Aberrant DNA methylation of tumor suppressor genes (TSGs) plays a critical role in chronic myeloid leukemia (CML) pathogenesis. SOCS-3, a TSG, regulates various proliferative pathways, including MAPK signaling. Enhancing expression of TSGs through demethylation provides a potential target for cancer treatment. One of Nigella Sativa's main ingredients, thymoquinone (TQ), has proven anticancer properties. However, the mechanisms driving TQ's antileukemic influences were not entirely clarified. This research aimed to assess TQ’s abilities to demethylate and re-express SOCS-3 in CML mice model. A nude mouse model of CML was established, and the apoptotic influence of TQ was identified. TQ’s impact on the target gene expressions was examined using RT-qPCR, and SOCS-3 methylation was assessed by pyrosequencing. TQ’s effects on ERK1/2 phosphorylation were assessed using Jess Simple Western analysis. Molecular docking of TQ’s interaction with the anti-apoptotic proteins. TQ exerted a marked hypomethylating influence on SOCS-3 and reduced ERK1/2 phosphorylation level in K562-xenograft tumours. TQ also significantly upregulated Caspase-3, Caspase-9, Bim, Bax, Bak, PUMA, and Bmf and downregulated BCL-2, BCL-w, BCL-xL, MCL-1, BFL-1, Survivin, and XIAP in K562 cells. TQ also exhibited marked inhibitory properties on BFL-1, BCL-xL, MCL-1, and BCL-2. This led to growth inhibition and apoptosis of K562-tumor xenograft. These results indicate that TQ enhances CML cells' apoptosis by hypomethylating and re-expressing SOCS-3, inhibiting ERK1/2 and modulating the apoptosis-regulator gene expression and by showing consistent interaction with most of anti-apoptotic proteins, enhancing its potential as a scaffold for designing novel inhibitors to combat CML cells.
Al-Rawashde et al. (Sat,) studied this question.