Anticancer Traditional Chinese Medicine Research Articles

Pharmacokinetics and drug-likeness of anti-cancer traditional Chinese medicine: molecular docking and molecular dynamics simulation study

MCM7 (Minichromosome Maintenance Complex Component 7) is a component of the DNA replication licensing factor, which controls DNA replication. The MCM7 protein is linked to tumor cell proliferation and has a function in the development of several human cancers. Several types of cancer may be treated by inhibiting the protein, as it is strongly produced throughout this process. Significantly, Traditional Chinese Medicine (TCM), which has a long history of clinical adjuvant use against cancer, is rapidly gaining traction as a valuable medical resource for the development of novel cancer therapies, including immunotherapy. Therefore, the goal of the research was to find small molecular therapeutic candidates against the MCM7 protein that may be used to treat human cancers. A computational-based virtual screening of 36,000 natural TCM libraries is carried out for this goal using a molecular docking and dynamic simulation technique. Thereby, ∼8 novel potent compounds i.e., ZINC85542762, ZINC95911541, ZINC85542617, ZINC85542646, ZINC85592446, ZINC85568676, ZINC85531303, and ZINC95914464 were successfully shortlisted, each having the capacity to penetrate the cell as potent inhibitors for MCM7 to curb this disorder. These selected compounds were found to have high binding affinities compared to the reference (AGS compound) i.e. < −11.0 kcal/mol. ADMET and pharmacological properties showed that none of these 8 compounds poses any toxic property (carcinogenicity) and have anti-metastatic, and anticancer activity. Additionally, MD simulations were run to assess the compounds’ stability and dynamic behavior with the MCM7 complex for about 100 ns. Finally, ZINC95914464, ZINC95911541, ZINC85568676, ZINC85592446, ZINC85531303, and ZINC85542646 are identified as highly stable within the complex throughout the 100 ns simulations. Moreover, the results of binding free energy suggested that the selected virtual hits significantly bind to the MCM7 which implied these compounds may act as a potential MCM7 inhibitor. However, in vitro testing protocols are required to further support these results. Further, assessment through various lab-based trial methods can assist with deciding the action of the compound that will give options in contrast to human cancer immunotherapy. Communicated by Ramaswamy H. Sarma

Xihuang Pill enhances anticancer effect of anlotinib by regulating gut microbiota composition and tumor angiogenesis pathway

Lung cancer poses a serious threat to human health. Although targeted therapies have led to breakthroughs in the treatment of lung cancer, drug resistance and side effects limit their clinical applications. Xihuang pill (XHW), a classical anti-cancer traditional Chinese medicine formula, has been clinically proven to be an effective complementary therapy in the treatment of various of cancers. However, the underlying mechanism for its use in combination with anti-cancer drugs remains unclear. Here, we explored the anti-lung cancer effect of XHW combined with anlotinib in mice bearing Lewis lung cancer (LLC). We used gut microbiota and transcriptomics to elucidate the regulatory properties of XHW in improving anti-lung cancer effect of anlotinib. The results showed that combination treatment of XHW with Anlotinib significantly inhibited tumor growth in LLC-bearing mice. We found that XHW played a key role in the regulation of gut microbiota using 16 s rRNA sequencing analysis. Specifically, XHW increased the proportion of the beneficial bacteria Bacteroides and g_norank_f_Muribaculaceae. Based on transcriptomic analysis of tumor tissues, differentially expressed genes in the combination therapy group were related to biological processes concerning angiogenesis, such as regulation of blood vessel diameter, regulation of tube diameter, and regulation of tube size. Our data suggest that XWH enhances the anticancer effect of anlotinib by regulating gut microbiota composition and tumor angiogenesis pathway. Combination therapy with anlotinib and XHW may be a novel therapeutic strategy for lung cancer patients.

Identification of multi-target anti-cancer agents from TCM formula by in silico prediction and in vitro validation.

Cancer is a complex disease associated with multiple gene mutations and malignant phenotypes, and multi-target drugs provide a promising therapy idea for the treatment of cancer. Natural products with abundant chemical structure types and rich pharmacological characteristics could be ideal sources for screening multi-target antineoplastic drugs. In this paper, 50 tumor-related targets were collected by searching the Therapeutic Target Database and Thomson Reuters Integrity database, and a multi-target anti-cancer prediction system based on mt-QSAR models was constructed by using naïve Bayesian and recursive partitioning algorithm for the first time. Through the multi-target anti-cancer prediction system, some dominant fragments that act on multiple tumor-related targets were analyzed, which could be helpful in designing multi-target anti-cancer drugs. Anti-cancer traditional Chinese medicine (TCM) and its natural products were collected to form a TCM formula-based natural products library, and the potential targets of the natural products in the library were predicted by multi-target anti-cancer prediction system. As a result, alkaloids, flavonoids and terpenoids were predicted to act on multiple tumor-related targets. The predicted targets of some representative compounds were verified according to literature review and most of the selected natural compounds were found to exert certain anti-cancer activity in vitro biological experiments. In conclusion, the multi-target anti-cancer prediction system is very effective and reliable, and it could be further used for elucidating the functional mechanism of anti-cancer TCM formula and screening for multi-target anti-cancer drugs. The anti-cancer natural compounds found in this paper will lay important information for further study.

Research progress on chemical constituents, pharmacological action and quality control of Scutellaria barbata

Scutellaria barbata is a recognized anti-cancer traditional Chinese medicine, with the effects of clearing heat and detoxi-fication, dispelling blood stasis and stopping bleeding, diuresis and detumescence. At present, terpenoids, flavonoids, polysaccharides and volatile oils have been isolated from S. barbata, which have many pharmacological effects, such as resisting tumor, virus, bacteria and oxidation, and immunomodulation. This paper reviews the studies on the chemical constituents, pharmacological action and quality control of S. barbata, in the expectation of providing ideas and references for the further development and studies of S. barbata.

Comprehensive TCM molecular networking based on MS/MS in silico spectra with integration of virtual screening and affinity MS screening for discovering functional ligands from natural herbs.

Accessing the rich source of compounds from natural herbs for use in the pharmaceutical industry using conventional bioassay-based screening platforms has low efficiency and is cost-prohibitive. In this study, we developed a new method involving traditional Chinese medicine (TCM) molecular networking and virtual screening coupled with affinity mass spectrometry (MN/VS-AM) for the efficient discovery of herb-derived ligands. The in silico MS/MS fragmentation database (ISDB) generated by molecular networking of TCM can rapidly identify compounds in complex herb extracts and perform compound activity mapping. Additionally, the pre-virtual screening conveniently includes candidate herbs with potential bioactivity, while affinity MS screening completely eliminates the requirement for a tedious pure compound preparation at the initial screening phase. After applying this approach, two types of compounds, isoamylene flavanonols and 20(s)-protopanoxadio saponins, which were confirmed to interact with the small GTPase of Ras, were successfully identified from a dozen anti-cancer TCM herbs. The results demonstrate that the modified screening strategy dramatically improved the accuracy and throughput sensitivity of ligand screening from herbal extracts. Graphical abstract.

Anticancer effects of Qizhen Capsule in human colorectal cancer cells in vitro and in vivo

Qizhen capsule is a new type of anti‐cancer traditional Chinese medicine preparation. As an adjuvant therapy for cancer, it has been widely used in clinical practice with remarkable therapeutic effects in clinic. According to the current research reports, Qizhen capsule is mainly used for the treatment of lung, gastric and breast cancer. However, whether Qizhen capsule has an inhibitory effect on colorectal cancer has not been reported, and the specific molecular mechanism of its anti‐tumor activity has not been well studied. In this study, the effect of Qizhen capsule water extracts on the proliferation and apoptosis of human colon cancer HCT116 cells was studied in vitro and in vivo. MTT assay revealed that Qizhen capsule at 0.3 to 0.7 mg/ml significantly inhibited proliferation of HCT116 cells in a dose‐and time‐dependent manner. Furthermore, Qizhen capsule water extracts induced apoptosis in HCT116 cells that determined by flow cytometric, which is associated with deregulation of the expression of key genes and proteins (Bcl‐2, Bax, PARP, caspase‐3 and caspase‐9) that regulate apoptosis. Moreover, oral administration of 4.5 g/kg and combination treatment of 1.5 g/kg Qizhen capsule and 5‐Fu significantly inhibited HCT116 xenograft tumor growth in nude mice by reducing HIF‐1α, Bcl‐2, NF‐κB and c‐FOS at mRNA levels, and up‐regulating PARP, FoxO3a and NAG‐1 at protein levels, which was further confirmed by suppressed Ki‐67, caspase‐3, Bcl‐2 and PCNA staining in tumor samples as determined by immunochemistry. Taken together, our study suggests that Qizhen capsule could inhibit the development of colorectal cancer by inhibiting cell proliferation, inducing cell apoptosis, and suppressing tumor growth. These results also suggest that Qizhen capsule may be a promising anticancer drug for the prevention and treatment of colorectal cancer.Support or Funding InformationNational Natural Science Foundation of China (Grant No. 81473397).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Study on Traditional Chinese Medicine Maintenance Therapy for Advanced Non-small Cell Lung Cancer

Objective: To evaluate the efficacy and application advantages of traditional Chinese medicine (TCM) for patients with advanced non-small cell lung cancer (NSCLC), and to explore the factors related to the maintenance effect of TCM. Methods: Case data in this study were obtained from the Oncology Wards and Outpatient Clinics of Guang’anmen Hospital, China Academy of Chinese Medical Sciences. According to the inclusion and exclusion criteria, patients with advanced NSCLC meeting the study criteria, who were controlled by first-line chemotherapy, were divided into two groups: the maintenance treatment group and the control group according to whether there was TCM intervention and the degree of intervention. The data and treatment status were recorded through retrospective research, and the patients were followed up to record their survival time. The efficacy of TCM maintenance treatment was evaluated together by the patient’s overall survival time (PFS, OS) and quality of life (syndrome score, Karnofsky performance status, weight); and then relevant factor analysis was carried out. Results: A total of 66 eligible patients were included in the study, including 36 patients in the TCM maintenance treatment group and 30 patients in the control group. There was no significant difference between the two groups in terms of age, gender, smoking status, comorbidities, tumor location, stage, pathological type, complications, chemotherapy cycle and the first-line treatment effect in the baseline data. At the end of the study, it was found that the median progression-free survival (PFS) of the treatment group was 5.6 months, and that of the control group was 3 months. The difference between the two groups was statistically significant (P = 0.014 0.05). In terms of quality of life, compared with the control group, the TCM maintenance treatment group of traditional Chinese medicine can significantly improve the patient’s syndrome score, Karnofsky performance status and weight of the patients. The difference was statistically significant (P < 0.0.5). Through binary logistic stepwise regression analysis, it was found that the PFS and quality of life in TCM maintenance treatment group had obvious correlation with the TCM maintenance treatment mode; that is to say, patients who simultaneously applied oral and intravenous anti-cancer TCM could obtain greater benefits in PFS and quality of life. Conclusion: The use of TCM maintenance treatment can extend the PFS of patients with advanced NSCLC after first-line therapy, and has a tendency to extend the overall survival time. TCM maintenance treatment Can significantly improve patients' symptoms, improve physical condition scores, and weight, thus Improve the quality of life in patients with advanced NSCLC.

Anticancer efficacy of the ethyl acetate extract from the traditional Chinese medicine herb Celastrus orbiculatus against human gastric cancer

Ethnopharmacological relevanceThe traditional Chinese medicine (TCM) herb Celastrus orbiculatus is an important folk medicinal plant in China that has been used as an anti-inflammatory, antitumor, and analgesic in various diseases. The ethyl acetate extract of C. orbiculatus (C. orbiculatus extract, COE) was reported to show significant antitumor effects. However, no study in China or abroad has reported the effect and mechanism of COE in triggering apoptosis of gastric cancer (GC) cells. Aim of studyTo further uncover the molecular mechanism underlying COE's apoptotic and anti-proliferative effects and lay a foundation for the development of novel, effective antitumor TCM agents. Materials and methodsThe effect of COE on AGS and BGC-823 GC cell viability was examined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis of AGS and BGC-823 cells induced by COE was analyzed using flow cytometry and a mitochondrial membrane potential assay kit (JC-1). The proliferating GC cells were identified and examined using a 5-bromo-2ʹ-deoxyuridine (BrdU) staining kit and flow cytometric analysis. A western blot assay was used to detect the effect of COE on apoptosis-related proteins, B-cell lymphoma-2 (Bcl-2), Bcl-extra-large (Bcl-xL), Bcl-2-like protein 12 (Bcl-L12), Bcl-2-associated X protein (Bax), and caspase as well as proliferation-related proteins, phosphoinositide 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR)/p70s6k. Transmission electron microscopy (TEM) and an animal imaging technique were used to evaluate the microstructure of apoptotic GC cells and the effect of COE on tumor cell growth in vivo, respectively. ResultsThe results indicate that COE significantly inhibited proliferation and induced apoptosis of GC AGS and BGC-823 cell lines both in vivo and in vitro. COE significantly decreased the cell mitochondrial membrane potential. Moreover, COE downregulated the levels of Bcl-2, Bcl-xL, and PI3K/Akt/mTOR/p70s6k while those of Bax and caspase were upregulated. More interestingly, COE altered the microstructure of the mitochondria. ConclusionAll these data collectively indicate that COE not only has significant antiproliferative effects but also has both in vivo and in vitro apoptotic effects. In addition, COE altered the structure and function of the mitochondria, which is another potential pathway for the antitumor activity of COE. These findings may provide a basis for the development of new anticancer TCM candidates.

Current topics on cancer biology and research strategies for anti-cancer traditional Chinese medicine

Cancer, an abnormal cell proliferation resulted from multi-factors,has the highest morbidity and mortality among all the serious diseases. Considerable progress has been made in cancer biology in recent years. Tumor immunology, cancer stem cells (CSCs), autophagy, and epithelial-mesenchymal transition (EMT) have become hot topics of interests in this area. Detailed dissection of these biological processes will provide novel directions, targets, and strategies for the pharmacological evaluation, mechanism elucidation, and new drug development of traditional Chinese medicine.

Mechanism Study of Traditional Medicine Using Proteomics Alone or Integrated with Other Systems Biology Technologies.

The efficacy of traditional medicine such as traditional Chinese medicine (TCM) had been confirmed by many years of clinical use. However, the mechanisms of traditional medicine remained obscure. Since the development of systems biology in 2000, systems biology technologies have been popularly used in the mechanism study of traditional medicine. In this special issue, we particularly picked reviews and research papers related to mechanism study of TCM, TCM diagnosis, or TCM therapy methods using proteomics as well as other systems biology technologies. There are 10 papers collected in this special issue, in which 3 papers are reviews and 7 papers are original research papers. The 3 reviews in the present issue introduce the advancements in applications of proteomics technologies in the study of TCM and the achievements in the mechanism study of TCM. Q. Ji et al. summarized the applications of proteomics technologies in TCM syndrome research as well as the mechanistic study of TCM treatments, including Chinese herbal medicine, Chinese herbal formula, and acupuncture. Furthermore, they introduced the combined analyses of proteomics with other “-omics” technologies in the study of TCM. Y. A. Sulistio and K. Heese discussed the utility of comparative proteomics for a better understanding of the mechanisms involved in TCM activities and its potential application as complementary therapy for the treatment of Alzheimer's disease (AD). Additionally, they reviewed the data from comparative proteomics studies of AD patients and established the relevance of the data with available AD hypotheses and potential TCM-based treatments, most notably regarding the ubiquitin proteasome system. Y. Yang et al. focused on discussing various results of proteomics studies of mechanisms of anticancer TCM, including terpenes, flavonoids, and glycosides. And they suggested future research strategies such as integrating translating mRNA analysis with proteomics in the study of the mechanisms of anticancer TCM. Four of the research papers reported results of mechanism studies of TCM. J.-Y. Shiau et al. studied the mechanism of 2-β-D-glucopyranosyloxy-1-hydroxytrideca-5,7,9,11-tetrayne, an active component of Bidens pilosa, in human T-cell acute lymphocytic leukemia cells by using combined differential proteomics and bioinformatics approaches. M.-N. Shi et al. reported the protective effects of scutellarin, a flavone isolated from Erigeron breviscapus (Vant.) Hand.-Mazz, on human cardiac microvascular endothelial cells against hypoxia-reoxygenation injury. Possible target-related proteins of scutellarin were searched using proteomics analysis and a possible interaction network was predicted using bioinformatics analysis. C.-C. Guo et al. studied the antiosteoporotic effects and possible target-related proteins of Huangqi Sanxian decoction, a traditional Chinese formula composed of Radix astragali, Epimedii folium, Cistanche herba, Radix notoginseng, Radix Salviae Miltiorrhiae, Corydalis rhizoma, Radix Angelicae sinensis, and Radix Clematidis, in cultured rat osteoblasts. Z. Bo et al. investigated the molecular mechanism of fibroblast regulation and the treatment of recurrent oral ulcer by Shuizhongcao granule-containing serum. Shuizhongcao granule is a TCM formula composed of buffalo horn, urine sediment, callicarpa, and so forth, and it exhibited great efficacy in the clinical treatment of recurrent oral ulcer. In the present issue, there are also 3 research papers reporting about the mechanisms of TCM used for the diagnosis of diseases or specialized TCM therapy methods such as moxibustion. In the TCM system, tongue diagnosis has been an important diagnostic method. X. Liu et al. used the GC/MS technology to determine the potential changes of metabolites and identify special metabolic biomarkers in the tongue coating of H. pylori infected chronic gastritis patients. W.-T. Dang et al. studied the expression of caspase-1 gene transcript variant mRNA in peripheral blood mononuclear cells of patients with primary gout in different TCM syndromes. X.-L. Shi et al. investigated the effects of moxibustion, a traditional Chinese practice that involves heated Artemisia vulgaris (mugwort) stimulation, on hormonal imbalance and ovarian granulosa cell apoptosis in a rat model of perimenopause. In summary, this special issue provides a snapshot of the current status of mechanism studies of traditional medicine, especially TCM, using proteomics and other systems biology technologies. Authors of the present issue highlight both the achievements and challenges faced in the field of the mechanism study of traditional medicine. Hopefully, this publication will help readers to follow mechanism studies of traditional medicine and will contribute to improved applications of proteomics or other systems biology technologies in research of traditional medicine.

Proteomic Analysis of Anticancer TCMs Targeted at Mitochondria.

Traditional Chinese medicine (TCM) is a rich resource of anticancer drugs. Increasing bioactive natural compounds extracted from TCMs are known to exert significant antitumor effects, but the action mechanisms of TCMs are far from clear. Proteomics, a powerful platform to comprehensively profile drug-regulated proteins, has been widely applied to the mechanistic investigation of TCMs and the identification of drug targets. In this paper, we discuss several bioactive TCM products including terpenoids, flavonoids, and glycosides that were extensively investigated by proteomics to illustrate their antitumor mechanisms in various cancers. Interestingly, many of these natural compounds isolated from TCMs mostly exert their tumor-suppressing functions by specifically targeting mitochondria in cancer cells. These TCM components induce the loss of mitochondrial membrane potential, the release of cytochrome c, and the accumulation of ROS, initiating apoptosis cascade signaling. Proteomics provides systematic views that help to understand the molecular mechanisms of the TCM in tumor cells; it bears the inherent limitations in uncovering the drug-protein interactions, however. Subcellular fractionation may be coupled with proteomics to capture and identify target proteins in mitochondria-enriched lysates. Furthermore, translating mRNA analysis, a new technology profiling the drug-regulated genes in translatome level, may be integrated into the systematic investigation, revealing global information valuable for understanding the action mechanism of TCMs.

Ethnopharmacological and bioactivity guided investigation of five TCM anticancer herbs

Ethnopharmacological relevanceFive herbs, Curcuma longa L. (CL), Scutellaria baicalensis Georgi (SBC), Scutellaria barbata D. Don (SBB), Hedyotis diffusa Willd. (HD) and Solanum nigrum L. (SN), are often prescribed in the polyherbal formulas for cancer treatment by traditional Chinese medicine (TCM) practitioners. The purpose of the present study was to identify important anticancer herbs used in TCM and carry out bioactivity-directed fractionation and isolation (BDFI) using six cancer cell lines as well as peripheral blood mononuclear cells (PBMCs), to identify constituents with anticancer activity but devoid of toxic effects against healthy immune cells. Materials and methodsOf 243 document anticancer TCM treatments, 199 anticancer TCM herbs were ranked by the number of literature reports for each herb. Five herbs were identified from the top 50 ranked herbs by at least two out of three TCM practitioners as frequently used in the TCM treatment of cancer. BDFI using MTS assay was applied to determine the active anticancer extracts, fractions, and finally discrete compounds. ResultsFive herbs were selected for study of their anticancer activities. The extracts of Curcuma longa L., Scutellaria barbata D. Don, and Hedyotis diffusa showed antiproliferative activity to various extents, extracts of Scutellaria baicalensis Georgi and Solanum nigrum L. showed little anticancer activity. Seven out of the 21 fractions obtained from Hedyotis diffusa Willd. showed anticancer activity. One new compound, ethyl 132 (S)-hydroxy-chlorophyllide a(1), along with 10 known compounds, i.e. 2-methyl-3-methoxyanthraquinone (2), 2-hydroxymethylanthraquinone(3), 2-hydroxy-3-methylanthraquinone(4), 2-hydroxymethy-1-hydroxyanthraquinone(5), 1-methoxy-2-hydroxyanthraquinone(6), 2-hydroxy-3-methyl-1-methoxyanthraquinone (7), oleanolic acid (8), ursolic acid (9), stigmasterol (10) and docosanoic acid (11), were isolated and identified. Compounds 2–6, 8 and 9 dose-dependently inhibited the cell viability of cancer cells within a concentration range of 1–200µM. Furthermore, compounds 2, 3, 5 and 9 showed significantly stronger inhibition of tested cancer cell lines than on that of PBMCs. ConclusionThis study identified anticancer herbs, extracts, fractions and eventually compounds from the documented anticancer TCM herbs by using BDFI. It also determined the antiproliferative activity in cancer and healthy immune cells of the isolated compounds from Hedyotis diffusa. The results will be useful in the validation of the clinical application of these herbs and the development of novel anticancer therapeutics.

The Interaction of Cytotoxic Sm (III) Complex of Plumbagin with Bovine Serum Albumin

Plumbagin (PLN) is isolated from Plumbago Zeylanica, an anticancer Traditional Chinese Medicine. The interaction between cytotoxic complex [Sm (PLN)3(H2O)2]H2O and bovine serum albumin (BSA) is investigated by fluorescence, synchronous fluorescence, and UV-vis spectra. It is observed that Sm(III) complex can reduce the fluorescence intensity of BSA by the way of static quenching.

Analysis of Anti-cancer Traditional Chinese Medicine Injections based on Market Performance

Abstract Traditional Chinese medicine injections (TCMIs) have played vital roles in the treatment of cancer, cardiovascular diseases, virus and so on. This article analyzed the market of anti-cancer TCMIs in China, with special emphasis on Kang'ai Injection, Shenqi Fuzheng Injection, Aidi Injection, Lentinan Injection and Compound Kushen Injection, which presented excellent market performances. An analysis on the technical features and clinical applications of these five anti-cancer TCMIs was also conducted. Finally, we pointed out constraints and possible solutions to the development of anti-cancer TCMIs.

Synthesis, characterization, and in vitro antitumor properties of gold(III) compounds with the traditional Chinese medicine (TCM) active ingredient liriodenine

Liriodenine, an oxoaporphine alkaloid with anticancer activity isolated from Zanthoxylum nitidum (rutaceous anticancer traditional Chinese medicine), was selected as a bioactive ligand to react with HAuCl(4) and NaAuCl(4) to afford [LH][AuCl(4)] (1) and [AuCl(3)L] (2), respectively (where L is liriodenine). The structures of 1 and 2 were characterized by IR spectroscopy, electrospray ionization mass spectrometry, (1)H-NMR spectroscopy, and elemental analysis. The single-crystal X-ray diffraction analysis of 1 revealed that it is an ionic compound consisting of protonated liriodenine cation [LH](+) and [AuCl(4)](-) anion. The spectroscopic analysis showed that 2 is a coordination compound, in which one liriodenine coordinates to gold via its 7-N donor. In aqueous solution, 1 is relatively stable, but 2 undergoes rapid hydrolysis. The in vitro cytotoxicity towards five human tumor cell lines shows that 1 and 2 manifest roughly similar biological behavior and appreciable antiproliferative properties, with IC(50) values falling in the 2-16μM range. The flow-cytometric analysis of 1 and 2 suggests that both compounds induced an S-phase arrest. Compounds 1 and 2 significantly poison topoisomerase I in vitro at low concentration (25μM or less). DNA binding studies indicate that both 1 and 2 interact with DNA mainly via intercalation between the neighboring base pairs of the DNA double helix. Electrostatic interactions of 1 and 2 with the polyanionic DNA phosphate backbone may reinforce the intercalation because both 1 and 2 are composed of planar cationic species.

Synthesis, characterization and preliminary cytotoxicity evaluation of five Lanthanide(III)–Plumbagin complexes

Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone, H-PLN) was isolated from Plumbago zeylanica, the anticancer traditional Chinese medicine (TCM). Five new lanthanide(III) complexes of deprotonated plumbagin: [Y(PLN) 3(H 2O) 2] ( 1), [La(PLN) 3(H 2O) 2] ( 2), [Sm(PLN) 3(H 2O) 2]⋅H 2O ( 3), [Gd(PLN) 3(H 2O) 2] ( 4), and [Dy(PLN) 3(H 2O) 2] ( 5) were synthesized by the reaction of plumbagin with the corresponding lanthanide salts, in amounts equal to ligand/metal molar ratio of 3:1. The PLN–lanthanide(III) complexes were characterized by different physicochemical methods: elemental analyses, UV–visible, IR and 1H NMR and ESI-MS (electrospray ionization mass spectrum) as well as TGA (thermogravimetric analysis). The plumbagin and its lanthanide(III) complexes 1– 5, were tested for their in vitro cytotoxicity against BEL7404 (liver cancer) cell lines by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. The five PLN–lanthanide (III) complexes 1– 5 effectively inhibited BEL7404 cell lines growth with IC 50 values of 11.0 ± 3.5, 5.1 ± 1.3, 6.1 ± 1.1, 6.4 ± 1.3, and 9.8 ± 1.5 μM, respectively, and exhibited a significantly enhanced cytotoxicity compared to plumbagin and the corresponding lanthanide salts, suggesting a synergistic effect upon plumbagin coordination to the Ln(III) ion. The lanthanide complexes under investigation also exerted dose- and time-dependent cytotoxic activity. [La(PLN) 3(H 2O) 2] ( 2) and plumbagin interact with calf thymus DNA (ct-DNA) mainly via intercalation mode, but for [La(PLN) 3(H 2O) 2] ( 2), the electrostatic interaction should not be excluded; the binding affinity of [La(PLN) 3(H 2O) 2] ( 2) to DNA is stronger than that of free plumbagin, which may correlate with the enhanced cytotoxicity of the PLN–lanthanide(III) complexes.

Potential new inorganic antitumour agents from combining the anticancer traditional Chinese medicine (TCM) matrine with Ga(III), Au(III), Sn(IV) ions, and DNA binding studies

Three new compounds of Ga(III), Au(III), Sn(IV) with matrine (MT), [H-MT][GaCl4] (1), [H-MT][AuCl4] (2) and [Sn(H-MT)Cl5] (3), have been synthesized and characterized by elemental analysis, IR, ESI-MS and single crystal X-ray diffraction methods. The crystal structural analyses indicate that 1 and 2 are ionic compounds, whereas 3 is a tin(IV) complex formed by the monodentate MT via its carbonyl oxygen atom of MT coordinating to Sn(IV). Their in vitro cytotoxicity towards eight selected tumour cell lines has been evaluated by MTT (3-[4,5-Dimentylthiazole-2-yl]-2,5-diphenpyltetra-zolium bromide) method, and compounds 1 and 2 exhibit enhanced activity, such as 1 to SW480, 2 to HeLa, HepG2 and MCF-7, which exceeds matrine and cisplatin, and display synergistic contribution of their components. The cell cycle analyses show that compounds 1, 3 and MT exhibit cell cycle arrest at the G2/M phase. Interactions of these compounds with calf thymus DNA (ct-DNA) have been investigated by spectroscopic analyses. The planar extension of the intercalative metal–matrine compounds increases the interaction of the metal–matrine with DNA, indicating that the cationic metal ions and configuration of the intercalated metal–matrine will affect the extent of interaction. Compound 2, [H-MT][AuCl4], exhibits more intensive binding ability to DNA, which may correlate with intercalation and other action mode. The circular dichroism spectra of the ct-DNA bound with metal–MT compounds also suggest that ct-DNA interacted with 1, 2, 3 does not influence its secondary structure. Furthermore, both compounds 1 and 2 exhibit effective inhibition ability to topoisomerase (TOPO I) at concentration of 50μM, while matrine and compound 3 do not.

Cytotoxicity of the traditional chinese medicine (TCM) plumbagin in its copper chemistry

The anticancer traditional Chinese medicine (TCM), plumbagin (PLN), was isolated from Plumbago Zeylanica. Reaction of plumbagin with Cu(II) salt, afforded [Cu(PLN)(2)].2H(2)O (1). With 2,2'-bipyridine (bipy) as a co-ligand, PLN reacts with Cu(II) to give [Cu(PLN)(bipy)(H(2)O)](2)(NO(3))(2).4H(2)O (2). 1 and 2 were characterized by elemental analysis, IR, ESI-MS spectra. Their crystal structures were determined by single crystal X-ray diffraction methods. The in vitro cytotoxicity of PLN, 1 and 2 against seven human tumour cell lines was assayed. The metal-based compounds exhibit enhanced cytotoxicity vs. that of free PLN, suggesting that these compounds display synergy in the combination of metal ions with PLN. The binding properties of PLN, 1 and 2 to DNA were investigated through UV-vis, fluorescence, CD spectra, and gel mobility shift assay, which indicated that 1 and 2 were non-covalent binding and mainly intercalated the neighboring base pairs of DNA. PLN, 1 and 2 exhibit inhibition activity to topoisomerase I (TOPO I), but 1 and 2 were more effective than PLN.

Potential new inorganic antitumour agents from combining the anticancer traditional Chinese medicine (TCM) liriodenine with metal ions, and DNA binding studies

Liriodenine (), an active component of the anticancer traditional Chinese medicine (TCM), was isolated from Zanthoxylum nitidum. Its reactions with Pt(II) and Ru(II) afforded three metal complexes: cis-[PtCl2(L)] (), cis-[PtCl2(L)(DMSO)] (), and cis-[RuCl2(L)(DMSO)2].1.5H2O (), the crystal structures of , and were determined by single-crystal X-ray diffraction methods. These complexes were fully characterized by elemental analysis, IR spectrophotometry, 1H and 13C NMR spectroscopies, and ES mass spectrometry. The in vitro cytotoxicity of and complexes against 11 human tumour cell lines was assayed. The metal-based compounds exhibit enhanced cytotoxicity vs. free , suggesting that these compounds display synergy in the combination of metal ions and liriodenine. The binding properties of and its complexes to ct-DNA were investigated through UV-vis, fluorescence, CD spectra, viscosity and agarose gels electrophoretic measurements.

Divalent later transition metal complexes of the traditional chinese medicine (TCM) liriodenine: coordination chemistry, cytotoxicity and DNA binding studies

Liriodenine (L), a natural alkaloid, was isolated as an active component from the anticancer traditional Chinese medicine (TCM), Zanthoxylum nitidum. It reacted with Mn(II), Fe(II), Co(II) and Zn(II) to afford four metal complexes: [MnCl(2)(L)(2)] (1), [FeCl(2)(L)(2)] (2), [Co(L)(2)(H(2)O)(2).Co(L)(2)(CH(3)CH(2)OH)(2)](ClO(4))(4) (3), and [Zn(2)(L)(2)(mu(2)-Cl)(2)Cl(2)] (4), which were characterized by elemental analysis, IR, ESI-MS. Their crystal structures were determined by the single crystal X-ray diffraction method. The in vitro cytotoxicity of L and complexes 1-4 against 10 human tumour cell lines was assayed. Some of these metal-based compounds exhibited enhanced cytotoxicity vs. free L to selected tumour cell lines. The binding properties of L and its complexes 1-4 to ct-DNA were investigated by spectroscopic methods and viscosity measurements. Agarose gel electrophoresis experiments were also carried out to evaluate their unwinding ability towards plasmid DNA and their inhibition towards Topoisomerase I. All the results indicate that complexes 1-4 may bind more intensively to the DNA helix than does L, and intercalative binding for complexes 1-4 and electrostatic interactions for complexes 3-4 to DNA should be considered. For complex 4, covalent binding to DNA may exist. Of special note, all these metal complexes effectively inhibit Topoisomerase I even at low concentration (< or = 10 microM).