Growth inhibitory activity of biflavonoids and diterpenoids from the leaves of the Libyan Juniperus phoenicea against human cancer cells

Three biflavonoids [cupressuflavone ( 1 ), amentoflavone ( 2 ), and sumaflavone ( 3 )], four diterpenoids [13‐epi‐cupressic acid ( 4 ), imbricatholic acid ( 5 ), 3‐hydroxy‐sandaracopimaric acid ( 6 ), and dehydroabietic acid ( 7 )], and one lignan [β‐peltatin methyl ether ( 8 )] were isolated from the cytotoxic fractions of the extracts of the leaves of the Libyan Juniperus phoenicea L. The structures of these compounds were elucidated by spectroscopic means. Cytotoxicity of compounds 1 – 6 were assessed against the human lung cancer cell line A549 using the MTT assay. Compounds 1 and 3 showed cytotoxicity against the A549 cells (IC₅₀ = 65 and 77 μM, respectively), whereas compound 2 did not show any activity. Diterpenes 4 – 6 exhibited weak cytotoxicity against the A549 cells with the IC₅₀ values of 159, 263, and 223 μM, respectively. The cytotoxicity of each compound was compared with the anticancer drug, etoposide (IC₅₀ = 61 μM). Cupressuflavone ( 1 ) was evaluated also for cytotoxicity against both the human PC3 cancer cell line and the normal prostate cell line (PNT2), and this compound revealed a high degree of cytotoxic selectivity towards the prostate cancer cells (PC3), with IC₅₀ value of 19.9 μM, without any evidence of cytotoxicity towards the normal prostate cell line (PNT2).     

Resveratrol derivatives from Commiphora africana (A. Rich.) Endl. display cytotoxicity and selectivity against several human cancer cell lines

Commiphora africana (A. Rich.) Endl. (Burseraceae) is a medicinal plant widely used in Nigerian ethnomedicine. The in vitro cytotoxicity of the stem bark extract of C. africana and isolated cytotoxic compounds was investigated. Three resveratrol derivatives: (E)‐resveratrol 3‐O‐rutinoside ( 1 ), 5‐methoxy‐(E)‐resveratrol 3‐O‐rutinoside ( 2 ), and pinostilbene ( 3 ), together with 3‐hydroxy‐5‐methoxybenzoic acid ( 4 ) were isolated from the methanol fraction of C. africana. Their structures were determined by extensive analysis of their HREIMS and NMR spectra. The cytotoxicity of the isolated compounds against four human carcinoma cells was determined using the MTT assay. Compound 1 displayed the highest antiproliferative effect on the cell lines, with IC₅₀ values of 16.80, 21.74, 17.89, and 17.44 μM, against MCF7, A549, PC3, and HepG2 human cancer cell lines, respectively. In addition, compounds 1 – 3 showed low toxicity against normal human prostate cell line, with selectivity indices greater than five across the carcinoma cells, indicating that the compounds possess potential in the development of low‐toxicity chemotherapeutic agents. These results support the traditional use of this plant in the treatment of cancer.     

Zanthoxylum usambarense (Engl.) Kokwaro (Rutaceae) Extracts Inhibit the Growth of the Breast Cancer Cell Lines MDA‐MB‐231 and MCF‐7, But Not the Brain Tumour Cell Line U251 In Vitro

Zanthoxylum usambarense (Engl.) Kokwaro has traditionally been used for the treatment of malaria, upper respiratory tract infections, cough, rheumatism, tooth decay and sore gums in Kenya and other African countries. Dried ground parts of Z. usambarense were extracted by maceration using methanol (MeOH) at room temperature, extract was dried and reconstituted in 70% aq. MeOH and partitioned against n‐hexane and chloroform (CHCl₃) to obtain MeOH, n‐hexane and CHCl₃ extracts. All extracts were assessed for cytotoxicity against two breast cancer cell lines, MDA‐MB‐231 and MCF‐7, and the brain tumour cell line U251 by the MTT assay. The free‐radical scavenging activity of the extracts was also determined by the 2,2‐diphenyl‐1‐picryhydrazyl (DPPH) assay. In the DPPH assay, the MeOH extract was found to be the most active free‐radical scavenger with a RC₅₀ value of 41.1 × 10^?3 mg/mL. It also displayed significant cytotoxicity against the MCF‐7 cell line (IC₅₀ 42.9 µg/mL) and appeared to have induced cell death through apoptosis. None of the test extracts showed any activity against the U251 cell line at test concentrations. The present findings demonstrated that Z. usambarense could be a potential source for new cytotoxic compounds for possible anticancer drug development. Copyright © 2012 John Wiley & Sons, Ltd.     

Steroidal Glycosides with Antiproliferative Activities from Digitalis trojana

The phytochemical investigation of Digitalis trojana led to the isolation of two cardiac glycosides (1, 2), one pregnane glycoside (3), three furostanol type saponins (4–6), along with three cleroindicins (7–9), four phenylethanoid glycosides (10–13), two flavonoids (14, 15) and two phenolic acid derivatives (16, 17). The structure elucidation of the isolates was carried out by NMR experiments as well as ESI‐MS. The cytotoxic activity of compounds 1–13 against a small panel of cancer cell lines, namely MCF‐7, T98G, HT‐29, PC‐3, A375 and SH‐SY5Y, was investigated. Compounds 1–6 showed antiproliferative activity against human breast MCF‐7 and colon HT‐29 cancer cell lines with IC₅₀ values ranging from 8.3 to 50 μM. In order to understand the mechanism involved in the cell death, the active compounds were tested as pro‐apoptotic agents using propidium iodide staining by flow cytometry method. No significant increase was observed in the apoptosis of the MCF‐7 and HT‐29 cancer cells. Moreover, the effects of the active compounds on cell proliferation were assessed on the same cancer cell lines by cell cycle analysis of DNA content using flow cytometry. No significative changes were observed in the cell cycle of MCF‐7, while significant changes in G₂/M cell cycle phase of HT‐29 cells were observed after treatment with digitalin (1), cariensoside (3) and 22‐O‐methylparvispinoside B (6) at 10 μM. Copyright © 2013 John Wiley & Sons, Ltd.     

Antiproliferative effect of flavonoids and sesquiterpenoids from Achillea millefolium s.l. on cultured human tumour cell lines

The antiproliferative activities of n‐hexane, chloroform, aqueous‐methanol and aqueous extracts of the aerial parts of the Achillea millefolium aggregate on three human tumour cell lines were investigated by means of MTT assays. The chloroform‐soluble extract exerted high tumour cell proliferation inhibitory activities on HeLa and MCF‐7 cells, and a moderate effect on A431 cells; accordingly, it was subjected to detailed bioactivity‐guided fractionation. As a result of the multistep chromatographic purifications (VLC, CPC, PLC, gel filtration), five flavonoids (apigenin, luteolin, centaureidin, casticin and artemetin) and five sesquiterpenoids (paulitin, isopaulitin, psilostachyin C, desacetylmatricarin and sintenin) were isolated and identified by spectroscopic methods. The antiproliferative assay demonstrated that centaureidin is the most effective constituent of the aerial parts of yarrow: high cell growth inhibitory activities were observed especially on HeLa (IC₅₀ 0.0819 µm ) and MCF‐7 (IC₅₀ 0.1250 µm ) cells. Casticin and paulitin were also highly effective against all three tumour cell lines (IC₅₀ 1.286–4.76 µm ), while apigenin, luteolin and isopaulitin proved to be moderately active (IC₅₀ 6.95–32.88 µm ). Artemetin, psilostachyin C, desacetylmatricarin and sintenin did not display antiproliferative effects against these cell lines. This is the first report on the occurrence of seco‐pseudoguaianolides (paulitin, isopaulitin and psilostachyin C) in the Achillea genus. Copyright © 2008 John Wiley & Sons, Ltd.     

Acylated Iridoids and Rhamnopyranoses from Premna odorata (Lamiaceae) as Novel Mesenchymal–Epithelial Transition Factor Receptor Inhibitors for the Control of Breast Cancer

Phytochemical investigation of Premna odorata Blanco, Lamiaceae, leaves afforded three new acylated iridoid glycosides 1–3 and two new acylated rhamnopyranoses 9 and 10, in addition to ten known compounds. The structures of the new compounds were confirmed using extensive 1D and 2D NMR analysis. Molecular modeling study suggested the potential of the acylated rhamnopyranoses to bind at the c‐Met kinase domain. Cell‐free Z′‐LYTE? assay testing revealed the good c‐Met phosphorylation inhibitory activity of 9, followed by 8, and 10, with IC₅₀ values of 2.5, 6.9, and 12.7 μM, respectively. The (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) cell proliferation assay testing against the human c‐Met expressing highly invasive MDA‐MB‐231 suggested compound 9 as the most active with IC₅₀ value of 13.3 μM. Testing of compound 9 against multiple phenotypic breast cancer cell lines including MCF‐7, BT‐474 cells, and MDA‐MB‐468 proved enhanced activity against the highly c‐Met expressing triple‐negative breast cancer cell lines. Acylated rhamnopyranoses are potential novel c‐Met inhibitors appropriate for future optimizations to control c‐Met‐dependent breast malignancies. Copyright © 2017 John Wiley & Sons, Ltd.     

Bioactivity‐guided Isolation of Cytotoxic Sesquiterpene Lactones of Gochnatia polymorpha ssp. floccosa

Phytochemical study of Gochnatia polymorpha (Less) Cabr. ssp. floccosa Cabr. trunk bark, guided by antiproliferative assays on 10 human cancer cell lines and the VERO cell line, yielded six known compounds identified as the triterpene bauerenyl acetate, the guaianolide 11α,13‐dihydrozaluzanin C and the dimeric guaianolides 10‐desoxygochnatiolide A, gochnatiolide A, 8‐hydroxi‐10‐desoxygochnatiolide A and 8‐hydroxigochnatiolide A. Extracts, fractions of extracts and isolated compounds were tested in vitro against a panel of human cancer cell lines, including U251 (glioma, CNS), UACC‐62 (melanoma), MCF‐7 (breast), NCI‐ADR/RES (drug‐resistant ovarian), 786.0 (kidney), NCI‐H460 (lung, no small cells), PC‐3 (prostate), OVCAR‐3 (ovarian), HT‐29 (colon), K562 (leukemia) and against the VERO no cancer cell line. Bauerenyl acetate was inactive, while 11α,13‐dihydrozaluzanin C showed weak activity against UACC62 and the VERO cell line. The most active compounds were 10‐desoxygochnatiolide A and gochnatiolide A, which inhibited the growth of kidney, melanoma, ovarian‐resistant and glioma cell lines with values of TGI (total growth inhibition) varying 0.21–1.09 µg/mL. This is the first report about cytotoxic activity of dimeric lactones against cell lines. Copyright © 2011 John Wiley & Sons, Ltd.     

Two New Xanthones from Hypericum sampsonii and biological activity of the isolated compounds

Phytochemical investigation of the CH₂Cl₂ extract of the aerial part of Hypericum sampsonii yielded two new prenylated xanthones, hypericumxanthone A and B, together with three known xanthones. Their structures were elucidated by analysis of physical and spectral (UV, IR, mass and NMR) data and comparison of spectroscopic data with those reported previously. All these compounds were evaluated for in vitro antibacterial activity against methicillin‐resistant Staphylococcus aureus (MRSA). Two new compounds were also tested for their cytotoxicity against human breast (MCF‐7), hepatoma (HepG2), colon (HT‐29) and lung (A549) tumour cell lines. Two new compounds showed moderate antibacterial activities at minimum inhibitory concentrations (MIC) of 16 and 32 µg/mL, respectively, whereas the positive standard antibacterial drug, vancomycin, showed an MIC of 8 µg/mL. The other compounds were inactive against MRSA. In addition, hypericumxanthone B showed weak inhibitory activities against four human tumour cell lines. Copyright © 2010 John Wiley & Sons, Ltd.     

Antiproliferative effect of benzophenones and their influence on cathepsin activity

The antiproliferative activity of two prenylated benzophenones isolated from Rheedia brasiliensis, the triprenylated garciniaphenone and the tetraprenylated benzophenone 7‐epiclusianone, was investigated against human cancer cell lines. The antiproliferative activity on melanoma (UACC‐62), breast (MCF‐7), drug‐resistant breast (NCI‐ADR), lung/non‐small cells (NCI460), ovarian (OVCAR 03), prostate (PC03), kidney (786‐0), lung (NCI‐460) and tongue (CRL‐1624 and CRL‐1623) cancer cells was determined using spectrophotometric quantification of the cellular protein content. The effect of these benzophenones on the activity of cathepsins B and G was also investigated. Garciniaphenone displayed cytostatic activity in all cell lines, whereas 7‐epiclusianone showed a dose‐dependent cytotoxic effect. The IC₅₀ values for cell proliferation revealed that 7‐epiclusianone is more active than garciniaphenone against most of the cell lines. Furthermore, the antiproliferative effects demonstrated by garciniaphenone and 7‐epiclusianone were related to their cathepsin inhibiting properties. In conclusion, 7‐epiclusianone is a promising naturally occurring agent which displays multiple inhibitory effects which may be working in concert to inhibit cancer cell proliferation in vitro. The putative pathway by which 7‐epiclusianone affects cancer cell development may involve cathepsin inhibition. Copyright © 2009 John Wiley & Sons, Ltd.     

Antiproliferative activity of Hungarian Asteraceae species against human cancer cell lines. Part II

The antiproliferative activities of aqueous and organic extracts prepared from 26 Hungarian species of the tribes Cynereae and Lactuceae (Asteraceae) were tested in vitro against HeLa (cervix epithelial adenocarcinoma), A431 (skin epidermoid carcinoma) and MCF7 (breast epithelial adenocarcinoma) cells by using the MTT assay. Of the tested 200 extracts of different plant parts obtained with n‐hexane, chloroform, 50% methanol and water, 16 extracts displayed noteworthy cell growth inhibitory activity (>50% inhibition at a concentration of 10 µg/mL). The IC₅₀ values of these extracts were determined, and their direct cytotoxic effects were measured. High differences between the antiproliferative and cytotoxic activities, demonstrating a real cell proliferation inhibitory activity rather than direct killing effects, were found for some Centaurea, Cirsium, Cichorium, Lactuca, Onopordum and Scorsonera extracts. Copyright © 2009 John Wiley & Sons, Ltd.     

Cytotoxic sesquiterpene lactones from the leaves of Vernonia guineensis Benth. (Asteraceae)

Ethnopharmacological relevance

Vernonia guineensis Benth. (Asteraceae) preparations are used in folk medicine in Cameroon to treat a number of ailments, including prostate cancer and malaria, and is used as an anthelmintic, adaptogen and antidote. The aim of this study was to continue the validation of the activity of Vernonia guineensis Benth. extracts and isolated molecules against cancer cell lines following the previous isolation of an anti-prostate cancer sugar ester from the root extract.

Materials and methods

Acetone extracts of Vernonia guineensis Benth. leaves were tested for activity against 10 cancer cell lines (Breast—MDA-MB-231, Breast—MCF-7, Colon—HCT-116, Leukemia—HL-60, Lung—A549, Melanoma—A375, Ovarian—OVCAR3, Pancreas—Mia-paca, Prostate—PC-3 and Prostate—DU-145). The acetone extract was subjected to bioactivity guided fractionation. Anti-proliferation and clonogenic activity of the isolated compounds were tested. The WST-1 assay was used for the anti-proliferation activity, while the standard clonogenic test was used to determine the clonogenic activity.

Results

The acetone extract of Vernonia guineensis Benth. demonstrated in vitro activity ranging from IC₅₀ 4–26 μg/mL against the 10 cell lines. Activity guided fractionation of this extract yielded two sesquiterpene lactones, isolated for the first time from the genus Vernonia. The compounds were characterized using spectroscopic experiments, including a combination of 1D and 2D NMR data. Vernopicrin (1) and Vernomelitensin (2) demonstrated in vitro activity against human cancer cell lines with IC₅₀ ranging from 0.35–2.04 μM (P<0.05) and 0.13–1.5 μM (P<0.05), respectively, between the most and least sensitive cell lines for each compound. Vernopicrin was most active against the human melanoma (A375) cell line and least active against the lung cancer (A549) cell line, while Vernomelitensin was also most active against the human melanoma (A375) cell line and least active against the breast cancer (MCF-7) cell line. Both compounds also demonstrated anticlonogenic activity.

Conclusion

The cytotoxicity demonstrated by the crude extract and isolated sesquiterpenes against cancer cell lines highlights the medicinal potential of V. guineensis. The selective anti-proliferation and dose dependent anticlonogenic activities suggest that the identified sesquiterpenes could be potential antitumor agents.     

Cytotoxicity of the Roots of Trillium govanianum Against Breast (MCF7), Liver (HepG2), Lung (A549) and Urinary Bladder (EJ138) Carcinoma Cells

Trillium govanianum Wall. (Melanthiaceae alt. Trilliaceae), commonly known as ‘nag chhatri’ or ‘teen patra’, is a native species of the Himalayas. It is used in various traditional medicines containing both steroids and sex hormones. In folk medicine, the rhizomes of T. govanianum are used to treat boils, dysentery, inflammation, menstrual and sexual disorders, as an antiseptic and in wound healing. With the only exception of the recent report on the isolation of a new steroidal saponin, govanoside A, together with three known steroidal compounds with antifungal property from this plant, there has been no systematic pharmacological and phytochemical work performed on T. govanianum. This paper reports, for the first time, on the cytotoxicity of the methanol extract of the roots of T. govanianum and its solid‐phase extraction (SPE) fractions against four human carcinoma cell lines: breast (MCF7), liver (HEPG2), lung (A549) and urinary bladder (EJ138), using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazoliumbromide cytotoxicity assay and liquid chromatography and electrospray ionization quadrupole time‐of‐flight mass spectrometry analysis of the SPE fractions. The methanol extract and all SPE fractions exhibited considerable levels of cytotoxicity against all cell lines, with the IC₅₀ values ranging between 5 and 16 µg/mL. Like other Trillium species, presence of saponins and sapogenins in the SPE fractions was evident in the liquid chromatography mass spectrometry data. Copyright © 2016 John Wiley & Sons, Ltd.     

Anti-cancer activity of compounds from Bauhinia strychnifolia stem

Ethnopharmacological relevance

The stem and root of Bauhinia strychnifolia Craib (Fabaceae family) have been traditionally used in Thailand to treat fever, alcoholic toxication, allergy and cancer. An EtOH extract of Bauhinia strychnifolia showed good inhibitory activity against several cancer cell lines including HT-29, HeLa, MCF-7 and KB. As there has been no previous reports on chemical constituents of Bauhinia strychnifolia, this study is aimed to isolate the pure compounds with anti-cancer activity.

Materials and methods

Five pure compounds were isolated from EtOH extract of Bauhinia strychnifolia stem using silica gel, dianion HP-20 and sephadex LH-20 column chromatography and were tested for their cytotoxic effects against HT-29, HeLa, MCF-7 and KB cell lines using the Sulforhodamine B (SRB) assay.

Results

Among five compounds, 3,5,7,3′,5′-pentahydroxyflavanonol-3-O-α-l-rhamnopyranoside (2) possessed very potent activity against KB (IC₅₀=0.00054 μg/mL), HT-29 (IC₅₀=0.00217 μg/mL), MCF-7 (IC₅₀=0.0585 μg/mL) and HeLa cells (IC₅₀=0.0692 μg/mL). 3,5,7-Trihydroxychromone-3-O-α-l-rhamnopyranoside (3) also showed good activity against HT-29 (IC₅₀=0.02366 μg/mL), KB (IC₅₀=0.0412 μg/mL) and MCF-7 (IC₅₀=0.297 μg/mL), respectively. The activity of 2 (IC₅₀=0.00054 μg/mL) against KB cell was ten times higher than that of the positive control, Camptothecin (anti-cancer drug, IC₅₀=0.0057 μg/mL). All compounds did not show any cytotoxicity with normal cells at the concentration of 1 μg/mL.

Conclusion

This is the first report of compounds 2 and 3 on anti-cancer activity and based on the anti-cancer activity of extracts and pure compounds isolated from Bauhinia strychnifolia stem, it might be suggested that this plant could be useful for treatment of cancer.     

Antiproliferative Activity of Polygonaceae Species from the Carpathian Basin against Human Cancer Cell Lines

Aqueous and organic extracts of 27 selected species from five genera (Fallopia, Oxyria, Persicaria, Polygonum and Rumex) of the family Polygonaceae occurring in the Carpathian Basin were screened in vitro for antiproliferative activity against HeLa (cervix epithelial adenocarcinoma), A431 (skin epidermoid carcinoma) and MCF7 (breast epithelial adenocarcinoma) cells, using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay. A total of 196 n‐hexane, chloroform, 50% methanol or water extracts of different plant parts were investigated. It was found that extracts of Polygonum hydropiper, Rumex acetosa, Rumex alpinus, Rumex aquaticus, Rumex scutatus and Rumex thyrsiflorus at 10 or 30 µg/mL demonstrated substantial cell growth inhibitory activity (at least 50% inhibition of cell proliferation) against one or more cell lines. R. acetosa and R. thyrsiflorus proved to be the most active and are considered worthy of activity‐guided phytochemical investigations. Copyright © 2012 John Wiley & Sons, Ltd.     

Withanolide sulfoxide from Aswagandha roots inhibits nuclear transcription factor‐kappa‐B,cyclooxygenase and tumor cell proliferation

Investigation of the methanol extract of Aswagandha (Withania somnifera) roots for bioactive constituents yielded a novel withanolide sulfoxide compound (1) along with a known withanolide dimer ashwagandhanolide (2) with an S‐linkage. The structure of compound 1 was established by extensive NMR and MS experiments. Compound 1 was highly selective in inhibiting cyclooxygenase‐2 (COX‐2) enzyme by 60% at 100 µm with no activity against COX‐1 enzyme. The IC₅₀ values of compound 1 against human gastric (AGS), breast (MCF‐7), central nervous system (SF‐268) and colon (HCT‐116) cancer cell lines were in the range 0.74–3.63 µm. Both S‐containing dimeric withanolides, 1 and 2, completely suppressed TNF‐induced NF‐κB activation when tested at 100 µm. The isolation of a withanolide sulfoxide from W. somnifera roots and its ability to inhibit COX‐2 enzyme and to suppress human tumor cell proliferation are reported here for the first time. In addition, this is the first report on the abrogation of TNF‐induced NF‐κB activation for compounds 1 and 2. Copyright © 2009 John Wiley & Sons, Ltd.     

Bioactive acylphloroglucinols from Hypericum densiflorum

Three acylphloroglucinol derivatives have been isolated from the hexane and acetone extracts of the aerial parts of Hypericum densiflorum Pursch. The compounds were characterized by NMR spectroscopy and mass spectrometry and identified as 4‐geranyloxy‐2,6‐dihydroxybenzophenone (1), 4‐geranyloxy‐1‐(2‐methylpropanoyl)‐ phloroglucinol (2) and 4‐geranyloxy‐1‐(2‐methylbutanoyl)‐phloroglucinol (3). Compounds 1–3 were evaluated for in vitro cell proliferation inhibitory activity against human breast (MCF‐7), lung (NCI H460), CNS (SF‐268), stomach (AGS) and colon (HCT‐116) tumor cell lines; antibacterial activity against methicillin‐resistant Staphylococcus aureus (MRSA); inhibition of cyclooxygenase (COX‐1 and ‐2) enzymes; and antioxidant activity in the lipid peroxidation (LPO) assay. All three compounds showed moderate to strong antitumor, antibacterial, antioxidant and inhibition of COX‐2 activities. Also, this is the first reported occurrence of compound 3 in the Hypericum genus. Copyright © 2009 John Wiley & Sons, Ltd.     

Cytotoxic Impact of Costunolide Isolated from Costus speciosus on Breast Cancer via Differential Regulation of Cell Cycle—An In‐vitro and In‐silico Approach

Costunolide, a sesquiterpene lactone, is a biologically active molecule found in most of the medicinally valuable plants. The present study aims to evaluate the anticancer property of costunolide isolated from Costus speciosus against breast cancer cell lines (MCF‐7 and MDA‐MB‐231). Costunolide effectively reduced the viability of both MCF‐7 and MDA‐MB‐231 cell lines at an IC₅₀ value of 40 μM. Flow cytometric analysis revealed costunolide mediated cell cycle arrest at G2/M phase in both the cell types. Western blotting results confirmed the alterations in the expression of cell cycle regulators (cyclin D1, D3, CDK‐4, CDK‐6, p18 INK4c, p21 CIP1/Waf‐1 and p27 KIP1) and apoptosis inducers (caspase‐3 and caspase‐9) upon costunolide treatment in comparison with their expressions in normal breast cell line (MCF‐10A). Costunolide mediated downregulation of positive cell cycle regulators and upregulation of negative cell cycle regulators were related to the induction of apoptosis in cancer cells. The above results were validated with in‐silico results that predicted stable interactions between costunolide and cancer targets. Thus costunolide effectively induced breast cancer cell apoptosis targeting cell cycle regulation, and the compound can be used as an effective herbal therapeutic molecule to treat breast cancer with further explorations. Copyright © 2015 John Wiley & Sons, Ltd.     

Inhibitory Activities of Thai Medicinal Plants with Promising Activities Against Malaria and Cholangiocarcinoma on Human Cytochrome P450

Malaria and cholangiocarcinoma remain important public health problems in tropical countries including Southeast Asian nations. Newly developed chemotherapeutic and plant‐derived drugs are urgently required for the control of both diseases. The aim of the present study was to investigate the propensity to inhibit cytochrome P450‐mediated hepatic metabolism (CYP1A2, CYP2C19, CYP2D6 and CYP3A4) of the crude ethanolic extract of eight Thai medicinal plants with promising activities against malaria and cholangiocarcinoma, using human liver microsomes in vitro. Piper chaba Linn. (PC) and Atractylodes lancea (thung.) DC. (AL) exhibited the most potent inhibitory activities on CYP1A2‐mediated phenacetin O‐deethylation with mean IC₅₀ of 0.04 and 0.36 µg/mL, respectively. Plumbago indica Linn. (PI) and Dioscorea membranacea Pierre. (DM) potently inhibited CYP2C19‐mediated omeprazole 5‐hydroxylation (mean IC₅₀ 4.71 and 6.92 µg/mL, respectively). DM, Dracaena loureiri Gagnep. (DL) and PI showed the highest inhibitory activities on dextromethorphan O‐demethylation (mean IC₅₀ 2.93–9.57 µg/mL). PC, DM, DL and PI exhibited the most potent inhibitory activities on CYP3A4‐mediated nifedipine oxidation (mean IC₅₀ 1.54–6.43 µg/mL). Clinical relevance of the inhibitory potential of DM, PC and PI is of concern for the further development of these plants for the treatment of malaria and/or cholangiocarcinoma. Copyright © 2015 John Wiley & Sons, Ltd.     

Hedera nepalensis K. Koch: A Novel Source of Natural Cancer Chemopreventive and Anticancerous Compounds

Traditional medicinal plants are often used for both the prevention and the treatment of local diseases. Taking into consideration the medicinal importance of Hedera nepalensis within local Pakistani traditions, the present study was undertaken to analyze the in vitro cancer chemopreventive and cytotoxic properties of the plant. The in vitro cancer chemopreventive testing was performed using nitrite assay, NFκB assay, aromatase assay, and quinone reductase 1 (QR1) assay. The cytotoxic potential was evaluated on three cancer‐cell lines: MCF‐7, MDA‐MB‐231, and HeLa using sulforhodamine B (SRB) assay. The results of cancer chemopreventive assays show that n‐hexane and ethyl acetate fractions of tested plant have promising cancer chemopreventive potential. Lupeol isolated from n‐hexane as well as ethyl acetate fraction showed lowest IC₅₀ (0.20 ± 1.9 μM) in NFκB assay. Crude extract and its fractions inhibited the growth of three cancer cell lines by more than 60%, IC₅₀ value of lupeol varied from 2.32 to 10.2 μM. HPLC‐DAD‐based quantification of lupeol in different plant tissues demonstrated that leaves of H. nepalensis are a rich source of lupeol (0.196 mg/100 mg dry weight). Our data have shown that H. nepalensis harbors cancer chemopreventive and cytotoxic agents. 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.