Phytochemistry Reviews (v.13, #4)

Investigation of Vietnamese plants for potential anticancer agents by Lynette Bueno Pérez; Patrick C. Still; C. Benjamin Naman; Yulin Ren; Li Pan; Hee-Byung Chai; Esperanza J. Carcache de Blanco; Tran Ngoc Ninh; Bui Van Thanh; Steven M. Swanson; Djaja D. Soejarto; A. Douglas Kinghorn (727-739).
Higher plants continue to afford humankind with many new drugs, for a variety of disease types. In this review, recent phytochemical and biological progress is presented for part of a collaborative multi-institutional project directed towards the discovery of new antitumor agents. The specific focus is on bioactive natural products isolated and characterized structurally from tropical plants collected in Vietnam. The plant collection, identification, and processing steps are described, and the natural products isolated from these species are summarized with their biological activities.
Keywords: Anticancer agents; Natural products; Tropical plants; Vietnam

The genus Pinus: a comparative study on the needle essential oil composition of 46 pine species by Efstathia Ioannou; Aikaterini Koutsaviti; Olga Tzakou; Vassilios Roussis (741-768).
The fresh needles of 46 pine species, including 37 and 17 taxa of the subgenera Pinus and Strobus, respectively, were subjected to hydrodistillation and the essential oils obtained were analyzed by means of GC–FID and GC–MS. The comprehensive analyses of the needle oils, which allowed for the identification of 161 constituents comprising the majority of the volatiles, showed significant, not only quantitative, but also qualitative differences between the samples. Monoterpenes, sesquiterpenes and diterpenes dominated the pine foliage oils, with the presence of the monoterpene hydrocarbons α- and β-pinene and the sesquiterpene hydrocarbon germacrene D characterizing most of the oils. This is the first report on the chemical composition of the essential oils of 21 pine taxa, including 15 taxa of subgenus Pinus and 6 taxa of subgenus Strobus.
Keywords: Chemical composition; Essential oil; Gas chromatography; Needle volatiles; Pinus

Compounds from Allium species with cytotoxic and antimicrobial activity by Virginia Lanzotti; Felice Scala; Giuliano Bonanomi (769-791).
Garlic (Allium sativum L.) is a bulb-shaped plant belonging to the Allium genus which also includes onions (Allium cepa L.), leek (Allium ampeloprasum L. var. porrum Gay), shallot (Allium ascalonicum L), scallion (A. fistulosum L.) and chives (Allium schoenoprasum L.). The biological activity of garlic has been known since ancient times. Babylonians, Egyptians, Phoenicians, Greeks and Romans used garlic as a remedy for intestinal disorders, respiratory infections, skin diseases, bacterial infections, worms, wounds and tumors. In particular, before the discovery of antibiotics, garlic has been used against amoebic dysentery and epidemic diseases such as typhus, cholera, diphtheria, and tuberculosis. To date, more than 3,000 publications scientifically supported the use of garlic in the ethno-medicine. But what makes garlic and Allium species effective against cancer? The effect of garlic may arise from its antibacterial properties or from its ability to block formation on cancer-causing substances, half the activation of cancer causing substances, enhance DNA repair, reduce cell proliferation or induce cell death. Epidemiological studies have found that an increase of consumptions of Allium spp. reduce the risk of prostate and gastric cancers and this has been mainly related to two main classes of compounds: the apolar sulphur compounds and the polar saponins. These latter compounds, compared to the more studied thiosulphinates, have the advantages of not being pungent and more stable during cooking. Recently, there has been increasing scientific attention given to such compounds. In this paper, the literature about the major volatile and non-volatile organic compounds of garlic and other Allium plants has been reviewed. Particular attention is given to the compounds possessing antibacterial and cytotoxic activity in garlic and in the other Allium species and their mechanism of action.
Keywords: Garlic; Onion; Anticancer activity; Antioxidant activity; Antibacterial activity

Oleanane triterpenoids in the prevention and therapy of breast cancer: current evidence and future perspectives by Nisha R. Parikh; Animesh Mandal; Deepak Bhatia; Kodappully Sivaraman Siveen; Gautam Sethi; Anupam Bishayee (793-810).
Breast cancer is one of the most frequently diagnosed cancers and major cause of death in women in the world. Emerging evidence underscores the value of dietary and non-dietary phytochemicals, including triterpenoids, in the prevention and treatment of breast cancer. Oleanolic acid, an oleanane-type pentacyclic triterpenoid, is present in a large number of dietary and medicinal plants. Oleanolic acid and its derivatives exhibit several promising pharmacological activities, including antioxidant, anti-inflammatory, hepatoprotective, cardioprotective, antipruritic, spasmolytic, antiallergic, antimicrobial and antiviral effects. Numerous studies indicate that oleanolic acid and other oleanane triterpenoids modulate multiple intracellular signaling pathways and exert chemopreventive and antitumor activities in various in vitro and in vivo model systems. A series of novel synthetic oleanane triterpenoids have been prepared by chemical modifications of oleanolic acid and some of these compounds are considered to be the most potent anti-inflammatory and anticarcinogenic triterpenoids. Accumulating studies provide extensive evidence that synthetic oleanane derivatives inhibit proliferation and induce apoptosis of various cancer cells in vitro and demonstrate cancer preventive or antitumor efficacy in animal models of blood, breast, colon, connective tissue, liver, lung, pancreas, prostate and skin cancer. This review critically examines the potential role of oleanolic acid, oleanane triterpenoids and related synthetic compounds in the chemoprevention and treatment of mammary neoplasia. Both in vitro and in vivo studies on these agents and related molecular mechanisms are presented. Several challenges and future directions of research to translate already available impressive preclinical knowledge to clinical practice of breast cancer prevention and therapy are also presented.
Keywords: Chemoprevention; Mammary cancer; Oleanolic acid; Synthetic oleananes; Treatment

Cancer chemopreventive pharmacology of phytochemicals derived from plants of dietary and non-dietary origin: implication for alternative and complementary approaches by Mohammad F. Ullah; Showket H. Bhat; Eram Husain; Faisel Abu-Duhier; S. M. Hadi; Fazlul H. Sarkar; Aamir Ahmad (811-833).
The poor survival statistics of the fatal cancer diseases highlight the need for multiple alternative treatment options. An impressive embodiment of evidence shows that naturally occurring herbal products contain a wide variety of phytochemicals that are regarded as effective cancer protective agents, possessing the ability to retard, block or reverse carcinogenesis. These include dietary agents often termed as nutraceuticals and also the components of non-dietary plants. Many studies in different cell lines, animal models and human epidemiological trials suggest a protective role of a large number of medicinal molecules of herbal origin against different types of cancers. The standard chemotherapeutic regime against cancer faces an unequivocal challenge due to the severity of the side-effects and the post therapeutic management of the disease. Cancer control may therefore benefit from the anti-cancer potential of alternative therapies that may include herbal treatment which nonetheless has been an effective curative strategy reported for a number of diseases since ancient times. In congruence of the above idea, it has been observed that in recent years the demand to utilize alternative approaches to the treatment of cancer is escalating. Additionally, the emergence of resistance to cancer chemotherapy has forced researchers to turn to natural products of herbal and marine origin. Currently, in the armamentarium of anti-cancer pharmaceuticals there are effective plant-derived drugs such as paclitaxel (a complex taxane diterpene isolated from the bark of Taxus brevifolia) which acts as microtubule disruptor. Further there are plant-based dietary agents such as sulphoraphane (an isothiocyanate derived from cruciferous vegetables) and non-dietary agents such as pomiferin (an isoflavonoid from Maclura pomifera) which strongly mimic chemotherapeutic drugs such as vorinostat (suberoylanilidehydroxamic acid) possessing histone diacetylase inhibition activity. In this review we provide a comprehensive outline of the translational potential of plant-based herbal medicine for complementing the current treatment modalities as an adjuvant or alternative therapy for cancer patients.
Keywords: Phytochemicals; Chemoprevention; Alternative and complementary therapy

Cytotoxic activity and mechanism of action of metabolites from the Goniothalamus genus by Chee-Yan Choo; Norkamilah Abdullah; Marc Diederich (835-851).
The World Health Organization estimates that 4 billion people or 80 % of the population use plants for curative purposes or for their natural health benefits. Accordingly, biodiversity is an important source of active natural products especially used in traditional medicine as healers transmitted knowledge of traditional usage of medicinal plants from generation to generation whereas pharmacologically active compounds within remained obscure. The present review documents cytotoxicity and anti-cancer potential of known compounds of the Goniothalamus species from the Annonaceae family existing in tropical and subtropical Asia and being intensively used for medicinal purposes.
Keywords: Goniothalamus ; Annonaceae; Styryl lactones; Acetogenins; Alkaloids; Cancer; Apoptosis; Cell cycle

Phytoestrogens as natural prodrugs in cancer prevention: towards a mechanistic model by Randolph R. J. Arroo; Kenneth Beresford; Avninder S. Bhambra; Mike Boarder; Roberta Budriesi; Zhong Cheng; Matteo Micucci; Ketan C. Ruparelia; Somchaiya Surichan; Vasilis P. Androutsopoulos (853-866).
It has been widely acknowledged that regular consumption of fresh fruits and vegetables is linked with a relatively low incidence of cancers (e.g. breast, cervix, and colon). Notably, dietary polyphenolic compounds that show some structural similarity to human estrogen, e.g. isoflavones, coumestans, lignans, flavones, have been proposed to play a role in cancer prevention. However, at present there is no satisfactory explanation for the cancer preventative properties of this group of compounds. Whereas polyphenolic compounds have been shown to inhibit proliferation of tumour cells in vitro, the results of in vivo tests have mostly been disappointing in this respect. It seems that mammalian phase II detoxification mechanisms make that dietary polyphenols are rapidly and effectively removed from the body, i.e. their concentration in the blood plasma hardly ever reaches levels high enough to have a possible effect on tumour growth. The polymethoxyflavones nobiletin and tangeretin, common constituents of Citrus peel, are better absorbed than polyhydroxy flavonoids, and maintain their biological activity for a longer period of time. The compounds are known to be substrates for the estrogen-converting cytochrome P450 enzymes CYP1A1 and CYP1B1, which are typically over-expressed in a range of tumour tissues. The enzymes catalyse regioselective hydroxylation and dealkylation of the polymethoxyflavones, resulting in reaction products that appear to inhibit cell proliferation via interference with the MAPK/ERK cell signalling pathway.
Keywords: Flavonoids; Chemoprevention; Cancer; Polymethoxy flavones; Cell signalling; Cytochrome P450

Colorectal cancer is one of the leading causes of cancer incidence and death worldwide. For the past 30 years researchers have tried to find drugs suitable for the chemoprevention of the diseases. Epidemiological studies have demonstrated that adherence to the Mediterranean Diet (MD) is protective toward colon cancer development. Key components of this diet are olive oil (OO), fruits and vegetables, legumes and fish. Importantly, many bioactives present in these foods have shown anti-cancer activity in in vitro as well as in animal models of colon carcinogenesis, indicating a possible use as preventive agents. However, when translated to human trials, single bioactives have yielded conflicting results mostly due to irreproducibility of pre-clinical data. Since our preclinical models are usually designed to test single molecules at high concentrations and for very short time in order to provide significant effects, future studies should employ multiple bioactives that would resemble a more natural approach with possible significant synergisms that might be critical for cancer prevention. In this review we will discuss data obtained with components of the MD with a specific focus on OO, omega-3 polyunsaturated fatty acids and apples.
Keywords: Colon cancer; Omega 3; Ulcerative colitis; Olive oil; Apple; Mediterranean Diet

A review of the proximate composition and nutritional value of Marula (Sclerocarya birrea subsp. caffra) by Penny Hiwilepo-van Hal; Peter George Bille; Ruud Verkerk; Martinus A. J. S. van Boekel; Matthijs Dekker (881-892).
This review critically evaluated literature on proximate composition and nutritional value of Marula in comparison with other tropical and indigenous fruits in order to identify areas for future research. It was found that nutrients content and processing methods of Marula fruit varied greatly from study to study and according to place of origin, soil, climate, handling, analytical methods used and time that lapsed after harvesting before analysis took place. Marula fruit pulp is reported to have vitamin C content higher than that of most fruits, ranging from 62 mg/100 g to over 400 mg/100 g. Additionally, Marula fruit is reported to have an antioxidant capacity of between 8 and 25 mM, (ascorbic acid equivalents) and a total phenolic content ranging from 7.5 to 24 mg/g dry weight gallic acid equivalent. Marula kernels are also a good source of protein, oil, magnesium, phosphorus and potassium and their oil is used in food preparations. Marula fruits could play a vital role in terms of nutrition to rural community who rely on the usage of the fruits, as they do not have easy access to other sources of nutrients. Recommendation given for future research includes improving Marula fruits juice extraction and yields, investigating the effect of processing and storage on the retention of nutrients such as vitamin C and its antioxidant capacity in processed and unprocessed Marula products and further identifying Marula fruits flavor compounds and their effect on processing and storage.
Keywords: Sclerocarya birrea subsp. Caffra ; Marula; Composition; Vitamin C; Antioxidant

Biotechnological approaches for producing aryltetralin lignans from Linum species by S. Malik; O. Bíba; J. Grúz; R. R. J. Arroo; M. Strnad (893-913).
The genus Linum includes more than 230 globally distributed species, which have attracted great interest as they grow rapidly and are already sources of commercially important products, e.g. flax and linseed oil. Furthermore, they contain lignans such as podophyllotoxin (PTOX), deoxypodophyllotoxin (a precursor of both PTOX and 6-methoxypodophyllotoxin, the latter via β-peltatin, and β-peltatin-A-methyl ether) and various derivatives. Lignans are natural compounds derived from two 8,8′-linked C6C3 (propylbenzene) units. PTOX is an aryltetralin-lignan with strong cytotoxic and antiviral activities. Thus, it is used as a starting material for producing various semisynthetic derivatives that are widely used in chemotherapy, such as etoposide, teniposide and etopophos. It is currently produced largely from Podophyllum hexandrum and P. peltatum, slow-growing endangered species of the Berberidaceae. Hence, the possibility of producing it from Linum, especially members of section Syllinum under either in vitro or ex vitro conditions is highly attractive. This review summarizes related research, focusing on in vitro production of aryltetralin lignans from various Linum species and possible biotechnological strategies to improve their production. The key pathways, enzymes and genes involved are highlighted and future challenges that must be met to allow viable, large-scale production of this anticancer drug lead are discussed.
Keywords: 6-Methoxypodophyllotoxin; Anticancer drugs; In vitro cultures; Lignans; Podophyllotoxin; Medicinal plants

Euphorbia and Momordica metabolites for overcoming multidrug resistance by Maria-José U. Ferreira; Noélia Duarte; Mariana Reis; Ana Margarida Madureira; Joseph Molnár (915-935).
Multidrug resistance (MDR) is the major obstacle for cancer chemotherapy. MDR is a multifactorial phenomenon that can result from several mechanisms, including an increased drug efflux, due to overexpression of P-glycoprotein (P-gp) that transports anticancer drugs out of the cells. Thus, the role of this transporter has made it a therapeutic target and the development of P-gp modulators considered among the most realistic approaches for overcoming P-gp-mediated MDR. Many other strategies have been proposed. One of them is the identification of compounds that selectively kill multidrug resistant cells. In our search for MDR modulators from plants, the P-gp inhibition ability of a large number of compounds on resistant cancer cells was evaluated. These compounds, presented in this review, comprise mainly diterpenes, triterpenes and phenolic derivatives. The most relevant results were obtained from two sets of compounds: macrocyclic diterpenes with the jatrophane and lathyrane scaffold, and triterpenes of the cucurbitane-type isolated from Euphorbia species and Momordica balsamina L., respectively. Additionally, some of those macrocyclic diterpenes, and ent-abietane diterpenic lactones, also isolated from Euphorbia species, were found to be selectively toxic to drug-resistant phenotypes.
Keywords: Euphorbia ; ent-Abietane lactones; Macrocyclic diterpenes; Momordica balsamina L.; P-glycoprotein; Triterpenes

New perspectives on the use of nucleic acids in pharmacological applications: inhibitory action of extracellular self-DNA in biological systems by Stefano Mazzoleni; Fabrizio Cartenì; Giuliano Bonanomi; Guido Incerti; Maria Luisa Chiusano; Pasquale Termolino; Antonello Migliozzi; Mauro Senatore; Francesco Giannino; Max Rietkerk; Antonio Risitano; Virginia Lanzotti (937-946).
The research for new products against pathogens, parasites and infesting species, in both agriculture and medicine, implies huge and increasing scientific, industrial and economic efforts. Traditional approaches are based on random screening procedures searching for bioactive compounds. However, the success of such methodologies in most cases has been strongly limited by side-effects of the potential new drugs, especially toxicity and pharmacological resistance. The use of nucleic acids in drug development has been introduced searching for target-specific effect. In addition, a recent discovery revealed that randomly fragmented extracellular self-DNA may act as highly species-specific inhibitory product for different species, suggesting an unprecedented use of DNA for biological control. On this base, a new scenario of pharmacological applications is discussed.
Keywords: Drug discovery; Random screening; Combinatorial synthesis; Nucleosides analogues; Conspecific DNA; Antisense oligonucleotides; Autotoxicity