6‐Acetoxy Cyperene,a Patchoulane‐type Sesquiterpene Isolated from Cyperus rotundus Rhizomes Induces Caspase‐dependent Apoptosis in Human Ovarian Cancer Cells

Cyperus rotundus (Cyperaceae) has been widely used in traditional medicine for the treatment of various diseases, including cancer. Although an anti‐tumour effect has been suggested for C. rotundus, the anti‐tumour effects and underlying molecular mechanisms of its bioactive compounds are poorly understood. The n‐hexane fraction of an ethanol extract of C. rotundus rhizomes was found to inhibit cell growth in ovarian cancer (A2780, SKOV3 and OVCAR3) and endometrial cancer (Hec1A and Ishikawa) cells. Among the thirteen sesquiterpenes isolated from the n‐hexane fraction, some patchoulane‐type compounds, but not eudesmane‐type compounds, showed moderate cytotoxic activity in human ovarian cancer cells. In particular, the patchoulane sesquiterpene 6‐acetoxy cyperene had the most potent cytotoxicity. In this regard, propidium iodide/Annexin V staining and terminal deoxynucleotidyl transferase dUTP (deoxynucleotide triphosphate) nick end labeling assay were performed to study cell cycle progression and apoptosis. 6‐acetoxy cyperene induced apoptosis, as shown by the accumulation of sub‐G1 and apoptotic cells. Furthermore, treatment with 6‐acetoxy cyperene stimulated the activation of caspase‐3, caspase‐8 and caspase‐9 and poly(ADP‐ribose)polymerase in a dose‐dependent manner. Pretreatment with caspase inhibitors neutralized the pro‐apoptotic activity of 6‐acetoxy cyperene. Taken together, these data suggest that 6‐acetoxy cyperene, a patchoulane‐type sesquiterpene isolated from C. rotundus rhizomes, is an anti‐tumour compound that causes caspase‐dependent apoptosis in ovarian cancer cells. Copyright © 2015 John Wiley & Sons, Ltd.     

Cranberry proanthocyanidins are cytotoxic to human cancer cells and sensitize platinum‐resistant ovarian cancer cells to paraplatin

Polyphenolic extracts of the principal flavonoid classes present in cranberry were screened in vitro for cytotoxicity against solid tumor cells lines, identifying two fractions composed principally of proanthocyanidins (PACs) with potential anticancer activity. Matrix‐Assisted Laser Desorption/Ionization Time‐Of‐Flight Mass Spectrometry (MALDI‐TOF‐MS) analysis of the proanthocyanidins (PACs) fractions indicated the presence of A‐type PACs with 1–4 linkages containing between 2–8 epicatechin units with a maximum of 1 epigallocatechin unit. PACs exhibited in vitro cytotoxicity against platinum‐resistant human ovarian, neuroblastoma and prostate cancer cell lines (IC₅₀ = 79–479 µg/mL) but were non‐cytotoxic to lung fibroblast cells (IC₅₀ > 1000 µg/ml). SKOV‐3 ovarian cancer cells treated with PACs exhibited classic apoptotic changes. PACs acted synergistically with paraplatin in SKOV‐3 cells. Pretreatment of SKOV‐3 cells with PACs (106 µg/ml) resulted in a significant reduction of the paraplatin IC₅₀ value. Similarly, in a BrdU incorporation assay, co‐treatment of SKOV‐3 cells with PACs and paraplatin revealed reduced cell proliferation at lower concentrations than with either individually. In SKOV‐3 cell cultures co‐treated with PAC‐1 and paraplatin, an HPLC analysis indicated differential quantitative presence of various PAC oligomers such as DP‐8, ‐9, ‐11 and ‐14 indicating either selective binding or uptake. Cranberry proanthocyanidins exhibit cell‐line specific cytotoxicity, induce apoptotic markers and augment cytotoxicity of paraplatin in platinum‐resistant SKOV‐3 ovarian cancer cells. Copyright © 2009 John Wiley & Sons, Ltd.     

Antiviral and anticancer activities of 13(E)‐labd‐13‐ene‐8α,15‐diol isolated from Brachyglottis monroi

The antiviral activity of 13(E)‐labd‐13‐ene‐8α,15‐diol (1), isolated from Brachyglottis monroi, was examined against human rhinovirus 2 (HRV2) and 3 (HRV3), and the anticancer activity on human cancer cells (A549 and Hep2). Compound (1) showed strong anti‐HRV2 and HRV3 activity with a 50% inhibitory concentration (IC₅₀) of 2.68 and 0.87 µg/mL, respectively, and a 50% cytotoxicity concentration (CC₅₀) of 59.45 µg/mL. Ribavirin only showed anti‐HRV3 activity with an IC₅₀ of 30.48 µg/mL and a CC₅₀ > 100 µg/mL. The addition of compound (1) to HRV‐infected HeLa cells directly reduced the formation of visible cytopathic effect (CPE) and it directly interacted with HRV particles. Furthermore, A549 and Hep2 cells incubated with 32 µg/mL of compound (1) for 48 h exhibited antilung and antilaryngeal cancer activities, with a viability of less than 50%. These results suggest that compound (1) may be used as a potential antiviral and anticancer agent. Copyright © 2009 John Wiley & Sons, Ltd.     

Apoptotic Effect of Sanggenol L via Caspase Activation and Inhibition of NF‐κB Signaling in Ovarian Cancer Cells

In the present study, the underlying apoptotic mechanism of sanggenol L was elucidated in ovarian cancer cells. Sanggenol L showed cytotoxic and antiproliferative effect in A2780, SKOV‐3, and OVCAR‐3 ovarian cancer cells in a concentration‐dependent fashion. Consistently, sanggenol L increased sub‐G1 phase population and early and late apoptotic portion in ovarian cancer cells. Also, sanggenol L activated caspase9/3, suppressed the phosphorylation of IκBα and p65 NF‐κB (nuclear factor kappa‐light‐chain‐enhancer of activated B cells), attenuated the expression of Cyclin D1, and cleaved poly(adenosine diphosphate ribose ‐ribose) polymerase in SKOV‐3, A2780, and OVCAR‐3 cells. Furthermore, sanggenol L blocked nuclear translocation of NF‐κB and also attenuated the expression of NF‐κB related genes such as c‐Myc, Cyclin D1, and Bcl‐_XL, Bcl‐2, in lipopolysaccharide‐treated SKOV‐3 cells. Overall, our findings for the first time suggest that sanggenol L induces apoptosis via caspase activation and inhibition of NF‐κB/IκBα phosphorylation as a potent chemotherapeutic agent for ovarian cancers. Copyright © 2015 John Wiley & Sons, Ltd.     

Artepillin C and Other Herbal PAK1‐blockers: Effects on Hair Cell Proliferation and Related PAK1‐dependent Biological Function in Cell Culture

PAK1 (RAC/CDC42‐activated kinase 1) is the major oncogenic kinase, and a number of herbal PAK1‐blockers such as propolis and curcumin have been shown to be anti‐oncogenic and anti‐melanogenic as well as anti‐alopecia (promoting hair growth). Previously, we found several distinct PAK1‐inhibitors in Okinawa plants including Alpinia zerumbet (alpinia). Thus, here, we tested the effects of these herbal compounds and their derivatives on the growth of cancer or normal hair cells, and melanogenesis in cell culture of A549 lung cancer, hair follicle dermal papilla cell, and B16F10 melanoma. Among these herbal PAK1‐inhibitors, cucurbitacin I from bitter melon (Goya) turned out to be the most potent to inhibit the growth of human lung cancer cells with the IC₅₀ around 140 nM and to promote the growth of hair cells with the effective dose around 10 nM. Hispidin, a metabolite of 5,6‐dehydrokawain from alpinia, inhibited the growth of cancer cells with the IC₅₀ of 25 μM as does artepillin C, the major anti‐cancer ingredient in Brazilian green propolis. Mimosine tetrapeptides (MFWY, MFYY, and MFFY) and hispidin derivatives (H1–3) also exhibited a strong anti‐cancer activity with the IC₅₀ ranging from 16 to 30 μM. Mimosine tetrapeptides and hispidin derivatives strongly suppressed the melanogenesis in melanoma cells. Copyright © 2015 John Wiley & Sons, Ltd.     

Activation of AMP‐activated protein kinase on human gastric cancer cells by apoptosis induced by corosolic acid isolated from Weigela subsessilis

Corosolic acid is one of the triterpenoids present in the leaves of Weigela subsessilis. The antidiabetic activity of corosolic acid has been reported previously, but to date, the anticancer effects on gastric cancer have been poorly studied. In this study, corosolic acid showed growth inhibition on SNU‐601 human gastric cancer cells, with an IC₅₀ value of 16.9 ± 2.9 μm . Corosolic acid also triggered the activation of caspase‐3 and poly (ADP‐ribose) polymerase, while it was recovered by Z‐VAD‐FMK. Moreover, the cell growth/apoptosis activities of corosolic acid were regulated by the AMP‐activated protein kinase‐mammalian target of rapamycin (AMPK‐mTOR) signals. These results showed that corosolic acid‐mediated AMPK activation leads to inhibition of mTOR, thus providing a possible mechanism of action of corosolic acid in the inhibition of cancer cell growth and the induction of apoptosis. Copyright © 2010 John Wiley & Sons, Ltd.     

Pachymic Acid Induces Apoptosis of EJ Bladder Cancer Cells by DR5 Up‐Regulation,ROS Generation,Modulation of Bcl‐2 and IAP Family Members

Pachymic acid (PA) is a lanostane‐type triterpenoid derived from Poria cocos mushroom that possess various biological effects such as anti‐cancer, antiinflammatory and anti‐metastasis effects. In this study, we investigated the anti‐cancer effects of PA in EJ bladder cancer cells. The results showed that PA significantly inhibited proliferation of EJ cells in a dose‐dependent manner. PA induced accumulation of sub‐G1 DNA content (apoptotic cell population), apoptotic bodies and chromatin condensation and DNA fragmentation in EJ cells in a dose‐dependent manner. PA also induces activation of caspase‐3, ‐8 and ‐9, and subsequent cleavage of poly (ADP‐ribose) polymerase, and significantly suppressed the inhibitor of apoptosis protein family proteins in a dose‐dependent manner. Furthermore, PA activates Bid and induced the loss of mitochondrial membrane potential (ΔΨ_m) with up‐regulated pro‐apoptotic proteins (Bax and Bad), down‐regulated anti‐apoptotic proteins (Bcl‐2 and Bcl‐xL) and cytochrome c release. In turn, PA increased the generation of reactive oxygen species (ROS); also, the ROS production was blocked by N‐acetyl‐L‐cysteine. The expressions of TNF‐related apoptosis inducing ligand and death receptor 5 were up‐regulated by PA in a dose‐dependent manner, suggesting extrinsic pathway also involved in PA‐induced apoptosis. This study provides evidence that PA might be useful in the treatment of human bladder cancer. Copyright © 2015 John Wiley & Sons, Ltd.     

Inhibition of human ovarian cancer cell lines by Devil's club Oplopanax horridus

Aim of the study

To search for more effective treatment of ovarian cancer, we investigated the in vitro anti-proliferation activities of Devil's club (OH) root bark extracts, an important medicinal plant of North America, on cisplatin sensitive and resistant human ovarian cancer cell lines.

Materials and methods

High performance liquid chromatography was used to provide the chemical profiling of the OH extracts. The anti-proliferation activities of OH extracts alone or in combination with cisplatin or paclitaxel were determined on four human ovarian cell lines by crystal violet assay. Flow cytometry and light microscopy were employed for cell cycle analysis, and also to detect apoptosis.

Results

Our data showed that water, 70% ethanol, 100% ethanol, and ethyl acetate extracts of OH inhibited the proliferation of human ovarian cancer cell lines A2780, A2780CP70, OVCAR3, and OVCAR10 in vitro. The respective 50% inhibition (IC₅₀) was estimated at 1/256, 1/74, 1/69, 1/53; 1/4156, 1/1847, 1/1029, 1/4530; 1/25,753, 1/3310, 1/3462, 1/5049; and 1/29,916, 1/2912 1/3828, and 1/4232 dilutions. Some combinations of non-cytotoxic dilutions (<IC₅₀) of 70% ethanol OH extract with cisplatin and paclitaxel enhanced its anti-proliferation IC₅₀ on A2780 and A2780CP70 cells. Cell cycle analysis demonstrated that the effect of OH extract on cell cycle was dependent on the concentration tested, blocking cells in the S and G2/M phases. At low concentrations it induced cell death by apoptosis, while at high concentrations, it kills cells by necrosis.

Conclusions

Our data showed that OH extracts exhibited significant anti-proliferation effect against both cisplatin sensitive and resistant human ovarian cell lines. Further research might result in discovery of agent(s) that can potentially be useful as an adjunct therapy for ovarian cancer cells. It is one of the few North American medicinal herbs that have been tested for anti-ovarian cancer activities.     

Inhibitory Activities of Compounds from the Twigs of Garcinia hombroniana Pierre on Human Low‐density Lipoprotein (LDL) Oxidation and Platelet Aggregation

The methanol extract of the twigs of Garcinia hombroniana, which showed strong LDL antioxidation and antiplatelet aggregation activities, was subjected to column chromatography to obtain 3,5,3′,5′‐tetrahydroxy‐4‐methoxybenzophenone, 1,7‐dihydroxyxanthone and eight triterpenoids, garcihombronane B, D, E and F, friedelin, glutin‐5‐en‐3β‐ol, stigmasterol and lupeol. The structures of the compounds were elucidated by spectroscopic methods. The compounds were evaluated for their ability to inhibit copper‐mediated LDL oxidation and arachidonic acid (AA)‐, adenosine diphosphate (ADP)‐, collagen‐induced platelet aggregation in vitro. Among the compounds tested, 3,5,3′,5′‐tetrahydroxy‐4‐methoxybenzophenone and 1,7‐dihydroxyxanthone showed strong inhibitory activity on LDL oxidation with half‐maximal inhibitory concentration (IC₅₀) values of 6.6 and 1.7 µm , respectively. 3,5,3′,5′‐Tetrahydroxy‐4‐methoxybenzophenone exhibited strong activity on AA‐, ADP‐ and collagen‐induced platelet aggregation with IC₅₀ values of 53.6, 125.7 and 178.6 µm , respectively, while 1,7 dihydroxyxanthone showed significant and selective inhibitory activity against ADP‐induced aggregation with IC₅₀ value of 5.7 µm . Of the triterpenoids tested, garcihombronane B showed moderate activity against LDL oxidation and garcihombronane D and F showed selective inhibition on ADP‐induced platelet aggregation. Copyright © 2012 John Wiley & Sons, Ltd.     

Antiproliferative activity and apoptosis induction by trijuganone C isolated from the root of Salvia miltiorrhiza Bunge (Danshen)

In this study, we found that the hexane fraction of Danshen, the dried root of Salvia miltiorrhiza (Lamiaceae), exerted antiproliferative effects on human leukemia cells. Phytochemical investigation of the hexane fraction achieved the isolation of the tanshinone diterpenes: dihydrotanshinone I ( 1 ), trijuganone C ( 2 ), trijuganone B ( 3 ), cryptotanshinone ( 4 ), tanshinone IIA ( 5 ), and tanshinone I ( 6 ). Compound 2 showed significant antiproliferative activities against human leukemia cells HL‐60, Jurkat, and U937. The antiproliferative activities of 2 against human cancer and normal cells indicated that 2 exhibited potent antiproliferative activities with IC₅₀ values less than 10 μM against HL‐60 and Jurkat cells as well as on the colon cancer cells DLD‐1, COLO 205, and Caco‐2. Compound 2 induced chromatin condensation, DNA fragmentation, activation of caspase‐3, ‐8, and ‐9, and the cleavage of poly (ADP‐ribose) polymerase (PARP) in HL‐60 cells. Moreover, 2 activated Bid and Bax, leading to the loss of mitochondrial membrane potential, and 2 induced the cytochrome c release from mitochondria into cytosol. In contrast, Bcl‐2 and Bcl‐xL were unaffected by 2 . These results suggest that 2 exerts antiproliferative effects via apoptosis induction mediated by mitochondrial dysfunction and caspase activation. Compound 2 may serve as a candidate of potential chemotherapeutic agent for human leukemia.     

Medicinal Plants Traditionally Used for Treatment of Obesity and Diabetes Mellitus – Screening for Pancreatic Lipase and α‐Amylase Inhibition

In order to find new pancreatic lipase (PL) and α‐amylase inhibitors from natural sources for the treatment of obesity and related diseases as diabetes mellitus II, 23 medicinal plants with weight‐reducing, serum glucose‐reducing or related potential were investigated. Methanolic and water extracts of the plants were evaluated by using two in vitro test systems. Our findings have shown that the methanolic extract of Hibiscus sabdariffa L. (Malvaceae) showed high inhibitory activities to PL (IC₅₀: 35.8 ± 0.8 µg/mL) and α‐amylase (IC₅₀: 29.3 ± 0.5 µg/mL). Furthermore, the methanolic extract of Tamarindus indica L. (Leguminosae) showed a high anti‐lipase (IC₅₀: 152.0 ± 7.0 µg/mL) and the aqueous extract a high anti‐amylase (IC₅₀: 139.4 ± 9.0 µg/mL) activity. This work provides a priority list of interesting plants for further study with respect to the treatment of obesity and associated diseases. Copyright © 2015 John Wiley & Sons, Ltd.     

β‐Bisabolene,a Sesquiterpene from the Essential Oil Extract of Opoponax (Commiphora guidottii), Exhibits Cytotoxicity in Breast Cancer Cell Lines

The essential oils from Commiphora species have for centuries been recognized to possess medicinal properties. Here, we performed gas chromatography‐mass spectrometry on the essential oil from opoponax (Commiphora guidotti) and identified bisabolene isomers as the main constituents of this essential oil. Opoponax essential oil, a chemical component; β‐bisabolene and an alcoholic analogue, α‐bisabolol, were tested for their ability to selectively kill breast cancer cells. Only β‐bisabolene, a sesquiterpene constituting 5% of the essential oil, exhibited selective cytotoxic activity for mouse cells (IC₅₀ in normal Eph4: >200 µg/ml, MG1361: 65.49 µg/ml, 4T1: 48.99 µg/ml) and human breast cancer cells (IC₅₀ in normal MCF‐10A: 114.3 µg/ml, MCF‐7: 66.91 µg/ml, MDA‐MB‐231: 98.39 µg/ml, SKBR3: 70.62 µg/ml and BT474: 74.3 µg/ml). This loss of viability was because of the induction of apoptosis as shown by Annexin V‐propidium iodide and caspase‐3/7 activity assay. β‐bisabolene was also effective in reducing the growth of transplanted 4T1 mammary tumours in vivo (37.5% reduction in volume by endpoint). In summary, we have identified an anti‐cancer agent from the essential oil of opoponax that exhibits specific cytotoxicity to both human and murine mammary tumour cells in vitro and in vivo, and this warrants further investigation into the use of β‐bisabolene in the treatment of breast cancers. Copyright © 2015 John Wiley & Sons, Ltd.     

Anti‐complement activity of isolated compounds from the roots of Clerodendrum bungei Steud.

To determine the anti‐complement activity of natural diterpenes, chromatographic separation of the acetone‐soluble fraction from the roots of Clerodendrum bungei (Verbenaceae) led to the isolation of five diterpenoids. An acetone‐soluble extract of the roots of C. bungei exhibited significant anti‐complement activity on the classical pathway complement system, which was expressed as total hemolytic activity. Five compounds isolated from the roots of C. bungei, namely 12‐O‐β‐d ‐glucopyranosyl‐3,11,16‐trihydroxyabieta‐8,11,13‐triene (1), 3,12‐O‐β‐d ‐diglucopyranosyl‐11,16‐dihydroxyabieta‐8,11,13‐triene (2), ajugaside A (3), uncinatone (4) and 19‐hydroxyteuvincenone F (5). Compounds 1, 2, 3, 4 and 5 showed inhibitory activity against complement system with 50% inhibitory concentrations (IC₅₀) values of 24 µm , 138 µm , 116 µm , 87 µm and 232 µm . Among the compounds tested, 1 showed the most potent anti‐complement activity (IC₅₀, 24 µm ). Copyright © 2010 John Wiley & Sons, Ltd.     

Neferine,an alkaloid from lotus seed embryo targets HeLa and SiHa cervical cancer cells via pro‐oxidant anticancer mechanism

Apoptosis and autophagy are important processes that control cellular homeostasis and have been highlighted as promising targets for novel anticancer drugs. This study aims to investigate the inhibitory effects and mechanisms of Neferine (Nef), an alkaloid from the lotus seed embryos of Nelumbo nucifera (N. nucifera), as a dual inducer of apoptosis and autophagy through the reactive oxygen species (ROS) activation in cervical cancer cells. Nef and N. nucifera extract suppressed the cell viability of HeLa and SiHa cells in a dose‐dependent manner. Importantly, Nef showed minimal toxicity to normal cells. Furthermore, Nef inhibited anchorage‐independent growth, colony formation and migration ability of cervical cancer cells. Nef induces mitochondrial apoptosis by increasing pro‐apoptotic protein bax, cytochrome‐c, cleaved caspase‐3 and caspase‐9, poly‐ADP ribose polymerase (PARP) cleavage, DNA damage (pH₂AX) while downregulating Bcl‐2, procaspase‐3 and procaspase‐9, and TCTP. Of note, apoptotic effect by Nef was significantly attenuated in the presence of N‐acetylcysteine (NAC), suggesting pro‐oxidant activity of this compound. Nef also promoted autophagy induction through increasing beclin‐1, atg‐4, atg‐5 and atg‐12, LC‐3 activation, and _P62/SQSTM1 as determined by western blot analysis. Collectively, these results demonstrate that Nef is a potent anticancer compound against cervical cancer cells through inducing apoptosis and autophagic pathway involving ROS.     

Auraptene Induces Apoptosis via Myeloid Cell Leukemia 1‐Mediated Activation of Caspases in PC3 and DU145 Prostate Cancer Cells

Although auraptene, a prenyloxy coumarin from Citrus species, was known to have anti‐oxidant, anti‐bacterial, antiinflammatory, and anti‐tumor activities, the underlying anti‐tumor mechanism of auraptene in prostate cancers is not fully understood to date. Thus, in the present study, we have investigated the anti‐tumor mechanism of auraptene mainly in PC3 and DU145 prostate cancer cells, because auraptene suppressed the viability of androgen‐independent PC3 and DU145 prostate cancer cells better than androgen‐sensitive LNCaP cells. Also, auraptene notably increased sub‐G1 cell population and terminal deoxynucleotidyl transferase dUTP nick end labeling‐positive cells as features of apoptosis in two prostate cancer cells compared with untreated control. Consistently, auraptene cleaved poly(ADP‐ribose) polymerase, activated caspase‐9 and caspase‐3, suppressed the expression of anti‐apoptotic proteins, including Bcl‐2 and myeloid cell leukemia 1 (Mcl‐1), and also activated pro‐apoptotic protein Bax in both prostate cancer cells. However, Mcl‐1 overexpression reversed the apoptotic effect of auraptene to increase sub‐G1 population and induce caspase‐9/3 in both prostate cancer cells. Taken together, the results support scientific evidences that auraptene induces apoptosis in PC3 and DU145 prostate cancer cells via Mcl‐1‐mediated activation of caspases as a potent chemopreventive agent for prostate cancer prevention and treatment. Copyright © 2017 John Wiley & Sons, Ltd.     

Anti‐allergic activity of principles from the roots and heartwood of caesalpinia sappan on antigen‐induced β‐hexosaminidase release

The dichloromethane extract of the roots and heartwood of Caesalpinia sappan exhibited potent inhibitory activity against β‐hexosaminidase release as marker of degranulation in rat basophilic leukemic (RBL‐2H3) cells, with inhibition of 98.7% and 87.5% at concentration of 100 µg/ml, respectively. These extracts were further separated by chromatographic techniques to give two chalcones and seven homoisoflavones. Among the compounds tested, sappanchalcone (2) possessed the most potent effect against allergic reaction in RBL‐2H3 cells with an inhibitory concentration (IC₅₀) value of 7.6 µM, followed by 3‐deoxysappanchalcone (1, IC₅₀ = 15.3 µM), whereas other compounds showed moderate and mild effects. The results suggested the following structural requirements of chalcones (1 and 2) and homoisoflavones (3‐9) for anti‐allergic activity: (i) chalcone exhibited higher activity than homoisoflavone (ii) vicinal hydroxylation at B‐ring of chalcone conferred higher activity than one hydroxylation; and (iii) for homoisoflavone, the hydroxyl groups at C‐3 and C‐4 positions decreased the activity. This is the first report of C. sappan for anti‐allergic activity. Copyright © 2009 John Wiley & Sons, Ltd.     

Potent modulation of P‐glycoprotein activity by naturally occurring phenylbutenoids from Zingiber cassumunar

Five phenylbutenoid derivatives from the rhizomes of Zingiber cassumunar Roxb. (Zingiberaceae) were evaluated for their P‐glycoprotein (P‐gp) inhibitory effects in a P‐gp over‐expressing multidrug resistant (MDR) human breast cancer cell line, MCF‐7/ADR. As a result, a phenylbutenoid dimer, (±)‐trans‐3‐(3,4‐dimethoxyphenyl)‐4‐[(E)‐3,4‐dimethoxystyryl]cyclohex‐1‐ene (1), exhibited highly potent P‐gp inhibitory activity, decreasing the IC₅₀ value of daunomycin (DNM) to 4.31 ± 0.40 µm in the cells (DNM IC₅₀ = 37.1 ± 0.59 µm ). The positive control, verapamil decreased the IC₅₀ value of DNM to 6.94 ± 0.40 µm . Three phenylbutenoid monomers, 2–4 from this plant, also resulted in a significant decrease in the IC₅₀ values of DNM compared with the control. In particular, compound 1 markedly enhanced [³H]‐DNM accumulation and significantly reduced [³H]‐DNM efflux compared with the control, and this effect was more potent than that of verapamil, a well‐known P‐gp inhibitor. These results suggest that compound 1 of Z. cassumunar can be developed as a potent chemo‐sensitizing agent that reverses P‐gp‐mediated MDR in human cancer chemotherapy. Copyright © 2008 John Wiley & Sons, Ltd.     

Anti‐Leishmanial,Anti‐Inflammatory and Antimicrobial Activities of Phenolic Derivatives from Tibouchina paratropica

A new phenolic derivative, 2,8‐dihydroxy‐7H‐furo[2,3‐f]chromen‐7‐one ( 1 ), together with isoquercitrin ( 2 ), was isolated from the aerial parts of Tibouchina paratropica. Compound structures were elucidated by spectroscopic methods. Both compounds show antimicrobial activit y towards a panel of bacterial and fungal pathogens, and compound 1 displayed potent anti‐parasitic activity against Leishmania donovani (IC₅₀ = 0.809 µg/mL). In addition, an 85% reduction in the secretion of the pro‐inflammatory cytokine IL‐6 was recorded when macrophages challenged with lipopolysaccharide were exposed to compound 1 , but no effect on the anti‐inflammatory IL‐10 was observed. Compound 2 showed neither anti‐parasitic nor anti‐inflammatory properties. In addition, no cytotoxic activities were observed against the human‐derived macrophage THP‐1 cells. Copyright © 2014 John Wiley & Sons, Ltd.     

Extracts from Epilobium sp. Herbs,Their Components and Gut Microbiota Metabolites of Epilobium Ellagitannins,Urolithins, Inhibit Hormone‐Dependent Prostate Cancer Cells‐(LNCaP) Proliferation and PSA Secretion

Extracts from Epilobium sp. herbs have been traditionally used in the treatment of prostate‐associated ailments. Our studies demonstrated that the extracts from Epilobium angustifolium, Epilobium parviflorum and Epilobium hirsutum herbs are potent prostate cancer cells (LNCaP) proliferation inhibitors with IC₅₀ values around 35 µg/ml. The tested extracts reduced prostate specific antigen (PSA) secretion (from 325.6 ± 25.3 ng/ml to ~90 ng/ml) and inhibited arginase activity (from 65.2 ± 1.1 mUnits of urea/mg of protein to ~40 mUnits of urea/mg protein). Selected constituents of extracts (oenothein B, quercetin‐3‐O‐glucuronide, myricetin‐3‐O‐rhamnoside) were proven to be active in relation to LNCaP cells. However, oenothein B was the strongest inhibitor of cells proliferation (IC₅₀ = 7.8 ± 0.8 μM), PSA secretion (IC₅₀ = 21.9 ± 3.2 μM) and arginase activity (IC50 = 19.2 ± 2.0 μM). Additionally, ellagitannins from E. hirustum extract were proven to be transformed by human gut microbiota into urolithins. Urolithin C showed the strongest activity in the inhibition of cell proliferation (IC₅₀ = 35.2 ± 3.7 μM), PSA secretion (reduced PSA secretion to the level of 100.7 ± 31.0 ng/ml) and arginase activity (reduced to the level of 27.9 ± 3.3 mUnits of urea/mg of protein). Results of the work offer an explanation of the activity of Epilobium extracts and support the use of Epilobium preparations in the treatment of prostate diseases. Copyright © 2013 John Wiley & Sons, Ltd.     

Apoptotic Effect of Astragalin in Melanoma Skin Cancers via Activation of Caspases and Inhibition of Sry‐related HMg‐Box Gene 10

Though Astragalin (kaempferol‐3‐glucoside) contained in Paeonia lactiflora and other plants was known to have anti‐oxidant, antiinflammatory, and anti‐tumor activity, the anti‐tumor mechanism of Astragalin has never been reported in melanomas until now. Thus, in the present study, the underlying apoptotic mechanism of Astragalin isolated from Aceriphyllum rossii was elucidated in A375P and SK‐MEL‐2 melanoma cells. Astragalin exerted cytotoxicity in A375P and SK‐MEL‐2 cells in a concentration‐dependent manner. Also, Astragalin significantly increased the number of TdT‐mediated dUTP nick end labeling positive cells and sub‐G1 population as a feature of apoptosis in A375P and SK‐MEL‐2 cells compared with untreated control. Consistently, western blotting revealed that Astragalin activated caspase 9/3 and Bax, cleaved poly (ADP‐ribose) polymerase, and attenuated the expression of cyclin D1, Mcl‐1, and Sry‐related HMg‐Box gene 10 (SOX10) in A375P and SK‐MEL‐2 cells. Of note, ectopic expression of SOX10 reduced the apoptotic ability of Astragalin to inhibit proliferation, cleave poly (ADP‐ribose) polymerase, and caspase 3 in A375P and SK‐MEL‐2 melanoma cells. Overall, our findings provide evidence that Astragalin induces apoptosis in A375P and SK‐MEL‐2 melanoma cells via activation of caspase9/3 and inhibition of SOX10 signaling. Copyright © 2017 John Wiley & Sons, Ltd.