Zeylenone promotes apoptosis in chronic myelogenous leukemia-derived K562 cells by a mechanism involving Jak2 and Src kinase

Abstract

Chronic myelogenous leukemia (CML) is a hematopoietic malignancy caused by the constitutive activation of BCR–ABL tyrosine kinase. Imatinib, an inhibitor of BCR–ABL, is very effective in controlling CML, however, the emergence of resistance remains a concern. Therefore, alternative strategies with unique targets are strongly desirable. Zeylenone (Zey), isolated from the leaves of Uvaria grandiflora Roxb. of the family Annonaceae, exhibits significant anticancer activity in various types of cancer cells. However, the anticancer effect of Zey on CML and the mechanism of action remains unclear. Thus, the present study was designed to investigate the anticancer effect of Zey on K562 cells both in vitro and in vivo, followed by exploring the underlying mechanisms. Initially, the effects of Zey on cell viability, proliferation, and apoptosis were measured in K562 cells after they were treated with Zey for the indicated time, and then the involved signaling pathways were investigated. Furthermore, the in vivo anti-tumor activity of Zey was assessed with nude xenografts. We identified that Zey dose-dependently decreased cell viability and proliferation, and induced cell apoptosis in K562 cells. Additional experiments revealed that Zey inhibited phosphorylation of Jak2 and Src and downregulated their downstream proteins, including p-Stat3, p-PI3K, p-AKT, p-mTOR, and p-ERK. Zey also suppressed tumor growth with low toxicity in a mouse xenograft model of K562 cells. Taken together, our data demonstrated that Zey substantially suppressed K562 cells both in vitro and in vivo through Jak2 and Src pathways. These findings suggest the potential of zeylenone as an effective anticancer agent in CML treatment.