Matrine Usage And Synthesis
Matrine (MT) is a kind of alkaloid components found in the roots of Sophora species, having various pharmacological activities and are demonstrated to have anti-inflammatory, anti-allergic, anti-virus, antifibrotic, and cardiovascular protective effects. It is recently proved to have anti-cancer potentials, such as inhibiting cancer cell proliferation, inducing cell cycle arrest, accelerating apoptosis, restraining angiogenesis, inducing cell differentiation, inhibiting cancer metastasis and invasion, reversing multidrug resistance, and preventing or reducing chemotherapy- or radiotherapy-induced toxicity when combined with other chemotherapeutic drugs.
Sophora root, which is a traditional herb medicine found in China, Japan and some European countries, is the dried root of Sophora flavescens Aiton (Leguminosae) and includes matrine (MT), a major tetracycloquinolizindine alkaloids, as its primary components (chemical structure are shown in Fig. 1)[1–3]. It was reported that MT exhibit many biological activities and possess a wide range of pharmacological effects, such as anti-inflammation, anti-arrhythmia, anti-virus, antifibrotic, anti-allergy, analgesic, and immunosuppression, leading to wide clinical use in the treatment of viral hepatitis, liver fibrosis, cardiac arrhythmia, skin diseases, and autoimmune disease in China. Recently, MT has been extensively studied, for their cancer chemopreventive potential against various cancers, for instance gastric cancer, lung cancer, breast cancer, hepatocellular carcinoma, pancreatic cancer, melanoma, leukemia, cervix cancer, and osteosarcoma[5-7]. However, the precise mechanism underlying the anticancer activity of MT is largely unknown. Therefore, in the present study, we focus on the current studies regarding various aspects of MT as they relate to their efficacy against cancer and associated molecular mechanisms.
Figure 1 the chemical structure of matrine
Pharmacokinetic and Bioavailability
Within the past decade, several research groups have evaluated the pharmacokinetics of MT an extracts in vivo. Zhang et al. investigated the pharmacokinetics of MT in human plasma by liquid chromatography/tandem mass spectrometry (LC/MS/MS) method. After oral administration of MT soft gelatin capsules 100, 200 and 400 mg, as the major pharmacokinetic parameters of MT, the area under the plasma concentration-time curve (AUC) and the maximum plasma concentrations (Cmax) increased in proportion to dose increase, but the time of occurrence (Tmax) had no apparent change as the dose ascended. So they draw a conclusion that MT had linear pharmacokinetic trends in healthy Chinese volunteers. This result could be used as a suitable reference in clinical practice. In order to enhance the bioavailability of MT, Ruan et al. prepared the matrine phospholipid complex (MPC) by solvent evaporation method. And after oral administration, the absolute bioavailability of MT was drastically increased from 25 to 84.6 % by the formation of MPC, with an outstanding relative bioavailability of 338 %. This result suggests MPC possesses great potential for clinical application. These two studies indicate a bright way to improve the clinical efficacy of MT. Fan et al. determined a specific and sensitive liquid chromatography mass spectrometry (LC-MS) method of oxymatrine (OMT) and its active metabolite MT after administration of OMT oral solution in human plasma. The test showed only part of OMT is absorbed by the gastrointestinal tract while most of it was absorbed after arrived in the intestines and quickly transformed into MT, which in turn plays a very good role during the treatment of liver injuries. This result showed OMT oral solution had good absorption, quick effect and long acting time. Wu et al. conducted a study of OMT and its metabolite MT in human plasma after i.v. Infusion administration of 600 mg of OMT in 100 ml of 5 % glucose. They found the plasma concentration time profiles of OMT and MT obtained were best fitted with two-compartment and one-compartment models, respectively, and the Cmax, Tmax, AUC0–t were (20,519±7,581) and (247±45) ng/ml, (0.5±0.1) and (5.6±1.7) h, (20,360±5,205) and (3,817±610) ng h/ml, respectively.
Recently, drug–drug interactions, which can manifest as impaired drug efficacy and/or enhanced toxicity in combination use of natural products and prescribed drugs, have been documented in both pre-clinical and clinical investigations . MT displays the synergistic effect with the anti-cancer agents trichostatin A (a histone deacetylase inhibitor), celecoxib (a cyclooxygenase-2 inhibitor) and rosiglitazone against the tumor proliferation and VEGF secretion. Hu et al. reported that the inhibitory effect of combined MT and 5-FU is superior to MT or 5-FU alone on the growth of transplanted human gastric cancer in nude mice. They also found combining MT and 5-FU can increase the inhibitory effect on proliferative hemopoietic bone marrow cells and does not affect the resting bone marrow stem cells. Yang et al. showed that, in patients with non-small cell lung cancer, the effect of intra-operative pleural perfusion with cisplatin plus MT is superior to cisplatin alone. They concluded that pleural perfusion chemotherapy with cisplatin plus MT might be considered as an early-phase intervention against probable tumor metastasis. All these studies indicated that MT could enhance the efficacy of many anticancer drugs by drug–drug interactions.
Carcinogenesis is a multistep process that can be activated by altered expression of onco-proteins and transcriptional factors involved in cell proliferation, cell cycle regulation, apoptosis, angiogenesis, cell differentiation, cell invasion, and metastasis. Deregulated cell cycle progression and apoptosis together with increased proliferation capacity, angiogenic potential, invasion, and metastasis have been described as symbol of cancer. Accordingly, the agents that could target one or more of these processes should be ideal cancer chemopreventive agents. MT exerts their anti-cancer activities by various channels, mainly manifested in inhibiting cancer cell proliferation, inducing cell cycle arrest and differentiation, accelerating apoptosis, restraining agiogenesis, inhibiting metastasis and invasion, reversing multidrug resistance and preventing or reducing chemotherapyand radiotherapy-induced toxicity.
MT and OMT treatments have been shown to inhibit the proliferation of tumor cells in various cancers, including gastric cancer (MKN45 and SGC-7901), breast cancer (MDA-MB-231), hepatoma (SMMC-7721), colon cancer (SW1116), melanoma (M21), glioma (C6), osteosarcoma (UMR-108), pancreatic cancer (PANC-1), and leukemia (U937) in a dose-dependent manner[15-17].
Modulation of cell cycle progression
MT could inhibit proliferation of cells by inhibiting cell cycle progression at different phases of the cell cycle, such as an increase of G0/G1 phase and a decrease of S phase in human hepatoma cells. Studies from Zhao et al. demonstrated that MT induces G1 phase arrest in human retinoblastoma Y79, WERI-RB1, and SO-RB50 cells, and the molecular mechanisms are associated with up-regulation of CDK inhibitors p21 and p27 and down-regulation of cyclin D1 protein. MT induces significant G0/G1 accumulation and G2/M depletion by increasing p21 mRNA and decreasing cyclin D1 mRNA. Furthermore, MT can result in cell cycle arrest in G0/G1 phase in gallbladder carcinoma GBC-SD cells and induce cell apoptosis by down-regulation of cyclin E expression. It is reported that the E2F family of transcription factors control the G1/S transition in eukaryotic cells. MT treatment could obviously up-regulate the expression of E2F1, as well as down-regulate Rb, an inhibitor of E2F-1 activity, and finally lead to cell apoptosis in K562 cells [19-21].
Induction of cell apoptosis
Apoptosis is a ubiquitous and highly regulated mechanism by which cells undergo programmed cell death. Cancer cell is resistant to apoptosis. Studies have reported that MT exerts anti-cancer effects by inducing apoptosis in different type of cancers. Liang et al. showed that MT induces apoptotic cell death in human osteosarcoma cells by activating of caspase-3, caspase-8 and caspase-9 and increasing the expression of factor associated suicide/factor-associated suicide ligand (Fas/FasL). This major caspase-dependent pathway plays an important role in regulation of cell apoptosis. In retinoblastoma cells human breast cancer MDA-MB-231 cells, MT induces apoptosis by decreasing the expression of antiapoptotic protein Bcl-2 and increasing expression of proapoptotic protein Bax. MT causes apoptosis in V600EBRAF harboring M21 cells by inhibiting the PI3K/Akt pathway that is associated with activation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). It has been shown that MT induces apoptosis in human acute myeloid leukemia cells by collapsing the mitochondrial membrane potential, inducing the cytochrome C release from mitochondria, reducing the ratio of Bcl-2/Bax, increasing activity of caspase-3, and decreasing the levels of phosphorylated Akt and phosphorylated ERK1/2.
Angiogenesis is a physiological process of microvascular generation and growth, and plays an important role in the growth and spread of cancer. MT exerts its anti-angiogenic activity in human NSCLC A549 cells by reducing the secretion of vascular endothelial growth factor (VEGF), a key regulator of normal and abnormal angiogenesis. Chen et al. demonstrated that OMT inhibits the growth and survival of human pancreatic cancer PANC-1 cells by inhibiting capillary tube formation. The molecular events associated with these effects include a decrease of
NF-κB mRNA and NF-κB p65 protein, which has been reported associated with angiogenesis, and a down-regulation of VEGF levels. Qu et al. found, after administration of MT, that the solid tumors in H22 tumor-bearing mice were inhibited in a dose-response relationship and the quality of life were improved; the anti-cancer effect may be related to the down-regulation of VEGF.
Induction of autophagy
Autophagy, an important cell death process besides apoptosis, regulates cell death in both physiological and pathophysiological conditions. The genetic or pharmacological inhibition of autophagy can sensitize cancer cells to various cancer therapies. Therefore, the inhibition of autophagy is therapeutically beneficial for anticancer therapies. After treatment with MT, the HepG2 hepatoma cells exhibited remarkable morphological changes, including an appearance of abundant autophagic vacuoles (AVs) of varied sizes, and an increased expression of Beclin 1, which is the first identified mammalian gene to induce autophagy. In addition, 3MA, an inhibitor that blocks autophagic sequestration, prevented the accumulation of Avs. After treatment with MT, the massive AVs in SGC7901 gastric cancer cells and C6 glioma cells were observed under transmission electron microscopy, and the expression of BNIP1, BNIP2, NNIP3 andDRPK1 were all increased in C6 glioma cells. Recently, Wang et al. observed that MT promotes the accumulation of AVs accompanied by attenuation of proteinase activity in lysosomes. Meanwhile, MT alters the pH environment of lysosomes, thereby resulting in an inhibition of trafficking and proteolytic activation of lysosomal enzymes.
Induction of cell differentiation
It is reported that MT has an ability to induce cell differentiation in human erythro-leukemia K562 cell line accompanied by loss of telomerase activity. MT treatment up-regulates the expression of p27kip1, a potential downstream molecule in cell differentiation and apoptosis pathways, and induces K562 cells to exhibit apoptotic characteristics, demonstrating that MT-induced erythroid differentiation in K562 cells is associated with cell apoptosis.
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