Anti-tumor Promoters Research Articles

Evaluation of Flavoglaucin, Its Derivatives and Pyranonigrins Produced by Molds Used in Fermented Foods for Inhibiting Tumor Promotion

Flavoglaucin, its derivatives, and pyranonigrins, which are antioxidants produced by the molds used in fermented foods, were examined for their inhibition of tumor promotion by the Epstein-Barr virus early antigen activation test. Flavoglaucin and its derivatives exhibited high activity. Flavoglaucin and such a derivative as isodihydroauroglaucin inhibited mouse skin tumor promotion in a two-stage carcinogenesis test and appear to be antitumor promoters.

Cancer preventive agents 10. Prenylated dehydrozingerone analogs as potent chemopreventive agents

Dehydrozingerone analogs and related compounds were screened as potential antitumor promoters by using the in vitro short-term 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced Epstein–Barr virus early antigen activation assay. Among the 40 synthesized compounds, the prenylated analogs 16 and 34–36 showed the most significant and promising activity (100% inhibition of activation at 1 × 103 mol ratio/TPA, and 82–80%, 37–35%, and 13–11% inhibition at 5 × 102, 1 × 102, and 1 × 10 mol ratio/TPA, respectively) in this screening. Their activity profiles were comparable to those of the reference standard curcumin. While a prenyl moiety conferred potent chemopreventive activity, an extended prenyl unit such as a farnesyl moiety did not improve activity. Because in vitro inhibitory effects in this assay generally correlate well with in vivo inhibitory effects on tumor promotion, our results strongly suggested that prenylated 16 and 34–36 are likely to be promising antitumor promoters.

New Lobane and Cembrane Diterpenes from Two Comorian Soft Corals

Preliminary biological investigation of a collection of Comorian soft corals resulted in the selection of two specimens, one of Sarcophyton and the other of Lobophytum, on the basis of their toxicity on larvae of the brine shrimp (Artemia salina) and inhibition of acetylcholinesterase, respectively. Bioassay-guided fractionations provided a known antitumor promoter cembrane diterpenoid, (+)-sarcophytol-A (1), along with a new lobane diterpenoid, carbomethoxyfuscol (2), from Sarcophyton sp., and a new cembranoid, crassumolide E (3), from Lobophytum sp. The structures of compounds 1–3 were determined by spectroscopic analysis and by comparison of the spectral data with previously reported values. The cembranoid 3 was found to exhibit a moderate inhibitory effect on acetylcholinesterase.

Short Regioselective Chemoenzymatic Synthesis and Biological Evaluation of 1‐O‐Acyl‐2‐O‐(β‐D‐sulfoquinovopyranosyl)‐sn‐glycerols

AbstractA convenient chemoenzymatic synthesis of a new class of non‐natural sulfo‐glycolipids – 2‐O‐(β‐D‐sulfoquinovosyl)‐monoacylglycerols (2‐O‐β‐D‐SQMG) – derived from 2‐O‐(β‐D‐glucopyranosyl)glycerol and carrying acyl chains ofvarious lengths at the 1‐position of the sn‐glycerol moiety, was performed with the aid of a key step involving regioselective lipase‐catalyzed acylation of 2‐O‐(6‐deoxy‐6‐tosyl‐β‐D‐glucopyranosyl)‐sn‐glycerol (4) at its 1‐position, reported here for the first time. Elaboration of the sugar moiety through thioacetate substitution of the selectively inserted tosyl group with subsequent Oxone® oxidation in the presence of unprotected primary and secondary hydroxy groups efficiently afforded the target compounds, the hexanoyl, dodecanoyl, and octadecanoyl derivatives 1a–c, which were active when tested in the EBV‐EA in vitro assay for antitumor promoters. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

A Simple Analogue of Tumor-Promoting Aplysiatoxin Is an Antineoplastic Agent Rather Than a Tumor Promoter: Development of a Synthetically Accessible Protein Kinase C Activator with Bryostatin-like Activity

Protein kinase C (PKC) is widely recognized as a therapeutic target in intractable diseases such as cancer, Alzheimer's disease (AD), and acquired immune deficiency syndrome (AIDS). While inhibition of PKC is a general therapeutic strategy for the treatment of cancer, PKC activators are potential therapeutic agents for AD and AIDS. However, concerns have been raised about their therapeutic use since PKC activators such as phorbol esters exhibit potent tumor-promoting activities. Naturally occurring bryostatin 1 (bryo-1), prostratin, and 12-deoxyphorbol 13-phenylacetate (DPP) are fascinating PKC activators without tumor-promoting activities. Bryo-1 is currently in clinical trials for the treatment of cancer and is also effective against AD. Prostratin and DPP are attractive candidates for the adjunctive treatment of human immunodeficiency virus (HIV) infection. However, their limited availability from natural sources and synthetic complexity have hampered further development as therapeutic agents. We report here easy access (22 steps) to a simple analogue (1) of the tumor-promoting aplysiatoxin (ATX) as a novel PKC activator with anticancer and anti-tumor-promoting activities. Anticancer activities of 1 against several human cancer cell lines were comparable to those of bryo-1. Moreover, 1 as well as bryo-1 significantly inhibited the Epstein-Barr virus early antigen (EBV-EA) induction by the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA), whereas ATX strongly induced EBV-EA. This inhibitory effect is characteristic of antitumor promoters. Compound 1 as well as bryo-1 displayed significant binding and activation of PKCdelta and induced its translocation to the nuclear membrane in CHO-K1 cells. This study provides a synthetically accessible PKC activator with bryo-1-like activities, which could be another therapeutic lead for cancer, AD, and AIDS.

ChemInform Abstract: Lanostane‐Type Triterpenoids from the Sclerotia of Inonotus obliquus Possessing Antitumor Promoting Activity.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Anti-tumor promoters phenolics and triterpenoid from Hippophae rhamnoides

A 70% ethanol extract of the branches of Hippophae rhamnoides exhibited remarkable antitumor activity in an in vivo two-stage carcinogenesis test in mice using 7,12-dimethylbenz[a]anthracene as an initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as a promoter. From the active fraction of the 70% ethanol extract, three phenolic compounds, (+)-catechin (1), (+)-gallocatechin (2), and (-)-epigallocatechin (3) and a tritepenoid, ursolic acid (4) were isolated and identified. These compounds were evaluated for their inhibitory effects on TPA-induced inflammation (1 microg/ear) in mice. Within the tested compounds, 3 and 4 showed marked anti-inflammatory effects, with a 50% inhibitory dose of 1.7 and 0.2 mumol/ear.

N-Butanolic fraction of endofitic fungi of Buah Makasar increases apoptotic effect of doxorubicin on MCF-7 cells

Makassar fruit, Brucea javanica (L.) Merr., showed chemopreventive activity. Secondary metabolites come from B. javanica fruit, brucatol and bruceantine, induced cell differentiation and apoptosis on Leukemia cell, while quassinoid and its derivates acted as antitumor promoter. Butanolic fraction of supernatan of endofitic fungi 1.2.11 isolate fermentation which isolated from B. javanica fruit showed cytotoxycity toward several cancer cells. This fraction has been predicted contain secondary metabolites from B. javanica and has been identified as Bruceosin and Canthin-6-one derivates. Butanolic fraction (FB) of supernatan from endofitic fungi 1.3.11 isolate fermentation is predicted for having similiar cytotoxycity as active as 1.2.11 isolate. This research is aimed to explore cytotoxycity potention and apoptosis induction of BF from 1.3.11 isolate and combination effect of BFdoxorubicin on MCF-7 breast cancer cell. Synergism of BF-doxorubicin combination detect from cell viability inhibition and apoptosis induction on MCF-7, a breast cancer cell lines which shows resistancy toward doxorubicin. Cell viability on single treatment of FB and doxorubicin and its combination were carried out by MTT assay to determine IC50 and combination index (CI). Apoptosis induction of FB, doxorubicin and its combination were carried out by ethidium bromideacridine orange DNA staining. n- Butanolic fraction and doxorubicin showed cell viability inhibition on MCF-7 cell with IC50 48 μg/mL dan 148 nM, respectively. Both of FB and doxorubicin showed apoptosis induction on IC50. Combination of FBdoxorubicin showed synergism and increased apoptosis induction on MCF-7 cell. Key words: Brucea javanica, endofitic fungi, MCF-7 cell, synergism, doxorubicin.

ANTHOCYANIN AND POTENTIAL THERAPEUTIC TRAITS IN CLITORIA, DESMODIUM, CORCHORUS, CATHARANTHUS AND HIBISCUS SPECIES

The USDA, ARS, Plant Genetic Resources Conservation Unit curates several important nutraceutical and medicinal plant species. Anthocyanins are responsible for flower, leaf and seed coat color in plants, and are antioxidants as well. However, little is known about anthocyanin content in Clitoria ternatea, Desmodium adscendens, Corchorus olitorius, Catharanthus roseus, Hibiscus sabdariffa and Acer saccharum. This study was conducted to identify anthocyanin indexes and additional health enhancing components in these species. An anthocyanin meter with an LED diode of 520 nm was used to measure the anthocyanin index of leaves and flowers from plants growing in the field during July, September and October 2006. We found anthocyanin indexes ranging from 4.1 to 52.4 for leaves and 0.8 to 26.8 for flowers in all five species. The highest leaf anthocyanin index average of 14.6 was found in D. adscendens (PI 316623) followed by sugar maple (A. saccharum) with a leaf anthocyanin average index of 13.0. Catharanthus roseus (PI 608581) also had the highest flower anthocyanin index average of 17.3. These data were recorded at or prior to 50% maturity. In addition, potential health uses for these species are discussed. Phytochemicals identified include but are not limited to an antimicrobial protein from C. ternatea, anthocyanin rich extracts from H. sabdariffa for potential use as a chemopreventive agent, and antitumor promoters in C. olitorius leaves. These anthocyanins and phytochemicals have potential value in the nutraceutical and medical industries. These variable anthocyanin indexes among these species will assist breeders and other scientists with valuable germplasm for development of anthocyanin enriched cultivars.

차 폴리페놀화합물의 사이토카인 생성 및 항암능에 대한 영향

국산 미생물 발효차의 폴리페놀 색소성분들인 데아플라빈(TF)과 데아루비긴(TR) 및 EGCG를 macrophage cell line (RAW264.7에 적용하여 nitric oxide 합성 및 사이토카인 생성을 평가하였다. 사이토카인 생성은 TF, TR 및 EGCG를 RAW264.5 cell에 적용하였을 때, <TEX>$80\;{\mu}g/ml$</TEX> 농도에서 대조군과 LPS 촉진 처리에 비하여 nitric oxide 생성은 약 1.5배 증가하였다. IL-6, <TEX>$TNF-{\alpha}$</TEX> 및 GM-CSF는 TF, TR 및 EGCG 농도에 의존적으로 증가하였다. <TEX>$TNF-{\alpha}$</TEX> 생성은 크게 증가하였으며, 이는 TF, TR 및 EGCG가 사이토카인 생성을 통하여 면역증강 효과를 가질 것으로 나타났다 TF, TR 및 EGCG는 총 페놀 함량에 비례하여 항산화능을 나타내었으며, 암세포 증식을 유의적으로 억제하였다. 이들 폴리페놀물질의 억제효과는 그 성분들의 항암촉진작용 및 항산화활성에 의한 것으로 판단된다. Theaflavins (TF) and thearubigins (TR) are constituents of tea pigments which are polyphenols derived from Korean fermentation tea. After TF, TR and [(-) epigallocatechin-3-gallate](EGCG) have been applied to macrophage cell line (RAW264.7) nitric oxide (NO) synthesis and cytokines production were estimated. Cytokines production by enzyme linked immune-sorbent assay (ELISA) determined. NO production was increased by about 1.5-folds at the dose of <TEX>$80\;{\mu}g/ml$</TEX> compared to control and lipopolysaccharide (LPS) stimulation when TF, TR and EGCG were applied to a RAW264.7 cell. Interleukin-6 (IL-6), Tumor necrosis factor (<TEX>$TNF-{\alpha}$</TEX>) and granulocyte-macrophage colony stimulating factor (GM-CSF) increased depended on concentrations of TF, TR and EGCG. The production of tumor necrosis <TEX>$factor-{\alpha}$</TEX> increased highly in TR, TF and EGCG group with LPS. These results suggest that TF, TR and EGCG have immune-enhancement effect through the cytokine production. TF, TR and EGCG inhibited cancer cell viability, the anticancer effect of these polyphenols may explain the anti-tumor promotion action and antioxidant activity of these tea constituents.

저산소유도인자 HIF-1, 암 억제인자 P53과 고아 핵수용체 Nur77의 발현을 지표로 하는 발암독성예측 세포주의 개발

Evaluation of potentials of chemicals to alter expression of genes that are involved in carcinogenesis may serve useful tools in toxicological research. In this investigation, we developed reporter cell lines that expressed luciferase in response to transactivation of hypoxia inducible factor-1, P53 tumor suppressor and Nur77 of which roles have been well established in cancer development and progression. Whereas these reporter cell lines displayed low constitutive backgrounds, the reporter activities were significantly enhanced in response to desferriosamine/CoCl₂, adriamycin or 6-mercaptopurine, which are hypoxia mimicking chemicals, P53 activator or Nur77 inducer, respectively. The activation of the reporter was time- and dose-dependent. Known tumor initiators and promoters, such as phorbol 12-myristate 13-acetate and phorbol 12,13-dicaprinate induced the reporter activity at as low as 10 nM in these stable cell lines. Further, known anti-tumor promoters, such as ascorbic acid and β-carotene repressed the reporter activities. These results indicate that our stable reporter cell lines could serve as a useful system for rapid assessment of carcinogenicity of toxic chemicals.

Cancer Chemopreventive Effects of Cycloartane-Type and Related Triterpenoids in in Vitro and in Vivo Models

Forty-eight natural and semisynthetic cycloartane-type and related triterpenoids have been evaluated for their inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells as a primary screening test for anti-tumor promoters. In addition, these triterpenoids have been tested for their inhibitory effects on activation of (+/-)-(E)-methtyl-2-[(E)-hydroxyimino]-5-nitro-6-methoxy-3-hexemide (NOR 1), a nitric oxide (NO) donor, as a primary screening test for anti-tumor initiators. All of the compounds tested exhibited inhibitory effects on both EBV-EA and NOR 1 activation. Six of these compounds having a C-24 hydroxylated side chain, viz., (24R)-cycloart-25-ene-3beta,24-diol (9), (24R)-cycloartane-3beta,24,25-triol (11), (24S)-cycloartane-3beta,24,25-triol (12), (24xi)-24-methylcycloartane-3beta,24,241-triol (14), (24xi)-241-methoxy-24-methylcycloartane-3beta,24-diol (15), and (24xi)-24,25-dihydroxycycloartan-3-one (27), showed higher inhibitory effects than the others tested on both EBV-EA (IC50 values of 6.1-7.4 nM) and NOR 1 activation. Furthermore, compounds 14 and 15 exhibited inhibitory effects on skin tumor promotion in an in vivo two-stage mouse skin carcinogenesis test using 7,12-dimethylbenz[a]anthracene (DMBA) as an initiator and TPA as a promoter.

Effects of polyphenols derived from fruit of Crataegus pinnatifida on cell transformation, dermal edema and skin tumor formation by phorbol ester application

The dried fruits of Crataegus pinnatifida have been used traditionally as oriental medicine and local soft drink material recently. Previously, we demonstrated that C. pinnatifida exhibited anti-oxidation and anti-inflammatory potential. To clarify the active components in anti-transformation and anti-tumor promotion, we collected the polyphenol fraction (CF-TP) of hot-water extracts from dried fruits of C. pinnatifida for the following study. By anchorage-independent transformation assay, CF-TP significantly inhibited 12- O-tetradecanoylphorbol-13-acetate (TPA)-induced cell transformation in JB6 P + cells. Moreover, we found that CF-TP inhibited the expression of osteopontin (OPN), a transformational marker, and the activation of NF-κB and AP-1 induced by TPA in JB6 P + cells. In addition, we evaluated the effect of CF-TP on TPA application to ICR mouse skin with measurement of H 2O 2 production, myeloperoxidase (MPO) activity, edema formation, epidermal thickness and leukocyte infiltration. As a result, CF-TP significantly inhibited the generation of reactive oxygen species (ROS) and the phenomena of inflammation induced by TPA. It also suppressed the expression of COX-2 and iNOS, and the activation of ornithine decarboxylase (ODC). Furthermore, CF-TP inhibited benzo[ a]pyrene (B[ a]P)/TPA-induced skin tumor formation and decreased the incidence of tumor. These results indicate that CF-TP possesses potential as a cancer chemopreventive agent against tumor promotion.

Anti‐Inflammatory and Anti‐Tumor‐Promoting Effects of Triterpene Acids and Sterols from the Fungus Ganoderma lucidum

A series of lanostane-type triterpene acids, including eleven lucidenic acids (3, 4, 9, 10, 13-19) and six ganoderic acids (20-22, 24, 26, 27), as well as six sterols (28-33), all isolated from the fruiting bodies of the fungus Ganoderma lucidum, were examined for their inhibitory effects on the induction of Epstein-Barr virus early antigen (EBV-EA) by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells, a known primary screening test for anti-tumor promoters. All of the compounds tested, except for ganolactone (27) and three sterols (29-31), showed potent inhibitory effects on EBV-EA induction, with IC(50) values of 235-370 mol ratio/32 pmol TPA. In addition, nine lucidenic acids (1, 2, 5-8, 11, 12, 18) and four ganoderic acids (20, 23-25) were found to inhibit TPA-induced inflammation (1 microg/ear) in mice, with ID(50) values of 0.07-0.39 mg per ear. Further, 20-hydroxylucidenic acid N (18) exhibited inhibitory effects on skin-tumor promotion in an in vivo two-stage mouse-skin carcinogenesis test based on 7,12-dimethylbenz[a]anthracene (DMBA) as initiator, and with TPA as promoter.

Synthetic cinnamylphenol derivatives as cancer chemopreventive agents

Several substituted cinnamylphenol (1,3-diphenylpropene) derivatives were synthesized and tested for their inhibitory activities against in vitro Epstein-Barr virus early antigen activation induced by 12- O-tetradecanoylphorbol-13-acetate in Raji cells. The prenylated cinnamylphenols were found to show remarkably potent activity. Furthermore, prenylated cinnamylphenols ( 19 and 25) exhibited a marked inhibitory effect on mouse skin tumor promotion in an in vivo two-stage carcinogenesis test. These results indicate that some prenylated cinnamylphenols might be valuable as potential cancer chemopreventive agents (anti-tumor promoters).

Cancer Preventive Agents. 7. Antitumor-Promoting Effects of Seven Active Flavonolignans from Milk Thistle (Silybum marianum.) on Epstein-Barr Virus Activation

Seven pure flavonolignans were isolated from an extract of milk thistle [Silybum marianum.(L.) Gaertn (Asteraceae)], by semipreparative reverse-phase HPLC, and identified based on spectroscopic and LC-MS/IT-TOF data. All seven compounds were screened as potential antitumor-promoting agents by using the in vitro. short-term 12-O.-tetradecanoylphorbol-13-acetate (TPA)-induced Epstein-Barr virus early antigen (EBV-EA) activation assay in Raji cells. They showed good inhibitory activity (87.7–94.9%) at 1000 mol ratio/TPA. Silychristin A (1) and silychristin B (2) were slightly more potent than the well-known antitumor promoter β.-carotene. Silychristins A (1) and B (2) and isosilybins A (6) and B (7) were more active than the clinically proven cancer prevention components silybins A (4) and B (5).

Final Report on the Safety Assessment of Capsicum Annuum Extract, Capsicum Annuum Fruit Extract, Capsicum Annuum Resin, Capsicum Annuum Fruit Powder, Capsicum Frutescens Fruit, Capsicum Frutescens Fruit Extract, Capsicum Frutescens Resin, and Capsaicin1

Final Report on the Safety Assessment of Capsicum Annuum Extract, Capsicum Annuum Fruit Extract, Capsicum Annuum Resin, Capsicum Annuum Fruit Powder, Capsicum Frutescens Fruit, Capsicum Frutescens Fruit Extract, Capsicum Frutescens Resin, and Capsaicin1

Porritoxins, metabolites of Alternaria porri, as anti-tumor-promoting active compounds

To search for possible cancer chemopreventive agents from natural sources, we performed primary screening of metabolites of Alternaria porri by examining their possible inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. The ethyl acetate extract of A. porri showed the inhibitory effect on EBV-EA activation. Three porritoxins (1–3) were obtained as inhibitory active compounds for EBV-EA from ethyl acetate extract. 6-(3′,3′-Dimethylallyloxy)-4-methoxy-5-methylphthalide (2) showed the strongest activity among them. Inhibitory effect of porritoxin (1) and (2) was superior to that of β-carotene, a well-known anti-tumor promoter. Furthermore, the structure–activity correlation of porritoxins and their related compounds were discussed.

Cancer Preventive Agents. Part 6: Chemopreventive Potential of Furanocoumarins and Related Compounds

Twenty-one furanocoumarins and related compounds were synthesized and screened as potential antitumor promoters by using the in vitro. short-term 12-O.-tetradecanoylphorbol-13-acetate (TPA)-induced Epstein-Barr virus early antigen (EBV-EA) activation assay. Compounds 3a and 5a showed the greatest potency (96% inhibition at 1000 mol ratio/TPA). Consequently, they were further tested in an in vivo. two-stage mouse skin carcinogenesis assay. Compounds 3a and 5a were slightly more potent than curcumin, a well-known antitumor promoter. These data suggested that furanocoumarins might be valuable antitumor promoters or chemopreventors.

The role of stem cells and gap junctions as targets for cancer chemoprevention and chemotherapy

Since carcinogenesis is a multi-stage, multi-mechanism process, involving mutagenic, cell death and epigenetic mechanisms, during the “initiation/promotion/and progression” phases, chemoprevention must be based on understanding the mechanism(s) of each phase. Prevention of each phase could reduce the risk to cancer. Because reducing the initiation phase to a zero level is impossible, the most effective intervention would be at the promotion phase. Assuming the “target” cells for carcinogenesis are the pluri-potent stem cells and their early progenitor or transit cells, chemoprevention strategies for inhibiting the promotion of these two types of pre-malignant “initiated” cells will require different agents. A hypothesis will be proposed that involves stem cells, which lack gap junctional intercellular communication (GJIC-) or their early progenitor daughter cells, which express GJIC+ and are partially-differentiated, if initiated, will be promoted by agents that either inhibit secreted negative growth regulators or by inhibitors of GJIC. Chemopreventing agents to each of these two types of initiated cells must have different mechanisms of action. Assuming stem cells are target cells for carcinogenesis, an alternative method of chemoprevention would be to reduce the stem cell pool. Anti-tumor promoter chemopreventive agents, such as green tea components, resveratrol, caffeic acid phenethylene ester, that either up-regulate GJIC in stem cells or prevent the down regulation of GJIC by tumor promoters in early progenitor cells, will be provided. Human pluri-potent stem cell systems, that can be induced to form 3-dimensional “organoid” structures, will be discussed as a more realistic model system to screen for relevant chemopreventive agents.