A tumor is a disease with two defining characteristics: a proliferation disorder and an apoptosis obstacle. The inhibition of proliferation and the induction of apoptosis are regulated by a network of signaling pathways and transcription factors, which may represent potential targets for rational tumor therapy [
1,
2]. Apoptotic events are regulated by the interplay of proapoptotic and antiapoptotic proteins. The apoptotic pathways include two major signaling pathways: the death receptor-induced pathway and the mitochondria-apoptosome-mediated pathway. Elements of the death receptor pathway include cell death ligands and their receptors, such as tumor necrosis factor (TNF) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor, and downstream molecules, such as caspase 8. The major components of the mitochondrial pathway include apoptotic stimuli, mitochondria, the apoptosome, and key effector caspases [
1]. Crosstalk between these two apoptotic pathways is mediated through the truncation of the BH3-interacting death domain (Bid) protein. Inhibitors of apoptosis proteins include the X-linked inhibitor of apoptosis protein (XIAP), the cellular inhibitor of apoptosis protein (cIAP), survivin, and the phosphatidyl inositol 3 kinase/serine/threoninespecific protein kinase/nuclear factor-kappa B (PI3K/AKT/NF-κB) pathway. Recent studies had focused on inducing cancer cell apoptosis by targeting the core components of the apoptosis-related signaling pathway and had produced promising results [
3,
4]. Cancer is also a disease of the cell cycle, a series of events that a eukaryotic cell must undergo to result in its replication. The cyclin-dependent kinase inhibitor p21 plays a key role in cell-cycle regulation. Gartel and Tyner [
5] showed that p21-dependent cell cycle arrest occurs at the G2/M phase. The key regulator of the G2/M phase is the cell division cycle 2 (Cdc2)/Cyclin B, the activity of which can be regulated by p21 [
6]. Furthermore, p21 possesses proapoptotic functions in some systems. Overexpression of p21 increases the susceptibility of glioma cell lines [
7] and several p53-deficient human cell lines [
8] to chemotherapeutic agent-induced apoptosis. These studies had revealed a correlation between the expression level of p21 and patient survival [
9].
Alkaloids have been found to exhibit effective anti-cancer activities with multiple mechanisms. For example, camptothecin and its analogs exhibited strong anti-cancer activities by inhibiting the DNA-uncoiling function of topoisomerase I [
10]. Shikonin induced the apoptosis of Bcr/Abl-positive chronic myelogenous leukemia (CML) cells through a reactive oxygen species/c-Jun N-terminal kinase (ROS/JNK)-mediated process [
11]. Homoharringtonine promoted apoptosis in K562 cells [
12] and more than 90% of the leukaemic stem cells were killed after treatment with homoharringtonine in vitro [
13]. Leukemia is one of the most life-threatening hematological malignant cancers. Because of its potential sensitivity to chemical reagents [
14,
15], scientists are attempting to discover new specific and effective chemical drugs to fight this disease [
16]. Lycorine, an alkaloid extracted from Amaryllidaceae, has multiple pharmacological functions, such as anti-virus effects, anti-tumour effects, and emetic action [
17,
18]. In our previous work, we found that lycorine decreased the survival rate and inducing apoptosis in leukemia and multiple myeloma cell lines[
19,
20], and the mechanisms of induced apoptosis have mediated by stimulating the caspase pathway and increasing the Bax:Bcl-2 ratio through the down-regulation of Bcl-2 expression. In addition, lycorine induced apoptosis in human leukemia cells via the mitochondria pathway and caused a rapid turnover of myeloid cell leukemia 1 (Mcl-1) protein, which occurred before caspase activation [
21]. Lycorine exerted its in vitro antitumor activity through cytostatic rather than cytotoxic effects. Also, lycorine provided significant therapeutic benefit in mice bearing brain grafts of the B16F10 melanoma model at nontoxic doses [
22]. Lycorine exhibited in vivo anti-tumor activity when tested in SCID mice model with human acute promyelocytic leukemia (APL) cells and was a useful therapy against [
23]. The human leukemia (Jurkat) cells were investigated with the treatment of synthetic and natural lycorane alkaloids. The results showed that a free ring-C 1,2-diol in the lycorine series (lycorine and pseudolycorine) was required for potent apoptosis-inducing activity [
24]. The aim of this study was to investigate the molecular mechanism underlying lycorine-induced death of HL-60 cells and provide a mechanistic framework for further exploring the use of lycorine as a novel anti-leukemia agent.