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.
Citations
More filters
TL;DR: A number of semisynthetic derivatives of oleanane-, ursane- and quinone methide friedelane-type PTs with anticancer activity have been synthetized aiming to improve their therapeutic activity and pharmacokinetic properties, and decrease their toxicity.
110 citations
Cites background from "Pentacyclic triterpenes of the lupa..."
...Additionally, PTs are able to modulate the tumor microenvironment and the immune system, while displaying selective cytotoxic activity between tumor and non-tumor cells [1, 3, 9, 10, 16-27]....
[...]
TL;DR: In the present review, selected single chemical entity natural products of plant origin and their semi-synthetic derivatives currently in clinical trials are featured as examples of new cancer chemotherapeutic drug candidates.
Abstract: Small organic molecules derived from higher plants have been one of the mainstays of cancer chemotherapy for approximately the past half a century In the present review, selected single chemical entity natural products of plant origin and their semi-synthetic derivatives currently in clinical trials are featured as examples of new cancer chemotherapeutic drug candidates Several more recently isolated compounds obtained from plants showing promising in vivo biological activity are also discussed in terms of their potential as anticancer agents, with many of these obtained from species that grow in tropical regions Since extracts of only a relatively small proportion of the ca 300,000 higher plants on earth have been screened biologically to date, bioactive compounds from plants should play an important role in future anticancer drug discovery efforts
109 citations
Cites background from "Pentacyclic triterpenes of the lupa..."
...Pyridinum narciclasine (34) and sodium pancratistatin 3,4-O-cyclic phosphate (35) are prodrugs of narciclasine and pancratistatin, respectively, which have been produced to improve the water solubility of these two compounds (99, 103)....
[...]
...initiating ROS (reactive oxygen species) generation (34)....
[...]
TL;DR: 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.
Abstract: 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.
93 citations
Cites background from "Pentacyclic triterpenes of the lupa..."
...…anti-ulcer, cardiovascular, hypolipidemic, antiatherosclerotic, immunoregulatory, anticancer and cancer preventive activities (Ovesná et al. 2004; Laszczyk 2009; Petronelli et al. 2009; Yadav et al. 2010; Bishayee et al. 2011; Lanzotti et al. 2012; Patlolla and Rao 2012; Safe et al. 2012;…...
[...]
...and pharmacological effects, including anti-inflammatory, antibacterial, antiviral, hepatoprotective, gastroprotective, anti-ulcer, cardiovascular, hypolipidemic, antiatherosclerotic, immunoregulatory, anticancer and cancer preventive activities (Ovesná et al. 2004; Laszczyk 2009; Petronelli et al. 2009; Yadav et al. 2010; Bishayee et al. 2011; Lanzotti et al. 2012; Patlolla and Rao 2012; Safe et al. 2012; Shanmugam et al. 2012)....
[...]
TL;DR: Kinetic studies revealed that corosolic acid and oleanolic acid showed non-competitive inhibition and acarbose showed mixed-type inhibition against α-amylase, which provides valuable implications for the triterpenes alone or in combination with acarbOSE as a therapeutic agent for the treatment of diabetes mellitus.
88 citations
Cites background from "Pentacyclic triterpenes of the lupa..."
...These triterpenes are found in many plants, such as apple peelings, mistletoe, rosemary leaves, olive leaves, pears, prunes, cranberries, and figs.(13,14) Pentacyclic triterpenes have been reported to exhibit multiple biological activities, including...
[...]
TL;DR: Assigning biochemical functions to these P450s will be of interest to extend the knowledge on triterpene metabolism in diverse plant species and also for the sustainable production of valuable phytochemicals.
Abstract: Cytochrome P450 monooxygenases (P450s) represent the largest enzyme family of the plant metabolism. Plants typically devote about 1% of the protein-coding genes for the P450s to execute primary metabolism and also to perform species-specific specialized functions including metabolism of the triterpenes, isoprene-derived 30-carbon compounds. Triterpenes constitute a large and structurally diverse class of natural products with various industrial and pharmaceutical applications. P450-catalyzed structural modification is crucial for the diversification and functionalization of the triterpene scaffolds. In recent times, a remarkable progress has been made in understanding the function of the P450s in plant triterpene metabolism. So far, ∼80 P450s are assigned biochemical functions related to the plant triterpene metabolism. The members of the subfamilies CYP51G, CYP85A, CYP90B-D, CYP710A, CYP724B, and CYP734A are generally conserved across the plant kingdom to take part in plant primary metabolism related to the biosynthesis of essential sterols and steroid hormones. However, the members of the subfamilies CYP51H, CYP71A,D, CYP72A, CYP81Q, CYP87D, CYP88D,L, CYP93E, CYP705A, CYP708A, and CYP716A,C,E,S,U,Y are required for the metabolism of the specialized triterpenes that might perform species-specific functions including chemical defense toward specialized pathogens. Moreover, a recent advancement in high-throughput sequencing of the transcriptomes and genomes has resulted in identification of a large number of candidate P450s from diverse plant species. Assigning biochemical functions to these P450s will be of interest to extend our knowledge on triterpene metabolism in diverse plant species and also for the sustainable production of valuable phytochemicals.
88 citations
Cites background from "Pentacyclic triterpenes of the lupa..."
...Owing to the potent bioactivities, triterpenes have commercial applications in pharmaceutical, food and cosmetic sectors (Laszczyk, 2009; Sawai and Saito, 2011; Salvador et al., 2012; Moses et al., 2013)....
[...]
References
More filters
TL;DR: Attention is focussed on the ROS/RNS-linked pathogenesis of cancer, cardiovascular disease, atherosclerosis, hypertension, ischemia/reperfusion injury, diabetes mellitus, neurodegenerative diseases, rheumatoid arthritis, and ageing.
12,240 citations
TL;DR: The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment.
Abstract: The mediators and cellular effectors of inflammation are important constituents of the local environment of tumours. In some types of cancer, inflammatory conditions are present before a malignant change occurs. Conversely, in other types of cancer, an oncogenic change induces an inflammatory microenvironment that promotes the development of tumours. Regardless of its origin, 'smouldering' inflammation in the tumour microenvironment has many tumour-promoting effects. It aids in the proliferation and survival of malignant cells, promotes angiogenesis and metastasis, subverts adaptive immune responses, and alters responses to hormones and chemotherapeutic agents. The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment.
9,282 citations
TL;DR: This review examines the evidence for involvement of the oxidative stress in the carcinogenesis process and the role of enzymatic and non-enzymatic antioxidants in the process of carcinogenesis as well as the antioxidant interactions with various regulatory factors.
5,937 citations
TL;DR: Both oleanolic acid and ursolic acid are effective in protecting against chemically induced liver injury in laboratory animals and have been noted for their antitumor-promotion effects, which are stimulating additional research in this field.
1,345 citations
TL;DR: As a result of bioassay–guided fractionation, betulinic acid, a pentacyclic triterpene, was identified as a melanoma–specific cytotoxic agent and antitumour activity was mediated by the induction of apoptosis.
Abstract: As a result of bioassay-guided fractionation, betulinic acid, a pentacyclic triterpene, was identified as a melanoma-specific cytotoxic agent. In follow-up studies conducted with athymic mice carrying human melanomas, tumour growth was completely inhibited without toxicity. As judged by a variety of cellular responses, antitumour activity was mediated by the induction of apoptosis. Betulinic acid is inexpensive and available in abundant supply from common natural sources, notably the bark of white birch trees. The compound is currently undergoing preclinical development for the treatment or prevention of malignant melanoma.
829 citations