Pentacyclic triterpenes of the lupane, oleanane and ursane group as tools in cancer therapy.
01 Dec 2009-Planta Medica (© Georg Thieme Verlag KG Stuttgart · New York)-Vol. 75, Iss: 15, pp 1549-1560
TL;DR: This review summarizes the potential of triterpenes belonging to the lupane, oleanane or ursane group, to treat cancer by different modes of action and utilisation of different plants as their sources is of interest.
Abstract: Today cancer treatment is not only a question of eliminating cancer cells by induction of cell death. New therapeutic strategies also include targeting the tumour microenvironment, avoiding angiogenesis, modulating the immune response or the chronic inflammation that is often associated with cancer. Furthermore, the induction of redifferentiation of dedifferentiated cancer cells is an interesting aspect in developing new therapy strategies. Plants provide a broad spectrum of potential drug substances for cancer therapy with multifaceted effects and targets. Pentacyclic triterpenes are one group of promising secondary plant metabolites. This review summarizes the potential of triterpenes belonging to the lupane, oleanane or ursane group, to treat cancer by different modes of action. Since Pisha et al. reported in 1995 that betulinic acid is a highly promising anticancer drug after inducing apoptosis in melanoma cell lines in vitro and in vivo, experimental work focused on the apoptosis inducing mechanisms of betulinic acid and other triterpenes. The antitumour effects were subsequently confirmed in a series of cancer cell lines from other origins, for example breast, colon, lung and neuroblastoma. In addition, in the last decade many studies have shown further effects that justify the expectation that triterpenes are useful to treat cancer by several modes of action. Thus, triterpene acids are known mainly for their antiangiogenic effects as well as their differentiation inducing effects. In particular, lupane-type triterpenes, such as betulin, betulinic acid and lupeol, display anti-inflammatory activities which often accompany immune modulation. Triterpene acids as well as triterpene monoalcohols and diols also show an antioxidative potential. The pharmacological potential of triterpenes of the lupane, oleanane or ursane type for cancer treatment seems high; although up to now no clinical trial has been published using these triterpenes in cancer therapy. They provide a multitarget potential for coping with new cancer strategies. Whether this is an effective approach for cancer treatment has to be proven. Because various triterpenes are an increasingly promising group of plant metabolites, the utilisation of different plants as their sources is of interest. Parts of plants, for example birch bark, rosemary leaves, apple peel and mistletoe shoots are rich in triterpenes and provide different triterpene compositions.
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TL;DR: The most comprehensive picture over SFE of vegetable matrices is provided in this review, highlighting pertinent aspects and opportunities that may further consolidate the convincing route of this technology for the next years.
Abstract: Along more than a decade, R&D on supercritical fluid extraction (SFE) of vegetable matrices has been increasingly reported in the literature. Aiming at portraying the current state of this field and its evolution in terms of raw materials, products, modes of operation, optimization, modeling techniques, and closeness to industrial application, a large compilation of almost 600 essays from 2000 to 2013 has been deeply analyzed in order to unveil those indicators and their trends. Furthermore, strengths and weaknesses are identified, and some remarks that may drive upcoming research are provided. Globally, more than 300 species are reported in the literature, with prevalence of the extraction of seeds (28% of works) and leaves (17%). The main families of extracted compounds, cosolvents and operating conditions adopted are critically examined, being possible to conclude that researchers investigate many times working regions far from the optimum due to practical limitations or absence of experimental optimization. Current phenomenological, statistical and semi-empirical approaches are reviewed, along with scale-up studies, and economic analysis. In the whole, the most comprehensive picture over SFE of vegetable matrices is provided in this review, highlighting pertinent aspects and opportunities that may further consolidate the convincing route of this technology for the next years.
395 citations
TL;DR: The industrial uses and potential of saponins are discussed with respect to structure and activity, highlighting the undoubted value of these molecules as therapeutics.
Abstract: Saponins are widely distributed plant natural products with vast structural and functional diversity. They are typically composed of a hydrophobic aglycone, which is extensively decorated with functional groups prior to the addition of hydrophilic sugar moieties, to result in surface-active amphipathic compounds. The saponins are broadly classified as triterpenoids, steroids or steroidal glycoalkaloids, based on the aglycone structure from which they are derived. The saponins and their biosynthetic intermediates display a variety of biological activities of interest to the pharmaceutical, cosmetic and food sectors. Although their relevance in industrial applications has long been recognized, their role in plants is underexplored. Recent research on modulating native pathway flux in saponin biosynthesis has demonstrated the roles of saponins and their biosynthetic intermediates in plant growth and development. Here, we review the literature on the effects of these molecules on plant physiology, which collectively implicate them in plant primary processes. The industrial uses and potential of saponins are discussed with respect to structure and activity, highlighting the undoubted value of these molecules as therapeutics.
339 citations
Cites background from "Pentacyclic triterpenes of the lupa..."
...…by natural and semi-synthetic triterpenoids, alongside the triterpenoid and steroidal saponins and steroidal glycoalkaloids (Kannaiyan et al., 2011; Laszczyk, 2009; Lee et al., 2011; Liby & Sporn, 2012; Pollier & Goossens, 2012; Raju & Mehta, 2009; Shanmugam et al., 2013; Wu et al., 2007; Yadav et…...
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TL;DR: This review critically examines the potential role of naturally occurring terpenoids, from diverse origins, in the chemoprevention and treatment of liver tumors.
Abstract: Despite significant advances in medicine, liver cancer, predominantly hepatocellular carcinoma remains a major cause of death in the United States as well as the rest of the world. As limited treatment options are currently available to patients with liver cancer, novel preventive control and effective therapeutic approaches are considered to be reasonable and decisive measures to combat this disease. Several naturally occurring dietary and non-dietary phytochemicals have shown enormous potential in the prevention and treatment of several cancers, especially those of the gastrointestinal tract. Terpenoids, the largest group of phytochemicals, traditionally used for medicinal purposes in India and China, are currently being explored as anticancer agents in clinical trials. Terpenoids (also called “isoprenoids”) are secondary metabolites occurring in most organisms, particularly plants. More than 40 000 individual terpenoids are known to exist in nature with new compounds being discovered every year. A large number of terpenoids exhibit cytotoxicity against a variety of tumor cells and cancer preventive as well as anticancer efficacy in preclinical animal models. This review critically examines the potential role of naturally occurring terpenoids, from diverse origins, in the chemoprevention and treatment of liver tumors. Both in vitro and in vivo effects of these agents and related cellular and molecular mechanisms are highlighted. Potential challenges and future directions involved in the advancement of these promising natural compounds in the chemoprevention and therapy of human liver cancer are also discussed.
288 citations
TL;DR: In vitro and in vivo effects of these agents and related molecular mechanisms are presented and potential challenges and future directions involved in the advancement of these promising compounds in the prevention and therapy of human breast cancer are identified.
Abstract: Breast cancer remains a major cause of death in the United States as well as the rest of the world. In view of the limited treatment options for patients with advanced breast cancer, preventive and novel therapeutic approaches play an important role in combating this disease. The plant-derived triterpenoids, commonly used for medicinal purposes in many Asian countries, posses various pharmacological properties. A large number of triterpenoids are known to exhibit cytotoxicity against a variety of tumor cells as well as anticancer efficacy in preclinical animal models. Numerous triterpenoids have been synthesized by structural modification of natural compounds. Some of these analogs are considered to be the most potent antiinflammatory and anticarcinogenic triterpenoids known. This review examines the potential role of natural triterpenoids and their derivatives in the chemoprevention and treatment of mammary tumors. Both in vitro and in vivo effects of these agents and related molecular mechanisms are presented. Potential challenges and future directions involved in the advancement of these promising compounds in the prevention and therapy of human breast cancer are also identified.
267 citations
Cites background from "Pentacyclic triterpenes of the lupa..."
...They predominantly are found in various plants including seaweeds as well as in wax-like coatings of various fruits and medicinal herbs, including apples, cranberries, figs, olives, mistletoe, lavender, oregano, rosemary and thyme (21, 26, 28-30)....
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...An increasing number of triterpenoids have been reported to exhibit cytotoxicity against a variety of cancer cells without manifesting any toxicity in normal cells (24, 26, 27)....
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...The use of triterpenoids and related compounds for either chemoprevention or therapy of mammary carcinoma has not been extensively discussed previously although several excellent articles provide an overview of the antitumor potential of these agents against various cancers (24-27)....
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...They also demonstrate antitumor efficacy in preclinical animal models of cancer (26, 27)....
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TL;DR: The current state of knowledge about the health-promoting properties of this widespread, biologically active compound, as well as information about its occurrence and biosynthesis are presented.
Abstract: Ursolic acid (UA) is a natural terpene compound exhibiting many pharmaceutical properties. In this review the current state of knowledge about the health-promoting properties of this widespread, biologically active compound, as well as information about its occurrence and biosynthesis are presented. Particular attention has been paid to the application of ursolic acid as an anti-cancer agent; it is worth noticing that clinical tests suggesting the possibility of practical use of UA have already been conducted. Amongst other pharmacological properties of UA one can mention protective effect on lungs, kidneys, liver and brain, anti-inflammatory properties, anabolic effects on skeletal muscles and the ability to suppress bone density loss leading to osteoporosis. Ursolic acid also exhibits anti-microbial features against numerous strains of bacteria, HIV and HCV viruses and Plasmodium protozoa causing malaria.
260 citations
Cites background from "Pentacyclic triterpenes of the lupa..."
...Therefore different steps of the apoptotic process should be targeted to bypass such blocks [1]....
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References
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TL;DR: Because of its selective cytotoxicity against tumor cells and favorable therapeutic index, even at doses up to 500 mg/kg body weight, betulinic acid is a very promising new chemotherapeutic agent for the treatment of HIV infection and cancer.
Abstract: 3beta-Hydroxy-lup-20(29)-en-28-oic acid (betulinic acid) is a pentacyclic lupane-type triterpene that is widely distributed throughout the plant kingdom. A variety of biological activities have been ascribed to betulinic acid including anti-inflammatory and in vitro antimalarial effects. However, betulinic acid is most highly regarded for its anti-HIV-1 activity and specific cytotoxicity against a variety of tumor cell lines. Interest in developing even more potent anti-HIV agents based on betulinic acid has led to the discovery of a host of highly active derivatives exhibiting greater potencies and better therapeutic indices than some current clinical anti-HIV agents. While its mechanism of action has not been fully determined, it has been shown that some betulinic acid analogs disrupt viral fusion to the cell in a post-binding step through interaction with the viral glycoprotein gp41 whereas others disrupt assembly and budding of the HIV-1 virus. With regard to its anticancer properties, betulinic acid was previously reported to exhibit selective cytotoxicity against several melanoma-derived cell lines. However, more recent work has demonstrated that betulinic acid is cytotoxic against other non-melanoma (neuroectodermal and malignant brain tumor) human tumor varieties. Betulinic acid appears to function by means of inducing apoptosis in cells irrespective of their p53 status. Because of its selective cytotoxicity against tumor cells and favorable therapeutic index, even at doses up to 500 mg/kg body weight, betulinic acid is a very promising new chemotherapeutic agent for the treatment of HIV infection and cancer.
459 citations
TL;DR: The data support further preclinical studies of betulinic acid not confined to melanoma and neuroectodermal tumors independently of p53 status, and support the antineoplastic activity of this drug.
458 citations
Journal Article•
TL;DR: Results indicate that ursolic acid inhibits IB kinase and p65 phosphorylation, leading to the suppression of NF-B activation induced by various car- cinogens, which may mediate its antitumorigenic and chemosensitizing effects.
Abstract: The process of tumorigenesis requires cellular transformation, hyper- proliferation, invasion, angiogenesis, and metastasis. Several genes that mediate these processes are regulated by the transcription factor nuclear factor-B (NF-B). The latter is activated by various carcinogens, inflam- matory agents, and tumor promoters. Thus, agents that can suppress NF-B activation have the potential to suppress carcinogenesis. Ursolic acid, a pentacyclic triterpene acid, has been shown to suppress the ex- pression of several genes associated with tumorigenesis, but whether ursolic acid mediates its effects through suppression of NF- Bi s not understood. In the study described in the present report, we found that ursolic acid suppressed NF-B activation induced by various carcinogens including tumor necrosis factor (TNF), phorbol ester, okadaic acid, H2O2, and cigarette smoke. These effects were not cell type specific. Ursolic acid inhibited DNA binding of NF-B consisting of p50 and p65. Ursolic acid inhibited IB degradation, IB phosphorylation, IB kinase activa- tion, p65 phosphorylation, p65 nuclear translocation, and NF-B-depend- ent reporter gene expression. Ursolic acid also inhibited NF-B-dependent reporter gene expression activated by TNF receptor, TNF receptor-asso- ciated death domain, TNF receptor-associated factor, NF-B-inducing kinase, IB kinase, and p65. The inhibition of NF-B activation corre- lated with suppression of NF-B-dependent cyclin D1, cyclooxygenase 2, and matrix metalloproteinase 9 expression. Thus, overall, our results indicate that ursolic acid inhibits IB kinase and p65 phosphorylation, leading to the suppression of NF-B activation induced by various car- cinogens. These actions of ursolic acid may mediate its antitumorigenic and chemosensitizing effects.
417 citations
Journal Article•
TL;DR: Inhibitory effects of TP-69 or TP-72 on iNOS formation were not blocked by the glucocorticoid receptor antagonist RU-486, indicating that these triterpenoids do not act through the glucopreventive receptor, nor does TP- 72 act as an iN OS or COX-2 enzyme inhibitor when added to RAW cells in which synthesis of these two enzymes in response to LPS has already been induced.
Abstract: We have synthesized more than 80 novel triterpenoids, all derivatives of oleanolic and ursolic acid, as potential anti-inflammatory and chemopreventive agents. These triterpenoids have been tested for their ability to suppress the de novo formation of two enzymes, inducible nitric oxide synthase (iNOS) and inducible cyclooxygenase (COX-2), using IFN-γ-stimulated primary mouse macrophages or lipopolysaccharide (LPS)-activated RAW 264.7 macrophages as assay systems. Two synthetic oleananes, 3,12-dioxoolean-1-en-28-oic acid (TP-69) and 3,11-dioxoolean-1,12-dien-28-oic acid (TP-72), were highly active inhibitors of de novo formation of both iNOS and COX-2. Both TP-69 and TP-72 blocked the increase in iNOS or COX-2 mRNA induced by IFN-γ or LPS. In addition, TP-72 suppressed NF-κB activation in primary macrophages treated with the combination of IFN-γ and LPS or IFN-γ and tumor necrosis factor. The 3-α(axial)-epimer of ursolic acid suppressed de novo formation of COX-2, in contrast to naturally occurring 3-β(equatorial)-ursolic acid. Inhibitory effects of TP-69 or TP-72 on iNOS formation were not blocked by the glucocorticoid receptor antagonist RU-486, indicating that these triterpenoids do not act through the glucocorticoid receptor, nor does TP-72 act as an iNOS or COX-2 enzyme inhibitor when added to RAW cells in which synthesis of these two enzymes in response to LPS has already been induced. It may be possible to develop triterpenoids as useful agents for chemoprevention of cancer or other chronic diseases with an inflammatory component.
368 citations
TL;DR: Findings show that induction of mitochondrial permeability transition alone is sufficient to trigger the full apoptosis program and that some cytotoxic drugs such as BetA may induce apoptosis via a direct effect on mitochondria.
368 citations