Research Progress on the Synergistic Anti-Tumor Effect of Natural Anti-Tumor Components of Chinese Herbal Medicine Combined with Chemotherapy Drugs.

The application of chemotherapy drugs in tumor treatment has a long history, but the lack of selectivity of drugs often leads to serious side effects during chemotherapy. The natural anti-tumor ingredients derived from Chinese herbal medicine are attracting increased attention due to their diverse anti-tumor effects, abundant resources, and minimal side effects. An effective anti-tumor strategy may lie in the combination of these naturally derived anti-tumor ingredients with conventional chemotherapy drugs. This approach could potentially inhibit tumor growth and the development of drug resistance in tumor cells while reducing the adverse effects of chemotherapy drugs. This review provides a comprehensive overview of the combined therapy strategies integrating natural anti-tumor components from Chinese herbal medicine with chemotherapy drugs in current research. We primarily summarize various compounds in Chinese herbal medicine exhibiting natural anti-tumor activities and the relevant mechanisms in synergistic anti-tumor combination therapy. The focus of this paper is on underlining that this integrative approach, combining natural anti-tumor components of Chinese herbal medicine with chemotherapy drugs, presents a novel cancer treatment methodology, thereby providing new insights for future oncological research.

Natural Products and Gastric Cancer: Cellular Mechanisms and Effects to Change Cancer Progression.

Gastric cancer is a severe malignant tumor with high morbidity and mortality, which seriously affects people's health. At present, the most common treatment for gastric cancer is chemotherapy. However, chemotherapy is very harmful to the human body, and some of the injuries caused by chemotherapy are irreversible. Natural products have low toxicity and anti-cancer activity, so they are currently widely studied at present. Natural products are a large variety of compounds naturally found in fruits, vegetables, spices, and medicinal plants. It is reported that natural products have different anti-cancer properties. This review has summarized the study of natural products in inducing gastric cancer cell apoptosis, inhibiting gastric cancer cell metastasis, and inhibiting gastric cancer cell proliferation. The relevant references on gastric cancer and natural products were obtained from scientific databases, including Pub- Med, Web of Science, and Science Direct. This paper records dozens of natural products with anti-gastric tumor activity and describes the potential living anti-cancer chemical compounds, their element targets, and their underlying mechanism. This review may lay the foundation for future researchers to treat gastric cancer.

Antihepatic Fibrosis Effect of Active Components Isolated from Green Asparagus (Asparagus officinalis L.) Involves the Inactivation of Hepatic Stellate Cells.

Green asparagus (Asparagus officinalis L.) is a vegetable with numerous nutritional properties. In the current study, a total of 23 compounds were isolated from green asparagus, and 9 of these compounds were obtained from this genus for the first time. Preliminary data showed that the ethyl acetate (EtOAc)-extracted fraction of green asparagus exerted a stronger inhibitory effect on the growth of t-HSC/Cl-6 cells, giving an IC50 value of 45.52 µg/mL. The biological activities of the different compounds isolated from the EtOAc-extracted fraction with respect to antihepatic fibrosis were investigated further. Four compounds, C3, C4, C10, and C12, exhibited profound inhibitory effect on the activation of t-HSC/Cl-6 cells induced by TNF-α. The activation t-HSC/Cl-6 cells, which led to the production of fibrotic matrix (TGF-ß1, activin C) and accumulation of TNF-α, was dramatically decreased by these compounds. The mechanisms by which these compounds inhibited the activation of hepatic stellate cells appeared to be associated with the inactivation of TGF-ß1/Smad signaling and c-Jun N-terminal kinases, as well as the ERK phosphorylation cascade.

Effects of Callistephus chinensis flower polyphones on improving metabolic disorders in high-fat diet-induced mice.

The aim of this study was to investigate the effects of Callistephus chinensis flower (CCF) polyphones on symptoms of metabolic syndrome in a newly developed high-fat diet-induced non-alcoholic fatty liver disease (NAFLD) mouse model. C57BL/6J mice were fed a high fat diet (HFD; 50% energy as fat) with normal drinking fluid or HFD with CCF polyphones (50 mg L(-1) or 100 mg L(-1)) in drinking fluid for 12 weeks. As a comparison, mice fed a normal-fat (NFD; 10% energy as fat) and with normal drinking fluid were also included. The HFD group developed more severe symptoms of metabolic syndrome than the NFD group. CCF polyphones treatment significantly reduced fecal lipids compared to the HFD group, suggesting a strong indication of improved lipid metabolism. Liver damage and liver triglyceride levels were also decreased by CCF polyphones treatment. Moreover, both morphologic and histological detections indicated that CCF polyphones significantly reversed HFD-induced hepatic steatosis and liver injury. Furthermore, CCF polyphones significantly ameliorated both HFD-induced metabolic disorders, such as insulin resistance, and inflammatory cytokines, including interlukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Moreover, hepatic peroxisome proliferator-activated receptor (PPARα) and the gene involved in PPARα, Peroxisomal acyl-CoA oxidase (ACOX), were markedly up-regulated at protein levels by CCF polyphones. Our results demonstrate that the HFD produces metabolic syndrome of NAFLD, and CCF polyphones treatment can alleviate these symptoms. The beneficial effects of CCF polyphones are associated with improved lipid metabolism and reduced levels of inflammatory cytokines.

Anti-tumor activity of three ginsenoside derivatives in lung cancer is associated with Wnt/ß-catenin signaling inhibition.

Numerous compounds isolated from Ginseng have been shown to exhibit various biological activities, including antioxidant, anti-carcinogenic, anti-mutagenic, and anti-tumor activities. Recent research has focused on the potential values of these compounds in the prevention and treatment of human cancers. The anti-tumor activity of 25-hydroxyprotopanaxadiol (25-OH-PPD), a natural compound isolated from Panax ginseng, has been established in previous study. In the current study, we investigated the anti-tumor activity of three derivatives of 25-OH-PPD, namely xl, 1c, and 8b with respect to lung cancer. All three compounds significantly inhibited the growth of the human lung cancer cells A549 and H460. Oral administration of these compounds significantly inhibited the growth of xenograft tumors in mice without affecting body weight. Further mechanistic study demonstrated that these compounds could decrease the expression levels of ß-catenin and its downstream targets Cyclin D1, CDK4, and c-myc in lung cancer cells. Taken together, the results suggested that the anti-growth activity exerted by these 25-OH-PPD derivatives against lung cancer cells probably involved ß-catenin-mediated signaling pathway, a finding that could have important implication for chemotherapeutic strategy aiming at the treatment of lung cancer.

New cytotoxic compounds from flowers of Lawsonia inermis L.

Three new compounds, a bicoumarin A (1), a biflavonoid A (2), and a biquinone A (3), as well as 12 other known compounds, were isolated from the flower of Lawsonia inermis L. The structures were elucidated by spectral analysis and new compounds 2 and 3 then were further confirmed by ECD calculations and single-crystal X-ray diffraction crystallography respectively. The cytotoxicity of the compounds against four cancer cell lines, including MCF-7, Hela, HCT-116, and HT-29 were evaluated using MTT assay. The IC50 values of compounds 3 and 5 against MCF-7, Hela, HCT-116, and HT-29 were 2.24, 1.42, 24.29, and 7.02 µM and 6.1, 2.44, 5.58, and 10.21 µM respectively. The two compounds exhibited stronger inhibitory activities than the positive control 5-fluorouracil (IC50=7.34, 11.50, 36.17, 18.83 µM) against the four tested cell lines. These results demonstrated that compounds from the flowers of L. inermis L. showed cytotoxic activity on MCF-7, Hela, HCT-116, and HT-29 cell lines.

Anthocyanin contributes more to hydrogen peroxide scavenging than other phenolics in apple peel.

The phenolic compounds in apple peel extracts were quantified in the presence of hydrogen peroxide (H2O2) to identify which phenolic compound contributed more to H2O2 scavenging. The results showed that the phenolics extracted from 'Golden Delicious' apple peel had a strong ability for scavenging H2O2. After incubating with H2O2 for 30 min, cyanidin-3-galactoside concentrations in the phenolic extract decreased as H2O2 concentrations increased. In contrast, the concentrations of other phenolic compounds remained unchanged. Exogenous application of H2O2 enhanced the synthesis of phenolics, especially anthocyanin, in 'Golden Delicious' apple peel under sunlight. After incubating the peel extract of H2O2-treated apples in the dark for 30 min, the concentration of cyanidin-3-galactoside significantly decreased to a greater extent than that of other phenolic compounds. Based on these data, anthocyanin is more sensitive to H2O2 and contributes more to H2O2 scavenging than other phenolic compounds.

Anti-tumor activity of three novel derivatives of ginsenoside on colorectal cancer cells.

25-Hydroxyprotopanaxadiol (25-OH-PPD) is a natural compound isolated from Panax ginseng, and its anti-tumor activity has been studied in previous publication. In the current study, we investigated the anti-tumor activity of three novel derivatives synthesized from 25-OH-PPD, namely (20R)-12ß-O-(l-chloracetyl)-dammarane-3ß, 20, 25-triol (xl), (20R)-3ß-O-(l-alanyl)-dammarane-12ß, 20, 25-triol (1c), and (20R)-3ß-O-(Boc-l-arginyl)-dammarane-12ß, 20, 25-triol (8b). All three compounds significantly inhibited the growths of human colorectal cancer cells, while having lesser effect on the growth of normal primary muscle cells and spleno-lymphocytes. Further mechanistic study demonstrated that these compounds could induce apoptosis by activating the components of caspase-signaling pathways in HCT116 cells, but not in spleno-lymphocytes. Taken together, the results suggested that 25-OH-PPD derivatives exerted promising anti-tumor activity that is specific to human colorectal cancer cells, and may therefore represent a potential chemotherapeutic strategy for the treatment of colorectal cancer.

Inhibition of ß-catenin signaling involved in the biological activities of a lignan E2S isolated from Carya cathayensis fruits.

Carya cathayensis is a fruit-bearing plant that belongs to the Juglandaceae family and is widely distributed throughout the world. It possesses various important biological activities. We have previously isolated an antitumor compound from the shell of C. cathayensis fruits and named it E2S ((E)-3-[(2S,3R)-2,3-dihydro-2-(4'-hydroxy-3'-methoxyphenyl)-3-hydroxymethyl-7-methoxy-1-benzo[b]furan-5-yl]-2-propenal). In this study, we investigated the antitumor activity of E2S against various human colorectal cancer cell lines (HCT116, HT29, SW480, LoVo). The results showed that E2S could significantly inhibit the growth of cancer cells in a dose-dependent manner, as well as disrupt the progression of the cell cycle. Mechanistic study revealed that E2S could decrease the protein levels of ß-catenin and its downstream targets (such as c-myc, a key transcriptional target of ß-catenin) in the cells. In addition, it also significantly suppressed ß-catenin/TCF transcriptional activity. Taken together, the results suggested that E2S might partially exert an antiproliferative effect on human colorectal cancer cells by targeting ß-catenin signaling, a finding that might potentially translate into a chemotherapeutic strategy for the treatment of cancer. It might also have implications for cancer prevention strategies.

Selenium and sulindac are synergistic to inhibit intestinal tumorigenesis in Apc/p21 mice.

BACKGROUND: Both selenium and non-steroidal anti-inflammatory drug (NSAID) sulindac are effective in cancer prevention, but their effects are affected by several factors including epigenetic alterations and gene expression. The current study was designed to determine the effects of the combination of selenium and sulindac on tumor inhibition and the underlying mechanisms. RESULTS: We fed the intestinal tumor model Apc/p21 mice with selenium- and sulindac-supplemented diet for 24 weeks, and found that the combination of selenium and sulindac significantly inhibited intestinal tumorigenesis, in terms of reducing tumor incidence by 52% and tumor multiplicities by 80% (p<0.01). Mechanistic studies revealed that the combination of selenium and sulindac led to the significant induction of the expression of p27 and p53 and JNK1 phosphorylation, and led to the suppression of ß-catenin and its downstream targets. Impressively, the data also showed that demythelation on p21 promoter was associated with tumor inhibition by the combination of selenium and sulindac. CONCLUSIONS: The selenium is synergistic with sulindac to exert maximal effects on tumor inhibition. This finding provides an important chemopreventive strategy using combination of anti-cancer agents, which has a great impact on cancer prevention and has a promising translational potential.

Flavonoids and its derivatives from Callistephus chinensis flowers and their inhibitory activities against alpha-glucosidase.

Inhibitors of carbohydrate-hydrolysing enzymes play an important role for the treatment of diabetes. One of the therapeutic methods for decreasing of postprandial hyperglycemia is to retard absorption of glucose by the inhibition of carbohydrate- hydrolysing enzymes, such as α-glucosidase, in the digestive organs. To investigate the therapeutic potential of compounds from natural sources, Callistephus chinensis flowers (CCF) were tested for inhibition of α-glucosidase, and acarboes was used as the positive control. The 70 % ethanol extract of CCF exhibited significant α-glucosidase inhibitory activities with IC50 value of 8.14 µg/ml. The stepwise polarity fractions of CCF were tested further for in vitro inhibition of α-glucosidase. The ethyl acetate (EtOAc) fraction exhibited the most significant inhibitory activity. Eight pure compounds, apigenin, apigenin-7-O-ß-D- glucoside, kaempferol, hyperin, naringenin, quercetin, luteolin, and kaempferol-7-O-ß-D- glucoside, were isolated (using enzyme assay-guide fractionation method) from the EtOAc fraction. Among these, quercetin was the most active one (IC50 values 2.04 µg/ml), and it appears that the inhibiting percentages are close to acarbose (IC50 values 2.24 µg/ml), the positive control, on α-glucosidase inhibition. HPLC/UV analysis indicated that the major components of CCF are kaempferol, hyperin and quercetin. The presented results revealed that CCF containing these eight flavonoids could be a useful natural source in the development of a novel α-glucosidase inhibitory agent against diabetic complications.

Structures of new triterpenoids and cytotoxicity activities of the isolated major compounds from the fruit of Momordica charantia L.

Two new cucurbitane-type triterpene glycosides, charantagenins D (1) and E (2), and one new sterol, 7-oxo-stigmasta-5,25-diene-3-O-ß-d-glucopyranoside (3), were isolated from the fruit of Momordica charantia L. together with another eight known compounds. Their structures were determined on the basis of spectral analysis. Cytotoxicity activities of the isolated major compounds were evaluated against lung cancer cell line A549, glioblastoma cell line U87, and hepatoma carcinoma cell line Hep3B by using a 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) in vitro assay. Results showed compounds 1 and 7 (goyaglycoside d) with an -OMe substituent group in the side chain exhibited significant cytotoxic activities against cancer cells. Impressively, the IC(50) values of the new compound 1 to A549, U87, and Hep3B were 1.07, 1.08, and 14.01 µmol/L, respectively, which were much lower than those of other tested compounds.

New antitumor compounds from Carya cathayensis.

A new lignan (7R,8S,8'R)-4,4',9-trihydroxy-7,9'-epoxy-8,8'-lignan, and three new phenolics, carayensin-A, carayensin-B, and carayensin-C, together with 13 known compounds were isolated from the shells of Carya cathayensis. Their chemical structures were established mainly by 1D and 2D NMR techniques and mass spectrometry. All the compounds were evaluated for cytotoxicity against several human tumor types including human colorectal cancer cell lines (HCT-116, HT-29), human lung cancer cell line (A549), and human breast cancer cell line (MCF-7). The compounds 1, 5, 6, and 16 are considered to be potential as antitumor agents, which could significantly inhibit the cancer cell growth in a dose-dependent manner.

Functional and physical interaction between the selenium-binding protein 1 (SBP1) and the glutathione peroxidase 1 selenoprotein.

Selenium-binding protein (SBP) 1 is present in reduced levels in several cancer types as compared with normal tissues, and lower levels are associated with poor clinical prognosis. Another selenium-containing protein, glutathione peroxidase 1 (GPX1), has been associated with cancer risk and development. The interaction between these representatives of different classes of selenoproteins was investigated. Increasing SBP1 levels in either human colorectal or breast cancer cells by transfection of an expression construct resulted in the reduction of GPX1 enzyme activity. Increased expression of GPX1 in the same cell types resulted in the transcriptional and translational repression of SBP1, as evidenced by the reduction of SBP1 messenger RNA and protein and the inhibition of transcription measured using an SBP1 reporter construct. The opposing effects of SBP1 and GPX1 on each other were also observed when GPX1 was increased by supplementing the media of these tissue culture cells with selenium, and the effect of selenium on SBP1 was shown to be GPX1 dependent. Decreasing or increasing GPX1 levels in colonic epithelial cells of mice fed a selenium-deficient, -adequate or -supplemented diet resulted in the opposing effect on SBP1 levels. These data are explained in part by the demonstration that SBP1 and GPX1 form a physical association, as determined by coimmunoprecipitation and fluorescence resonance energy transfer assay. The results presented establish an interaction between two distinct selenium-containing proteins that may enhance the understanding of the mechanisms by which selenium and selenoproteins affect carcinogenesis in humans.

Anticancer activity of Panax notoginseng extract 20(S)-25-OCH3-PPD: Targetting beta-catenin signalling.

1. The Wnt/beta-catenin pathway plays a critical role in carcinogenesis and so agents that target Wnt/beta-catenin may have potential in cancer prevention and therapy. The aim of the present study was to evaluate the anticancer activity of the novel natural product dammarane-type triterpene sapogenin (20(S)-25-OCH3-PPD; PPD25) isolated from the leaves of Panax notoginseng. 2. The anticancer activity of PPD25 was evaluated in three colon cancer cell lines and in one lung cancer cell line. The effects of PPD25 to inhibit proliferation and to induce apoptosis were evaluated. In addition, the potential mechanisms underlying the effects of PPD25 were investigated. 3. It was found that the addition of 5 or 25 micromol/L PPD25 to the culture medium significantly inhibited cell proliferation and induced apoptosis in all four cancer cell lines. Mechanistic studies revealed that PPD25 significantly reduced the expression of beta-catenin, a key mediator in the Wnt pathway, as well as transcriptional targets of beta-catenin, namely c-myc, cyclin D1, cdk4 and T cell factor (TCF)-4. In addition, beta-catenin/TCF transcriptional activity was significantly suppressed by PPD25. 4. The data demonstrate that the PPD25 exerts its anticancer effect by targetting beta-catenin signalling, suggesting that PPD25 may have potential as a chemotherapeutic and/or chemopreventive agent for colon and lung cancer.