Trifolium Repens Blocks Proliferation in Chronic Myelogenous Leukemia via the BCR-ABL/STAT5 Pathway

Abstract

Some species of clover are reported to have beneficial effects in human diseases. However, little is known about the activity of the forage plant Trifolium repens, or white clover, which has been recently found to exert a hepatoprotective action. Scientific interest is increasingly focused on identifying new drugs, especially natural products and their derivatives, to treat human diseases including cancer. We analyzed the anticancer effects of T. repens in several cancer cell lines. The phytochemical components of T. repens were first extracted in a methanol solution and then separated into four fractions by ultra-high-performance liquid chromatography. The effects of the total extract and each fraction on cancer cell proliferation were analyzed by MTT assay and Western blotting. T. repens and, more robustly, its isoflavonoid-rich fraction showed high cytotoxic effects in chronic myelogenous leukemia (CML) K562 cells, with IC50 values of 1.67 and 0.092 mg/mL, respectively. The block of cell growth was associated with a total inhibition of BCR-ABL/STAT5 and activation of the p38 signaling pathways. In contrast, these strongly cytotoxic effects did not occur in normal cells. Our findings suggest that the development of novel compounds derived from phytochemical molecules contained in Trifolium might lead to the identification of new therapeutic agents active against CML.

Thymoquinone Induces Downregulation of BCR-ABL/JAK/STAT Pathway and Apoptosis in K562 Leukemia Cells

“…Furthermore, JAK2 protein intensity was reduced in HepG2 and MHCC97-H hepatocellular carcinoma cells after scutellarin treatment (Liu et al, 2019). STAT5 protein intensity was also lowered in K562 cells after treatment with Trifolium Repens extract compared to the untreated control (Sarno et al, 2020). In similarity, the results of the present study revealed a significant reduction in the intensity of JAK2 and STAT5 proteins (p < 0.001) in TQ treated K562 cells compared to untreated cells.…”

“…BCR-ABL and activated JAK/STAT signaling have been found to exert anti apoptotic effects in CML cells (Chen et al, 2016;Jiang et al, 2021). Additionally, TQ had induced apoptosis in U87MG human Glioblastoma multiforme cells (Khazaei and Pazhouhi, 2017) and CEM and Jurkat human acute lymphoblastic leukemia cells (Soltani et al, 2017;Houssein et al, 2020). Furthermore, the findings of the current study showed that TQ significantly induced apoptosis in K562 cells in a dose dependent manner.…”

Naturally Occurring Bicoumarin Compound Daphnoretin Inhibits Growth and Induces Megakaryocytic Differentiation in Human Chronic Myeloid Leukemia Cells

“…A previous in vivo study indicated that daphnoretin can inhibit the growth of P-388 lymphocytic leukemia in mice [ 19 ]. In addition, less than 10% cell death was reported after 48 h of daphnoretin treatment of K562 cells at a concentration of 0.07 mg/mL (approximately 0.2 μM) [ 24 ]. The results indicate that daphnoretin has antitumor activity and could have a novel therapeutic effect against myeloid leukemia or lymphocytic leukemia.…”

“…Moreover, daphnoretin can regulate the immune response by modulating dendritic cell development toward atypical maturation with impaired allostimulatory functions [ 22 ]. In addition, it has exhibited anticancer activity against several tumors, including Ehrlich ascites tumor cells [ 23 ], leukemia cells [ 19 , 24 ], cervical cancer HeLa cells [ 25 ], lung adenocarcinoma A549 cells [ 26 ], and colon cancer HCT116 cells [ 27 ]. Although these studies have shown the potential of daphnoretin in treating specific cancers, there is no evidence of its inhibitory or differentiation-inducing effect on human myeloid leukemia cells.…”

Sulfasalazine synergistically enhances the inhibitory effects of imatinib against hepatocellular carcinoma (HCC) cells by targeting NFκB, BCR/ABL, and PI3K/AKT signaling pathway‐related proteins

“…BCR/ABL kinase is considered to be an oncogene that controls and mediates expression of important downstream proteins that have a role in HCC pathogenesis [16]. Also, BCR/ABL was found to be overexpressed in HCC cases [17].…”