A quinoxaline-based derivative exhibited potent and selective anticancer activity with apoptosis induction in PC-3 cells through Topo II inhibition.

Quinoxaline constitutes a variety of derivatives that exhibit a range of biological characteristics, including anti-inflammatory and antitumor effects, and their importance in therapeutic chemistry is rising. The cytotoxicity effects of four quinoxaline compounds ( and ) against liver cancer cells (HepG2), prostate cancer cells (PC-3), and normal cells (Vero) were evaluated using the MTT assay. Compounds and had the most anti-proliferative effects and highly selective indices against PC-3 cells with IC values of 4.11 and 2.11 µM, respectively. The apoptotic cell death for compounds and in PC-3 cells was investigated using cell cycle, Annexin V-FITC/PI double staining-based flow cytometry, and DNA fragmentation assay. Compounds or arrested the cell cycle at the S phase and caused apoptosis in PC-3 cells. Compounds and showed inhibitory effects against topoisomerase II enzyme with IC values 21.98 and 7.529 µM, respectively, when compared to doxorubicin as a reference drug. Western Blot analysis displayed that compound treatment has significantly upregulated the pro-apoptotic proteins (p53, caspase-3, caspase-8) and downregulated the anti-apoptotic protein Bcl-2 in PC-3 cells in a dose-dependent manner, leading to cell apoptosis. The molecular docking study exhibited that compound had a good binding affinity for inhibiting topoisomerase II, consistent with the apoptotic mechanism. study using Ehrlich solid tumor model demonstrated that compound significantly reduced tumor volume and weight with minimal toxicity. This study reveals significant evidence for the antitumor efficacy of compound against prostate cancer cells as a topoisomerase II inhibitor.