Anticancer and Immunomodulatory Properties of Tinospora

Modern Ayurveda

Ayurveda the Science of Life

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Anil Mittal and Rana P. Singh

Abstract There has been an upsurge in the discovery of bioactive phytochemicals having a chemopreventive ability against various diseases including immunological disorders and cancer. Based on their uses in Ayurveda or herbal medicine, many plants have been the subject of experimental evaluation to provide a scientific rationale for their medicinal values. In this regard, Tinospora has a long history of use against various ailments including spasms, inflammation, arthritis, allergy, diabetes, cardiotoxicity, and immunosuppression. However, scientific evidences for its biological activities are limited. Recently, many studies have been carried out to support the acclaimed as well as to discover the novel potential of Tinospora which have also revealed its anticancer and radioprotective activities. Overall, the anticancer and immunomodulatory activities of Tinospora and its bioactive components could be further explored in relevant experimental model systems for its potential clinical benefits.

Keywords Tinospora ■ Anticancer ■ Immunomodulation ■ Antioxidant system ■ Radioprotection

Abbreviations and Symbols

AST Average survival time

Ag Antigen

CR-3 Complement receptor 3

CAPE Caffeic acid phenethyl ester

CFU Colony-forming units

CCL4 Carbon tetra chloride

DTD DT-diaphorase

DC Dendritic cells

Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University,

New Delhi, India, e-mail: [email protected]

K.G. Ramawat (ed.), Herbal Drugs: Ethnomedicine to Modern Medicine, DOI 10.1007/978-3-540-79116-4_12, © Springer-Verlag Berlin Heidelberg 2009

DL Dalton's lymphoma

EAC Ehrlich ascites carcinoma

GSH Reduced glutathione

GST Glutathione S-transferase

GPX Glutathione-peroxidase

GR Glutathione reductase

GM-CSF Granulocyte-monocyte colony-stimulating factor

YGT y-glutamyl transpeptidase

G1-4A Arabinogalactan

HMG1 High-mobility groupl iNOS Inducible nitric oxide synthase

IL Interleukin

IFN Interferon

LPx Lipid peroxidation

LDH Lactate dehydrogenase

LPS Lipopolysaccharide

MST Median survival time

MTD Maximum tolerated level dose

MCP-1 Monocyte chemo-attractant protein-1

MPO Myeloperoxidase

NK Natural killer

NO Nitric oxide

PAMP Pathogen-associated molecular pattern

PRR Pattern recognition receptors

RTc Root extract of Tinospora cordifolia

ROS Reactive oxygen species

SOD Superoxide dismutase

TCE Extract of Tinospora cordifolia

TIMP-1 Tissue inhibitor of metalloprotease-1

TAM Tumor-associated macrophages

TNF Tumor necrosis factor

TLR Toll-like receptor

VEGF Vascular endothelial cell growth factor

12.1 Introduction

Carcinogenesis is a multistep process induced by various types of carcinogens that ultimately lead to the development of cancer. Many biological and molecular events have been identified that are modulated by natural agents to inhibit the different stages of carcinogenesis. Epidemiological data suggest that consumption of a fiber-rich diet (low lipid content) and yellow-green vegetables can reduce the risk of various cancers [1-6]. Many laboratory studies for the chemoprevention of cancer using natural agents have revealed encouraging results [7]. In this regard, a large number of plants have been screened for their anticancer activities. These plants were found to contain specific antineoplastic phytochemicals that have been isolated from the different parts of the plants. For example, silibinin (polyphenolic flavonoid) extracted from the fruits or seeds of milk thistle has been shown to suppress prostate, skin, lung, and many other cancers [8, 9]; curcumin from turmeric inhibits colon cancer [10, 11], capsaicin from red chili inhibits prostate cancer [12], and resveratrol from red grapes inhibits breast cancer [13]. Similarly, lycopene from tomato, P-carotene from carrots, genistein from soybean, catechin from tea and ellagic acid from pomegranate etc have also been shown to possess anticancer activities [14].

Herbal medicines offer treatment for various diseases by modulation of the immune system and are classified as immunomodulators. These immunomodulators may alter the activity of the immune system by regulation of cytokine expression and secretion. Many plants have been found to have immunomodulatory activities by altering the expression of various cytokines. Such plants are Allium sativum, Ananas cosmosus, Echinacea purpuria, Grifolia frondosa, Poria cocos, Smilax glabra, Withania somnifera, Curcuma longa, and Tinospora cordifolia [15]. Tinospora has been shown to have various immunomodulatory properties. For example, the aqueous extract of T cordifolia stem, which contains arabinogalactan, shows immunological properties [16]. Plant-derived polysaccharides are regarded as excellent immunomodulators due to their therapeutic properties, less toxicity, and fewer side effects as compared to other immunomodulators [17].

There are various species of Tinospora, of which T cordifolia is the most extensively studied species for its biological activities. T. cordifolia is a glabrous, deciduous, and climbing shrub that belongs to the family Menispermaceae [18, 19] and is found throughout the tropical Indian subcontinent and China. It is popularly known as Giloy, Guduchi, or amritha and is used in Ayurvedic and veterinary medicines. In addition, it is well known for its various properties such as antispasmodic, an-tiperiodic, anti-inflammatory, antiarthritic, antiallergic, antidiabetic [20-22], antioxidant [23], antihepatotoxic [24], antifertility [25], and cardioprotective [26] properties including acetylcholine esterase inhibitory activity [27]. Tinospora root is specifically known for its antileprotic, antistress, and antimalarial activities [22, 28]. Pretreatment of animals with the aqueous extract of the stem of T. cordifolia shows protection against infection by E. coli and Staphylococcus aureus and also protects from mixed abdominal sepsis [29, 30].

A variety of constituents have been isolated from T cordifolia including alkaloids, diterpenoids, steroids, glycosides, phenolics, sesquiterpenoids, aliphatic compounds, and polysaccharides [22]. The leaves of T cordifolia contain large amounts of calcium, phosphorus, and protein [22, 31]. Various alkaloids like berberine, pulmatine, terbertarine, and magnoflorine have been isolated from the stem of T. cordifolia. The roots also contain other alkaloids such as choline, tinosporin, iso-columbin, and tetrahydropalmatine [32-34]. The methanolic extract of T cordifolia shows the presence of norditerpene furan glycosides, phenylpropanoids, diterpine furan glycosides, and plytoecdysones [35]. The following sections focus on the anticancer and immunomodulatory activities of Tinospora.

12.2 Effect of Tinospora on Carcinogen/Drug Metabolism and Antioxidant Systems

Xenobiotic metabolism plays a critical role in delivering the active carcinogenic dose of a potential carcinogen. Generally, it consists of phase I and phase II metabolizing enzyme systems in which, due to the activity of the former, the epoxide can be formed that is an active form of carcinogen known to bind with the DNA, resulting in mutation during cell proliferation. The phase II enzyme system can make it inactive to facilitate their excretion outside the body [36]. In this regard, it has been shown that the hydroalcoholic extract of aerial roots of T. cordifolia modulates both phase I and phase II enzymes as well as antioxidant enzymes including cy-tochrome p450 reductase, cytochrome b5 reductase, glutathione transferase (GST), DT-diaphorase (DTD), superoxide dismutase (SOD), catalase, glutathione peroxi-dase (GPX), and glutathione reductase (GR) in mouse liver [37]. This treatment also increases reduced glutathione (GSH) content in liver and extrahepatic organs (lung, kidney, forestomach) and SOD, catalase in kidney; catalase, GST, SOD in lung; and GST, DTD, and SOD in forestomach. Inhibition of lipid peroxidation has also been shown to occur by this treatment [37]. Thus, Tinospora acts as a bifunctional enzyme inducer because it induces both phase I and phase II enzyme systems. Additionally, T. cordifolia could remove oxidative stress conditions by activating antioxidant enzymes, thereby maintaining the reducing environment, along with the removal of the reactive oxygen species and neutralization of reactive intermediate species produced from the exposure to xenobiotics including chemical carcinogens [37, 38]. Together, these reports suggest the chemopreventive and antioxidant activities of Tinospora.

12.3 Anticancer Activity of Tinospora

Different extract preparations of Tinospora have been tested for their anticancer activity in various cancer model systems. In Ehrlich ascites carcinoma (EAC)-bearing mice, dichloromethane extract of T. cordifolia (TCE) has shown anticancer activity [32]. In this study, TCE is reported to have a dose-dependent increase in the survival of EAC-bearing mice receiving 25 to 100mg/kg doses of the extract. A 50 mg/kg body weight of dose has been found to have optimal effect on survival. Medium and average survival times for this dose were 53 and 56 d as compared to the respective non-drug-treated controls, which were 19 and 18 d, respectively. TCE has also shown a time-dependent decrease in glutathione (GSH) level but enhanced lipid peroxidation in EAC cells from mice receiving 50mg/kg dose of TCE [32]. These observations indicate the potential cytotoxic effects of TCE on EAC cells via oxidative mechanisms.

In another study, TCE has been reported to have a cytotoxic effect on HeLa cells [39]. This cytotoxic effect of TCE on HeLa cells was found to be associated with increased lipid peroxidation, release of lactate dehydrogenase (LDH), and decrease in GST activity [40]. Another report suggests that T. cordifolia has been used in the successful treatment of throat cancer in humans [41]. Overall, these reports suggest the anticancer potential of Tinospora.

12.4 Tinospora Inhibits Tumor Angiogenesis

Angiogenesis is the formation of new blood vessels from preexisting ones. The physiological process of angiogenesis is complex and strictly regulated, and its deregulation can cause a number of diseases including cancer, endometriosis, diabetic retinopathy, rheumatoid arthritis, and psoriasis [42, 43]. Angiogenesis is required at the very early stages of tumor development and is important for the metastatic spread and invasiveness of tumors. Angiogenesis plays an important role in the growth and progression of solid tumors, and without angiogenesis tumors cannot grow beyond ~2mm in size [44, 45]. Therefore, to control tumor growth, invasiveness, and metastasis, antiangiogenesis strategies represent promising approaches in the treatment of various cancers [46-48].

In a study, T. cordifolia was found to possess antiangiogenic activity in melanoma B16F10 cell-induced capillary formation in vivo and in vitro. Many proinflammatory cytokines such as IL-1a, IL-6, TNF-a, granulocyte-monocyte colony-stimulating factor (GM-CSF), and vascular endothelial cell growth factor (VEGF) are up-regulated by melanoma B16F10 cells. After intraperitonial administration of T. cordifolia extract, capillary formation and the level of these cytokines are decreased while antiangiogenic agents IL-2 and tissue inhibitor of metalloprotease-1 (TIMP-1) were increased. In another experiment, employing rat aortic ring assays, the non-toxic concentrations of T. cordifolia extract were found to inhibit proinflammatory cytokines secreted by melanoma B16F10 cells, along with the suppression of the microvessel outgrowth from aortic rings [49]. Thus, T. cordifolia could inhibit an-giogenesis by regulating cytokine expression and increasing the circulating level of antiangiogenic factors. This implies that Tinospora has the potential to inhibit tumor angiogenesis and suppress tumor growth and progression.

12.5 Tinospora Inhibits Cancer Metastasis

During metastasis, after getting detached from the primary cancer tissue, tumor cells penetrate the blood or lymph vessels and circulate with the body fluid and could form a secondary tumor at a distant site, which is a big obstacle in the treatment of cancer. During their journey, cancer cells encounter many immune cells, and hence any agent boosting the immune system could interfere with metastasis. Many phytochemicals have been observed to inhibit tumor cell metastasis [50]. In this regard, there are many properties associated with polysaccharide fraction isolated from the dried stem of T. cordifolia [16]. In vitro studies have shown that polysac-

charide is a specific mitogen of B-cells but does not affect T cells. A study has also shown that intraperitonial administration of this polysaccharide fraction results in a 72% reduction in the metastatic colony formation of B16F10 melanoma cells in the lungs of syngeneic C57BL/6 mice [51]. In this study, the polysaccharide fraction also reduced neoplastic markers such as lung hexosamine, collagen hydroxyproline, uronic acid, y-glutamyltranspeptidase (yGT), and sialic acid [51]. Overall, these observations indicate the antimetastatic effect of Tinospora; however, more studies on relevant animal models are needed to support this conclusion as well as to find out the associated mechanisms.

12.6 Radioprotective Potential of Tinospora

Radiotherapy-induced damage to normal tissues is the major limitation of the therapeutic response in antitumor therapy. On the other hand, radiation toxicity itself can cause many genetic aberrations leading to various diseases including cancer and immunosuppresion. In this regard, T. cordifolia has been shown to have promising radioprotective potential in terms of survival after whole-body irradiation. Additionally, it also modulates cell cycle progression, hematologic parameters, spleen-colony-forming units, and micronuclei formation. Preirradiation administration of a single dose of root extract of T cordifolia (RTc, 200 mg/kg b/w) offers 76% survival in mice exposed to 10 Gy lethal gamma-irradiation, but without RTc treatment irradiated mice suffer from 100% mortality within 10 to 15 d. Most radioprotec-tive agents show the maximum radioprotective effect at maximum tolerated level doses (MTD), but RTc shows significant protective effect at about 50% concentration of its MTD [52-54], and this ability makes T cordifolia more useful for clinical applications. Most of the radiation-induced damages are due to the interaction between radiation-induced free radicals and biomolecules, and hence molecules or agents that have the ability to neutralize or scavenge these free radicals could inhibit radiation-induced damages. T. cordifolia possesses the ability to scavenge free radicals and prevents radiation-induced damages [55]. However, the survival ability against radiation-induced damages could be a combination of different mechanisms including scavenging free radicals, inhibition of free-radical generation, and repair ofDNA and membranes [56]. Overall, these studies are indicative of the radioprotective potential of Tinospora; however, detailed studies are needed to explore its radioprotective mechanisms.

12.7 Tinospora Activates Tumor-Associated Macrophages of Dalton's Lymphoma

It has been found that the alcoholic extract of T. cordifolia can activate the tumor-associated macrophages (TAM) of Dalton's lymphoma (DL), which is spontaneously transplantable T-cell lymphoma. The basic functions of these macrophages are antigen presentation, phagocytosis, and secretion of IL-1, TNF, etc., which can be induced by intraperitonial administration of the Tinospora extract in DL-bearing mice together with the increase in life span of tumor-bearing mice and reduction in tumor growth. This extract treatment also shows the anticancer efficacy by desta-bilization of the membrane integrity of DL cells and activates the differentiation of TAM to dendritic cells (DC) in response to GM-CSF, tumor necrosis factor, and interleukin-4 [57, 58]. Overall, Tinospora could, in part, trigger its in vivo antitumor activity via activation of TAM.

12.8 Immunostimulating Properties of Tinospora

Many plants are known to produce immunogenic components. In this regard, various polysaccharides are known to stimulate the immune system, for example, P-glucans, which have structural identity with conserved pathogen-associated molecular patterns (PAMPs) that activate the immune system by binding the specific receptors, pattern recognition receptors. These receptors are found on various immune cells, including natural killer cells (NK cells), macrophages, monocytes, and neu-trophiles [59, 60], and stimulate cytotoxic, phagocytic, and antimicrobial activities by synthesis of cytokines, chemokines, reactive-oxygen species, and N2 intermediates. a-D glucan (RR1) from T. cordifolia consisting of (1 ^ 4) linked backbone and (1 ^ 6) linked branches is reported to stimulate the immune system [61]. It is found to be nontoxic and nonproliferative to tumor as well as normal cells at 0 to 1000 |g/ml concentrations and proficiently activates lymphocytes of different subpopulations like NK cells, T cells, and B cells at a 100 |g/ml concentration [62]. Activation of NK cells is associated with the killing of tumor cells. RR1-mediated induction of normal lymphocytes produces IL-1P, IL-12 p70, IL-12 p40, IL-18, IL-6, IFN-y, TNF-a, and monocyte chemoattractant proteins (MCP-1), and this cytokine profile is associated with the Th1 pathway with a self-regulatory mechanism. RR1 also increases the level of the alternative pathway component C3a des Arg of a complementary system, where C3a is a bioactive cleavage product of C3 during complementary activation in alternative pathways [63]. In another study, water extracts and/or ethanol extracts of the stems of T. cordifolia and T. sinensis were found to inhibit cyclophosphamide-caused immunosuppression and anemia in Swiss albino mice [64].

12.9 Mechanism of Macrophage Activation by (1 ^ 4) a-D Glucan from Tinospora

It has been shown that (1 ^ 4) a-D glucan isolated from T. cordifolia has many immunostimulating properties by which it modulates the macrophage functions. RR1 has been observed to inhibit phagocytosis of unopsonized zymosan bioparticles, which are yeast-derived particles containing P-glucan and mannan, in RAW 264.7 macrophages [60, 65, 66]. RR1 also inhibits the binding and internalization of opsonized zymosan A bioparticles but with lesser efficacy than that of laminarin, which is fungal-derived P-glucan [66-68]. For signaling of P-glucan, complement receptor 3 (CD11b/CD18 or CR-3) acts as a leukocyte receptor for soluble [69] and particulate glucans [70]. In RAW264.7 macrophage cells, CR3 monoclonal antibody does not inhibit RRI-induced TNF-a synthesis, suggesting that CR3 does not mediate internalization and opsonic binding of RR1; however, CR3 monoclonal antibody inhibited zymosan A-induced TNF-a synthesis [71]. RR1-induced TNF-a synthesis in macrophages is associated with NF-kB activation to elicit inflammatory response. It has also been observed that RR1 activates NF-kB by TLR-6 signaling, and this was evidenced by synthesis of IL-8 via NF-kB in TLR-6 trans-fected HEK293 cells [71]. However, there are many other phytochemicals that have been found to inhibit NF-kB activation in macrophages. For example, caffeic acid phenethyl ester (CAPE) and curcumin inhibit NF-kB activation as well as TNF-a synthesis in macrophages [72, 73]. Overall, NF-kB signaling appears to be an important mechanism for RR1-induced macrophage activation.

12.10 G1-4A, an Immunomodulatory Polysaccharide from Tinospora

Plant-derived polysaccharides are usually ideal immunomodulators because they show relatively less toxicity and fewer side effects as compared to other agents. Many studies show that they modulate the macrophage function by increasing phagocytosis, chemotaxis, and microbicidal activity and antigen presentation to T cells. For example, arabinogalactan, a polysaccharide (G1-4A) from the stem of T. cordifolia, modulates the macrophage function and protects against lipopolysac-charide (LPS)-induced endotoxic shock. LPS activates the cells of the immune system to release mediators of sepsis and endotoxic shock including IL-1, IL-2, IL-6, IL-8, TNF-a, endorphins, platelet-activating factor, various eicosanoids, high-mobility groups (HMG1), nitric oxide (NO), and macrophage MIF, leading to myocardial dysfunction, and renal and hepatic failure [74]. TNF-a has a crucial role in endotoxin-induced toxicity, and there are many drugs available that inhibit TNF-a production, e.g., pentoxyfilline [75], JTE-607 [76], thalidomide [77], 21-aminosteroids [78], and dexamethazone [79]. However, these drugs make the host immunocompromised [17].

G1-4A binds to macrophages and inhibits the binding of LPS to macrophages. Hence, G1-4A mimics LPS but is not toxic to mice up to a dose of 100 mg/kg body weight. Although a small amount of TNF-a is induced by G1-4A, pretreatment with G1-4A decreases the LPS-induced level of TNF-a (17). G1-4A also causes an increase in serum levels of IL-1 P and IFN-y in mice challenged with LPS. IL-1P causes a decrease in the surface expression of TLR-4, a crucial receptor for LPS, and also increases the serum level of glucocorticoids and their receptors on peritoneal macrophages [80, 81]. G1-4A also induces the NO in murine macrophages, which act as vasodilator and provide protection during endotoxic shock by inhibiting vascular thrombosis [17]. These reports provide evidence for the modulatory effects of G1-4A on cytokines and NO to induce tolerance against endotoxic shock.

12.11 Hepatoprotective Properties of Tinospora

Some preparations of Tinospora are used as liver tonic. Experimental studies also show that the extracts of T. cordifolia possess hepatoprotective and stimulatory properties, as has been observed in CCL4-induced hepatotoxicity in mature albino rats [24]. In this study, administration of CCL4 (0.7 ml/kg body weight for 7 d) causes liver damage marked by the elevation of certain specific enzymes such as serum glutamate pyruvate transminase, serum glutamate oxaloacetate transaminase, and alkaline phosphatase as well as the serum level of billirubin, which also happens in the case of jaundice. The enzyme levels return to normal after treatment with an extract of T. cordifolia comparable to that in a control group of rats. Tinospora has also been found to increase monocyte to macrophage differentiation, myelopoiesis, antigen presentation, levels of released cytokine and myeloperoxi-dase, and microbicidal and tumoricidal activities along with the stimulation of certain chemokines in CCL4-intoxicated rats [24]. Overall, these observations are suggestive of protective effects of T. cordifolia against CCL4-induced hepatotoxicity and immunosuppression.

12.12 Summary

The studies discussed so far suggest that T. cordifolia has great potential for cancer chemoprevention and immunomodulation. Tinospora acts as a bifunctional enzyme inducer for carcinogen/drug metabolism and induces antioxidant defense mechanisms to neutralize oxidative stress usually caused by xenobiotics including chemical carcinogens. It can inhibit angiogenesis as well as cancer metastasis. The anticancer effect of T. cordifolia increases the survival of EAC-bearing mice and can induce cell death in HeLa cells. It also has radioprotective potential in terms of whole-body survival, hematologic parameters, cell-cycle progression, spleen-colony-forming units (CFU), and micronuclei induction. The survival effect of T. cordifolia against radiation-induced damage involved various mechanisms including scavenging of free radicals, repair of DNA damage, and inhibition of free-radical generation.

T. cordifolia has many immunomodulatory functions as one of its constituents, a-D glucan polysaccharide (RR1)-activated lymphocytes of different subpopulations including NK cells, T cells, and B cells. Activation of NK cells is associated with the killing of tumor cells. RR1 induces normal lymphocytes to secrete various cytokines including interleukins, IFN-y, TNF-a, and monocyte chemoattractant protein (MCP-1). RR1 can activate the C3a des Arg component of an alternative pathway of a complementary system. RR1 can induce TNF-a synthesis in macrophages, which is associated with NF-kB activation by TLR-6 signaling. Other polysaccharides, such as arabinogalactan (G1-4A) from the stem extract of T. cordi-folia, modulate the macrophage function and protects against LPS-induced endo-toxic shock. T. cordifolia also has hepatoprotective activities and can counter the im-munosuppressive effects of CCL4. Together, these studies advocate for the detailed investigation of the anticancer and immunomodulatory properties of Tinospora. Nevertheless, the medicinal value of this plant has immense potential in clinical applications. In the future, the identification of all biologically active components could provide mechanistic insight into their preventive and therapeutic potential against various ailments including cancer and immune diseases.

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