that compound 8 was relatively non-toxic compared to the others. Western blot analysis indicated that compounds 5, 6, and 8 may interact with the P53/mTOR pathways. Based on these results, we concluded that compound 8 exhibits RCC growth inhibition properties and has lower toxicity, making it a candidate for further investigation in mammalian models. •cis-3,4-diaryl-α-methylene-γ-butyrolactams (compounds 5, 6, and 8) can cause the cell death of HTB-44.•Compound 8 is efficient in inhibiting cell growth of HTB-44 and CRL-1932 (fast growth).•Growth inhibition activity of compounds 5, 6, and 8 might be through the regulation of P53/mTOR pathways.