The imbalance between cell proliferation, apoptosis and differentiation leads to the development of clones of malignant cells. Based on the understanding of tumor biology in respect to the kinetics of cell populations, two new strategies, the induction of differentiation and apoptosis, have recently emerged in the fields of cancer chemoprevention and chemotherapy. Differentiation from malignant or premalignant cells into more mature or normal-like cells, as well as apoptosis in multi-step carcinogenesis, are theoretically amenable to preventive cancer intervention. Thus, a compound with differentiation effects could be a candidate for the prevention and/or treatment of cancer.
1,2)The HL-60 cell line, derived from a patient with acute promyelocytic leukemia, provides a unique in vitro model for studying the cellular and molecular events involved in the differentiation process. Moreover, a recent approach in the treatment of leukemia includes the use of differentiation-inducing agents such as interferon, 3) retinoids, 4) and 1a,25-dihydroxyvitamin D 3 . 5,6) Based on this, the strategy of HL-60 cell differentiation has been accepted as a valid model in detecting or screening for potential cancer chemopreventive and/or chemotherapeutic agents in preclinical evaluation.Thus, as a part of our screening program to evaluate the chemopreventive potential effect of natural compounds, we have investigated the effect of taraxinic acid-1Ј-O-b-D-glucopyranoside isolated from Taraxacum coreanum NAKAI and its hydrolysate, taraxinic acid, on HL-60 growth. The whole plant of Taraxacum coreanum NAKAI has long been used for medicinal purposes due to its diuretic and anti-inflammatory activities.7) Taraxinic acid, the enzymatic hydrolysate of taraxinic acid-1Ј-O-b-D-glucopyranoside (Fig. 1) isolated from Taraxacum coreanum NAKAI, showed significant cytotoxicity, supporting that the sesquiterpene lactone is a generally active moiety. The cytotoxic effect of taraxinic acid was assessed by its differentiation-inducing activity against HL-60 cells by various biochemical examinations in the present study. Furthermore, we demonstrated that the expression of p21 CIP1 and p27 KIP1 cyclin dependant kinase inhibitor (CDKI) were increased during 48 and 72 h, whereas c-myc oncogene expression was down-regulated during the taraxinic acid-induced differentiation of HL-60 cells. This is the first report showing the mechanism of the anti-cancer effect of taraxinic acid, which may be a candidate as a differentiation-inducing cancer chemopreventive agent.
MATERIALS AND METHODSMaterials P388 mouse leukemia, L-1210 mouse leukemia, SNU-C5 human colon cancer, HL-60 human promyelocytic leukemia, U-937 human histocytic lymphoma and HepG2 human hepatoma cell lines were obtained from the Korean Cell Line Bank (KCLB). RPMI 1640 medium, fetal bovine serum (FBS), penicillin, and streptomycin were obtained from Life Technologies, Inc. (Grand Island, NY, U.S.A.). b-Glycosidase, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tertazolium bromide (MTT), nitrobluetetra-...