Tamanoi The Enzymes

1. Auflage 2015
ISBN: 978-0-12-803877-2
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, Band Volume 37, 276 Seiten

Reihe: The Enzymes

Volume 37 will provide details on the major chemical constituents of medicinal plants and their mechanism of action as the anticancer compounds. This special issue, in addition to the previous volume (volume 36 of the Enzyme series was on the topic of Natural Products and Cancer Signaling Targets: Isoprenoids, Polyphenols and Flavonoids), will highlight the significant advance made in the field in elucidating mechanisms of anticancer effect of the major phytochemicals. - Contributions from leading authorities - Informs and updates on all the latest developments in the field

Autoren/Hrsg.

Tamanoi, Fuyuhiko

Leseproben

Chapter Two Quercetin and Tryptanthrin
Two Broad Spectrum Anticancer Agents for Future Chemotherapeutic Interventions
G. Mohan Shankar1; Jayesh Antony1; Ruby John Anto2    Cancer Research Program, Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
2 Corresponding author: email address: [e-mail]
1 These authors contributed equally. Abstract
The idea and practice of developing or identifying compounds capable of eliminating the transformed cells or cancer cells without being nontoxic to their normal counterparts deserves much importance. Since ages, plants have been considered and proven to be repertoires of chemicals possessing immense therapeutic potential. A proportion of these plant-derived compounds or phytochemicals were shown to be highly competent anticancer agents besides being effective against many other diseases. Representative compounds of different classes of phytochemicals are in clinical use against cancer. In this chapter, we discuss the anticancer potential of two compounds: quercetin, a flavonoid and tryptanthrin, an indoloquinazoline alkaloid, and the mechanisms behind their cytotoxic effects on cancers of different origin. The chapter also gives a brief mention of their properties that make them effective against cancer. Keywords Tryptanthrin Quercetin Anticancer agent Phytochemicals 1 Introduction
Scientific and epidemiological studies have highlighted the importance of food consumption on cancer prevention. As reported by The American Institute of Cancer Research, a high intake of fruits and vegetables is correlated to a low risk for tumor incidence. The National Academy of Sciences of the United States in 1982 has laid stress on the importance of fruits and vegetables on cancer prevention by including guidelines in its report on diet and cancer [1]. In this report, a special mention of adding citrus fruits, carotene-rich fruits and vegetables to the diet, and its significance on cancer prevention was given. Since decades, plant secondary metabolites have gained the attention of researchers owing to their effectiveness in curing or preventing a myriad of ailments, including cancer and cardiovascular diseases. Studies suggest that the health benefits, of plant product consumption are attributed to the additive or synergistic effects of different phytochemicals. However, with the focus on identifying novel lead compounds for drug discovery, ample investigations are being shaped for isolation and identification of bioactive compounds from plant sources. Though a large body of evidence has illustrated the chemotherapeutic and chemopreventive potential of different phytochemicals, only a very small proportion of them have entered clinical trials. In this chapter, we bring to the spotlight, two compounds: quercetin and tryptanthrin that has shown a great degree of effectiveness against cancer but is not yet being used in clinic to treat cancer. 2 Quercetin
2.1 Source
Quercetin is contained in abundance in apples, honey, raspberries, onions, red grapes, cherries, citrus fruits, and green leafy vegetables [2]. Among vegetables and fruits, quercetin content is highest in onions. The bulb color and type seems to be a determining factor for quercetin concentration in onions. Preparation and storage of food can affect quercetin content in it. Fried or boiled foods contain lower quercetin content with boiling being the main causative for reduction in quercetin level due to thermal degradation and leaching action of boiling water [3]. Long-term storage of foods was found to change their quercetin content. While onions lose their quercetin content by up to 33% in the first 12 days of storage [4], quercetin level in strawberries has been shown to increase by approximately 32% when stored at - 20 °C for 9 months. Apart from storage and preparation, the conditions of the growth of plants were found to be a factor that influence quercetin levels in them. This is clear from studies that indicate a higher quercetin content in plants exposed to greater amount of UV-radiation [3] is the cause of which is hypothesized to be a defence mechanism against UV-exposure. 2.2 Biosynthesis
The biosynthesis of flavonoids is a defensive response of plants against damage induced by the environment. Flavonoids are secreted in higher amounts as a response to UV-radiation. Previous studies have reported the increased synthesis of quercetin-3-O-ß-glucuronide when cell cultures are exposed to UV-radiation. 2.3 Structure and Antioxidative Property
The basic structure of flavonoids consists of two phenyl groups joined by a three carbon bridge. According to their structure, flavonoids are divided into two classes, those which have an open three carbon bridge and those in which three carbon bridge is involved in a heterocyclic ring referred to as ring C [4,5]. Quercetin (3,3,4,5,7-pentahydroxyflavone), existing in the natural form as a glycoside, consists of two aromatic rings A and B linked to each other by a heterocyclic oxygen containing ring. It forms the backbone for other flavonoids like hesperidin, naringin, rutin, and tameritin. When quercetin reacts with a free radical, it itself becomes a free radical by donating a proton. This quercetin radical is too low in energy to be reactive due to the delocalization of electrons by resonance [6]. The B ring o-dihydroxyl groups, the 4-oxo group in conjugation with the 2,3-alkene and the 3- and 5-hydroxyl groups is responsible for maintaining quercetin's stability and antioxidant activity when reacting with free radicals [4] (Fig. 1). Figure 1 The chemical structure of quercetin. 2.4 Properties
Quercetin exhibits a variety of properties that qualifies it to be used for many therapeutic purposes. It exhibits high antioxidant and metal ion-chelating capacity, inhibits the nitric oxide pathway and LDL oxidation, hinders inflammation and histamine activity, and also possess anticancer activity against tumors of many origins. 2.4.1 Antioxidant Property The cell's antioxidant system protects the organism from damage induced by reactive oxygen species (ROS) and reactive nitrogen species and other free radicals that accumulates as a result of normal cellular processes or by the action of external agents [7]. The major enzymes involved in the organism's antioxidative system are superoxide dismutase (SOD), catalase, and glutathione peroxidase. Apart from these enzymes, other molecules like vitamin A and vitamin C also plays a role in protecting the cells against oxidative damage. Quercetin, among other phytochemicals, proves to be a highly efficient antioxidant that inhibits the oxidation chain initiation and propagation. This may also include the termination of a chain by the reaction of two radicals. 2.4.2 Free Radical Scavenging Activity Free radicals produced as byproducts of various biochemical reactions have been implicated in many diseases like cancer, where they contribute to tumor initiation by inducing mutations in the genome. Quercetin's has been shown to be effective in reperfusion ischemic damage and atherosclerosis by blocking free radicals. 2.4.3 Nitric Oxide Inhibitory Action Nitric oxide, produced by macrophages and endothelial cells, participates in bountiful vital physiological processes like blood vessel dilation, transmission of nerve impulse, cell migration, etc. [8]. Depending on the site, timing, and concentration, this pleiotropic regulator can support or suppress tumor progression [9]. Nitric oxide, synthesized by the enzyme nitric oxide synthase, reacts with free radicals thereby producing peroxynitrate, a compound that ensures irreversible cell membrane damage by oxidizing LDLs. Quercetin's action as a free radical scavenger benefits the organism by preventing the reaction of free radicals with nitric oxide, thereby aborting subsequent mechanisms that lead to cell damage. Nitric oxide itself was reported to be a target of flavonoids [10]. 2.4.4 Inhibition of Xanthine Oxidase Xanthine oxidase is involved in oxidative injury of tissues especially after ischemia–reperfusion [11]. During oxidative stress and ischemic conditions, xanthine dehydrogenase, the enzyme present in normal physiological conditions gets converted to xanthine oxidase that triggers oxidative damage in cells. Xanthine oxidase was shown to upregulate hypoxia-induced factor-1a, a transcription factor that promotes angiogenesis, anaerobic metabolism, and cell survival. Inhibition of xanthine oxidase is included among other mechanisms by which quercetin reduce oxidative injury [12]. 2.4.5 Interaction with Other Enzyme Systems Quercetin was found to modulate different cellular pathways by interacting with a wide range of enzymes. It interacts with the calcium-binding regulatory protein, calmodulin [13], and thereby influencing the activity of calmodulin-dependent enzymes like ATPase and phospholipases, thus bringing about changes in membrane permeability [14]. Apart from modifying membrane permeability, inhibition of phospholipases leads to an arrest in the synthesis of arachidonic acid, the precursor molecule for the synthesis of inflammation promoting molecules...