lignans and Leukemia--Promyelocytic--Acute

Acute promyelocytic leukemia (APL) is a blood system disease caused by the accumulation of a large number of immature blood cells in bone marrow. Although the introduction of all-trans retinoic acid (ATRA) and arsenic has reached a high level of complete remission rate and 5-year disease-free survival rate, the occurrence of various adverse reactions still severely affects the quality of life of patients. As a natural product, honokiol (HNK) has the advantages of low toxicity and high efficiency, and it is a potential drug for the treatment of cancer. Since cancer cells can escape apoptotic cell death through multiple adaptive mechanisms, HNK, a drug that induces cancer cell death in a nonapoptotic way, has attracted much interest. We found that HNK reduced the viability of human APL cell line (NB4 cells) by inducing paraptosis-like cell death. The process was accompanied by excessive reactive oxygen species (ROS), mitochondrial damage, endoplasmic reticulum stress, and increased microtubule-associated protein 1 light chain 3 (LC3) processing. The inactivation of proteasome activity was the main cause of misfolded and unfolded protein accumulation in endoplasmic reticulum, such as LC3II/I and p62. This phenomenon could be alleviated by adding cycloheximide (CHX), a protein synthesis inhibitor. We found that mTOR signaling pathway participated in paraptosis-like cell death induced by HNK in an autophagy-independent process. Moreover, the mitogen-activated protein kinase (MAPK) signaling pathway induced paraptosis of NB4 cells by promoting endoplasmic reticulum stress. In summary, these findings indicate that paraptosis may be a new way to treat APL, and provide novel insights into the potential mechanism of paraptosis-like cell death.

Topics: Apoptosis; Biological Products; Biphenyl Compounds; Cell Death; Cell Line, Tumor; Cell Proliferation; Endoplasmic Reticulum Stress; Humans; In Vitro Techniques; Leukemia, Promyelocytic, Acute; Lignans; MAP Kinase Signaling System; Proteasome Endopeptidase Complex; Reactive Oxygen Species; Signal Transduction; TOR Serine-Threonine Kinases

Zanthoxylum schinifolium is an aromatic shrub, and its pericarp and leaves are widely used in culinary applications in East Asian countries. It has also long been used in traditional Oriental medicine for treating the common cold, stomach ache, diarrhea, and jaundice. In this study, we identified two new compounds, zanthoxyloside (1) and schinifolisatin A (13), along with 23 known coumarins (2-12) and lignans (14-25), from a methanol extract of the stems of Z. schinifolium . The chemical structures of the compounds were determined by mass, 1D-, and 2D NMR spectroscopy. The anticancer effects of the isolated compounds were examined in three human cancer cell lines. Compounds 10-12 significantly reduced the proliferation of HL-60 human acute promyelocytic leukemia cells with IC50 values of 4.62-5.12 μM. Treatment of PC-3 prostate cancer cells and SNU-C5 colorectal cancer cells with compound 10 resulted in potent antiproliferative activity, with IC50 values of 4.39 and 6.26 μM, respectively. Also, compounds 10-12 induced the apoptosis of three cancer cells. Furthermore, the induction of apoptosis was accompanied by down-regulation of p-ERK1/2 MAPK, p-AKT, and c-myc levels, in a time-dependent manner. These data suggested that compounds 10-12 from Z. schinifolium have potential in cancer treatment.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Cell Proliferation; Coumarins; HL-60 Cells; Humans; Leukemia, Promyelocytic, Acute; Lignans; Plant Extracts; Zanthoxylum

Anti leukemic-cell efficacy of 28 naturally occurring and synthetic flavonoids and 11 naturally occurring lignans on human promyelocytic leukemic cell line HL-60 were examined using MTT assay methods. Differences between anti cell-proliferative activity and cytotoxicity of these compounds were compared with those of 4 clinical anti-cancer agents. Eight of the 28 flavonoids and 4 of the 11 lignans showed considerable suppressive effects on HL-60 cell growth with IC50s ranging from 10-940 ng/ml. Among these compounds, genistein, honokiol, machilin A, matairesinol, and arctigenin had the strongest effects with IC50s less than 100 ng/ml, which were almost equivalent to the effects of current anti-cancer agents. The flavonoid genistein and the lignans, however, showed little or no cytotoxicity against HL-60 cells as assessed by dye exclusion tests (LC50s > 2,900 ng/ml), whereas the regular anti-cancer agents had potent cytotoxicity. All of the flavonoids and lignans, except for machilin A and arctigenin, were less effective against growth of human T lymphocytic leukemia cell line MOLT-4. In addition, the flavonoid and the lignans showed little or no inhibiting activity on mitogen-induced blastogenesis of human peripheral-blood lymphocytes. The lignans and genistein were strongly suppressive against incorporations of [3H]thymidine, [3H]uridine, and [3H]leucine into HL-60 cells. These results showed that some of the naturally occurring flavonoids and lignans inhibited HL-60 cell growth with a non-toxic mechanism, possibly via cessation of DNA, RNA, and/or protein synthesis of the leukemic cells.

Topics: Antineoplastic Agents; Cell Division; Drug Screening Assays, Antitumor; Flavonoids; Humans; Leucine; Leukemia, Promyelocytic, Acute; Leukemia, T-Cell; Lignans; Lymphocyte Activation; Lymphocytes; Tetrazolium Salts; Thiazoles; Thymidine; Tumor Cells, Cultured; Uridine