Evodiamine inhibits the proliferation of leukemia cell line K562 by regulating peroxisome proliferators-activated receptor gamma (PPARγ) pathway

Abstract

Evodiamine, a quinolone alkaloid, is one of the major bioactive compounds of Evodia rutaecarpa Bentham (Rutaceae). It exhibits excellent biological activities, especially the anticancer activity. This study aims to investigate the effect of evodiamine on the proliferation of leukemia cell line K562 and to explore the underlying mechanism. The effect of evodiamine on K562 cells proliferation was analyzed by trypan blue dye exclusion assay and MTT assay. The expression levels of peroxisome proliferators-activated receptor gamma (PPARγ), cyclin D1, and p21 were detected by western blot assay. The results demonstrated that evodiamine inhibited the proliferation and decreased the viability of K562 cells in a dose- and time-dependent manner. 2-Chloro-5-nitro-N-phenylbenzamide (GW9662) and/or PPARγ-siRNA pretreatment alleviated the cell growth suppression triggered by evodiamine. Meanwhile, evodiamine intervention elevated the expression of PPARγ in K562 cells, while pretreatment with GW9662 attenuated the enhanced upregulation of PPARγ expression induced by evodiamine. In addition, GW9662 and PPARγ-siRNA pretreatment also significantly attenuated the downregulation of the cell cycle control protein cyclin D1 and the upregulation of cyclin-dependent kinase inhibitor p21 induced by evodiamine. In conclusion, PPARγ signaling pathway may involve in the proliferation inhibition of evodiamine on K562 cells via inhibiting cylcin D1 and stimulating of p21.

Antiproliferative Effects of Alkaloid Evodiamine and Its Derivatives

“…In addition, evodiamine is not toxic to human normal peripheral blood mononuclear cell (PBMC) [ 57 , 58 ]. In another study, peroxisome proliferator-activated receptor γ (PPARγ) signaling pathway was reported to be involved in the proliferation inhibition of evodiamine on K562 cells via inhibiting cyclin D1 and stimulating of p21, the important factors for the regulation of cell cycle progression [ 59 ]. Moreover, evodiamine decreased NF-κB activity and expressions of NF-κB-dependent antiapoptotic, proliferative, and metastatic genes in human myeloid leukemia KBM-5 cells, which indicated NF-κB might be another potential target of evodiamine for anti-leukemia therapy [ 60 ] ( Figure 3 ).…”

Cell cycle arrest and apoptosis induction by methanolic leaves extracts of four Annonaceae plants

“…For example, berberine can inhibit the proliferation of cancer cell lines by interfering with cell proliferation [40] and inducing apoptotic cell death [41]. Evodiamine or quinolone alkaloid showed anti-cancer activities by inducing cell cycle blocking in the K562 erythroleukemic cell line [42], causing DNA damage in MCF-7 breast cancer cells [43], inducing apoptosis in U937 human leukemic cells [44], interfering with angiogenesis [45], and interfering with cell metastasis in Lewis lung carcinoma (LLC) and B16-F10 melanoma [46]. …”

Re-Purposing Evodiamine as an Anti-Cancer Drug: Effects on Migration and Apoptosis

“…Stimulation of cathecolamine secretion [2] Pain relief [3] Anti-inflammatory [4,5] Weight loss through increased thermogenesis (weight loss with EVO is a controversial issue which has not been fully clarified) [6][7][8] Vasodilation [9] Inhibitory effects on the synthesis of prostaglandin E2 (PGE2), this can be considered as part of its anti-inflamatory effects.…”

“…Another paragraph on the issue ANSES says: "The major alkaloids of Evodia, evodiamine and rutaecarpine, have modulatory effects on metabolizing enzymes, in particular cytochromes P450 CYP3A4, CYP1A2 and CYP1A1 (Ueng et al 2002; Wen et al 2014) [7] which metabolize many drugs". No other major adverse effects are described in this "opinion" of ANSES, and no other warnings are given.…”