Cytotoxicity of Vitex agnus-castus fruit extract and its major component, casticin, correlates with differentiation status in leukemia cell lines

Abstract

We have demonstrated that an extract from the ripe fruit of Vitex agnus-castus (Vitex) exhibits cytotoxic activities against various types of solid tumor cells, whereas its effects on leukemia cells has not been evaluated to date. In this study, the effects of Vitex and its major component, casticin, on leukemia cell lines, HL-60 and U-937, were investigated by focusing on proliferation, induction of apoptosis and differentiation. Identification and quantitation by NMR spectroscopy showed that casticin accounted for approximate 1% weight of Vitex. Dose-dependent cytotoxicity of Vitex and casticin was observed in both cell lines, and HL-60 cells were more sensitive to the cytotoxicity of Vitex/casticin compared to U-937 cells. Furthermore, compared to unstimulated HL-60 cells, phorbol 12-myristate 13-acetate (PMA)- and 1,25-dihydroxyvitamin D₃ (VD₃)-differentiated HL-60 cells acquired resistance to Vitex/casticin based on the results from cell viability and apoptosis induction analysis. Since the HL-60 cell line is more immature than the U-937 cell line, these results suggested that the levels of cytotoxicity of Vitex/casticin were largely attributed to the degree of differentiation of leukemia cells; that is, cell lines with less differentiated phenotype were more susceptible than the differentiated ones. RT-PCR analysis demonstrated that PMA upregulated the expression of intercellular adhesion molecule-1 (ICAM-1) in HL-60 cells, and that anti-ICAM-1 monoclonal antibody not only abrogated PMA-induced aggregation and adhesion of the cells but also restored its sensitivity to Vitex. These results suggested that ICAM-1 plays a crucial role in the acquired resistance in PMA-differentiated HL-60 cells by contributing to cell adhesion. These findings provide fundamental insights into the clinical application of Vitex/casticin for hematopoietic malignancy.

Casticin inhibits the activity of transcription factor Sp1 and the methylation of RECK in MGC803 gastric cancer cells

“…Although the toxicity of taxol in tumor cells is higher than that of casticin, it is less selective than casticin (34). Casticin causes no toxicity in healthy cells and tissues (23); however it significantly inhibits the proliferative activity of numerous malignant tumor cells (20). As a type of demethylation drug, casticin may become a novel preventive means for gastric cancer, due to its few adverse reactions.…”

“…Casticin exhibits weaker cytotoxicity but greater selectivity than taxol, (the IC 50 of taxol for tumor cells is at the nmol/l level, while the IC 50 of casticin is at the µmol/l level) (19). Although casticin has little or no effect on the apoptosis of normal cells and tissues, it is reported to have an inhibitory effect on the proliferation of malignant tumors (20)(21)(22)(23). However, it is currently unclear whether casticin affects methylation of the RECK gene in gastric cancer cells.…”

Casticin inhibits human prostate cancer DU 145 cell migration and invasion via Ras/Akt/NF‐κB signaling pathways

“…In Chinese population, casticin had been used as an anti-inflammatory agent for thousands of years (Shen, Du, Yang, Wang, & Jin, 2009). Casticin have been shown present biological activities including anticancer activity against human breast (Song, Zhang, Lei, & Dang, 2010), cervical (Xie, Bai, Sheng, Cao, & Xie, 2011), colon (Qu et al, 2014), epidermoid carcinoma (Kobayakawa, Sato-Nishimori, Moriyasu, & Matsukawa, 2004), gallbladder (Song et al, 2017), gastric (Zhou, Tian et al, 2013), glioma (Liu, Kuang, He, Xing, & Gu, 2013), leukemia (Kikuchi et al, 2013), liver (Yang et al, 2011), lung (Zhou, Peng et al, 2013), melanoma (Shih et al, 2017;Shiue et al, 2016), oral (Chou et al, 2018), ovarian (Jiang et al, 2013), and prostate (Meng et al, 2012) cancer cells. Recently, casticin has attracted increasing attention due to the inhibition of the epithelial-mesenchymal transition (EMT) via Hedgehog (Hh) signaling resulting in reduced migratory ability of ovarian cancer cells (Zhang, Cui, Sun, Cao, & Fang, 2018).…”

Rosehip inhibits xanthine oxidase activity and reduces serum urate levels in a mouse model of hyperuricemia

“…These food types also contribute to the promotion of self-medication, i.e., the use of over-the-counter medicines, including herbal and traditional products, to treat self-recognized illnesses or symptoms (1,2). Of particular interest is the biological activity and safety of natural products, including food, traditional herbs, kampo and their phytochemicals (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13).…”