Terpenes: Substances Useful in Human Healthcare

REVIEW

Arch. Immunol. Ther. Exp., 2007, 55, 315–327 DOI 10.1007/s00005-007-0039-1 PL ISSN 0004-069X

Terpenes: substances useful in human healthcare

Roman Paduch1, Martyna Kandefer−Szerszeń1, Mariusz Trytek2 and Jan Fiedurek2

1 Department of Virology and Immunology, Institute of Microbiology and Biotechnology, Maria Curie-Sk³odowska University, Lublin, Poland 2 Department of Industrial Microbiology, Institute of Microbiology and Biotechnology, Maria Curie-Sk³odowska University, Lublin, Poland Received: 2007.01.23, Accepted: 2007.05.10, Published online first: 2007.10.01

Abstract Terpenes are naturally occurring substances produced by a wide variety of plants and animals. A broad range of the biological properties of terpenoids is described, including cancer chemopreventive effects, antimicrobial, antifungal, antiviral, antihyperglycemic, anti-inflammatory, and antiparasitic activities. Terpenes are also presented as skin penetration enhancers and agents involved in the prevention and therapy of several inflammatory diseases. Moreover, a potential mechanism of their action against pathogens and their influence on skin permeability are discussed. The major conclusion is that larger-scale use of terpenoids in modern medicine should be taken into consideration. Abbreviations: 5-FU – 5-fluorouracil, AKBA – acetyl-11-keto-β-boswellic acid, AZT – zidovudine, CoQ – coenzyme Q, COX-2 – cyclooxygenase 2, DMAPP – dimethylallyl pyrophosphate, HIV – human immunodeficiency virus, HSV – herpes simplex virus, iNOS – inducible nitric oxide synthetase, IPP – isopentenyl pyrophosphate, LPS – lipopolysaccharide, NF-κB – nuclear κ β β factor B, NO – nitric oxide, PGE2 – prostaglandin E2, PLA2 – phospholipase A2, TGF- – transforming growth factor , TNF-α – tumor necrosis factor α. Key words: terpenes, terpene activity, antitumor, antimicrobial, antifungal, antiviral, antihyperglycemic, anti-inflammatory, antiparasitic.

Corresponding author: Dr. Roman Paduch, Department of Virology and Immunology, Institute of Microbiology and Biotechnology, Maria Curie-Sk³odowska University, Akademicka 19, 20-033 Lublin, Poland, tel. +48 81 537-59-42, fax. +48 81 537-59-40, e-mail: [email protected]

INTRODUCTION units with the molecular formula C5H8. The basic formula of all terpenes is (C5H8)n, where n is the number of Terpenes occur widely in nature. They are a large linked isoprene units [31]. Isoprene units may be linked and varied class of hydrocarbons which are produced by “head to tail” to form linear chains or they may be a wide variety of plants and by some animals. They are arranged to form rings. Terpenes can exist as hydrocar- also abundantly found in fruits, vegetables, and flowers bons or have oxygen-containing compounds such as [28]. Their concentration is generally high in plant hydroxyl, carbonyl, ketone, or aldehyde groups. After reproductive structures and foliage during and immedi- chemical modification of terpenes, the resulting com- ately following flowering [88]. Terpenes are also a major pounds are referred to as terpenoids. component of plant resins. In plants they function as For a long time the mevalonate pathway was consid- infochemicals, attractants or repellents, as they are ered the universal source of the terpenoid C5 precursors responsible for the typical fragrance of many plants [23, isopentenyl pyrophosphate (IPP) and dimethylallyl 88]. On the other hand, high concentrations of terpenes pyrophosphate (DMAPP). In this pathway, three mole- can be toxic and are thus an important weapon against cules of acetyl-CoA are condensed to 3-hydroxy-3- herbivores and pathogens. -methylglutaryl-CoA with subsequent reduction to Animal cholesterol and steroids and the higher mevalonate, which is converted to IPP and DMAPP triterpenes and phytosterols of plants are directly (Fig. 1). However, an mevalonate-independent path- involved in the stabilization of cell membranes and are way, “the Rohmer pathway” was recently discovered. regulators of permeability and enzymatic reactions [12]. The first intermediate, 1-deoxy-D-xylulose 5-phosphate, Terpenes are biosynthetically derived from isoprene is assembled by condensation of glyceraldehyde 3-phos- 316 R. Paduch et al.: Terpenes useful in healthcare

Mevalonate pathway

investigation Rohmer pathway

1 step Fig. 1. Mevalonate and non-mevalonate pathways in the biosynthesis of terpenoids.

phate and pyruvate, as shown in Fig. 1. In the second lycopene (tomatoes) and carotenes. Polyterpenes con- step the product is converted into 2C-methyl-D-erythri- sist of a long chain of many isoprene units. Natural rub- tol-4-phosphate which, by subsequent reactions, is con- ber is a polyisoprene with several cis double bonds. verted into IPP and DMAPP (Fig. 1). Archaea, fungi, The diverse array of terpenoid structures and func- and animals use only the mevalonate pathway. In plants, tions has provoked increased interest in their commer- the mevalonate pathway is utilized in the cytosolic com- cial use. Terpenoids have been found to be useful in the partment and the non-mevalonate pathway in plastids prevention and therapy of several diseases, including [82]. In the biochemical pathway of terpenoid synthesis, cancer, and also to have antimicrobial, antifungal, prenylotransferases participate in the condensation of antiparasitic, antiviral, anti-allergenic, antispasmodic, activated forms of isoprene units. IPP is linked with an antihyperglycemic, anti-inflammatory, and immunomo- isopentenyl diphosphate isomer of DMAPP in a “head- dulatory properties. They also act as natural insecticides -to-tail” manner. The linear chains of prenyl diphos- and can be of use as protective substances in storing phates that are formed in the reaction may also be mod- agriculture products [88]. ified through dimerization or cyclization by terpene syn- thases, forming terpenoids with new functions. The resulting terpenes are classified in order of size into ANTICANCER ACTIVITY hemiterpenes, monoterpenes, sesquiterpenes, diterpenes, triterpenes, tetraterpenes, and polyterpenes. Epidemiological studies suggest that dietary Hemiterpenes consist of a single isoprene unit and are monoterpenes may be helpful in the prevention and very often modified into oxygen-containing derivatives therapy of cancers [13, 80]. Among dietary monoter- called hemiterpenoids (e.g. isovaleric acid). Mono- penes, D-limonene and perillyl alcohol have been shown

terpenes consist of two isoprene units (C10) and may be to possess chemopreventive and therapeutic properties linear (myrcene, geraniol) or may contain rings (thymol, against many human cancers [57] (Fig. 2). At present menthol, α-pinene). Sesquiterpenes consist of three iso- they are claimed to inhibit, in a dose-dependent manner,

prene units (C15) and may be acyclic (farnesol) or con- the development of mammary, liver, skin, lung, colon, tain rings, as well as many other modifications (δ-ca- fore-stomach, prostate, and pancreatic carcinomas [5,

dinene). Diterpenes consist of four isoprene units (C20). 24, 37]. D-limonene is a natural monocyclic monoter- Examples of diterpenes are cembrene and retinal, which pene with chemopreventive and chemotherapeutic activ- is synthesized on the basis of the diterpene and is a fun- ities and low toxicity ascertained in pre-clinical studies damental chromophore involved in the transduction of [92]. There are multiple mechanisms of monoterpene light into visual signals. Triterpenes consist of six iso- chemopreventive actions. They may act during the initi-

prene units (C30). The linear triterpene squalene is ation phase of carcinogenesis, preventing interaction of a major constituent of shark-liver oil. Plant triterpenes carcinogens with DNA, or during the promotion phase, and their derivatives are a large group of biologically inhibiting cancer cell development and migration. The active substances. Tetraterpenes contain eight isoprene chemopreventive and therapeutic activities of monoter-

units (C40). Biologically important tetraterpenes include penes in later stages of carcinogenesis include induction R. Paduch et al.: Terpenes useful in healthcare 317

CH CH CH OH COOH CH3 3 3 CH3 2 H3C OH O OH OH

H C CH OH 3 3 OH CH H C CH OH H3C CH2 H3C CH2 H3C 2 3 2 H3C CH2 H3C

(+)-perillyl (+)-perillic acid D-limonene R-(-)-carvone sobrerol trans-limonene -1,2-diol uroterpenol alcohol

CH3 CH3 H3C CH3 H2C H3C H O OH H OH CH3 CH3 CH H CH CH H 3 CH3 3 3 OH O O CH H CH3 3 H CH3

H3C HO H HO H H CH H C CH H3C CH3 H3C 3 3 3

betulinic acid ursolic acid oleanolic acid

CH3 CH3

CH3 OH

CH2OH H C CH H3C CH3 3 3

farnesol geraniol

Fig. 2. Structures of selected terpenes with anticancer activity.

of cancer cell apoptosis, re-differentiation of tumor cells, exhibit clinical activity. Moreover, its toxicity is and influence on molecular mechanisms regulating their reversible and does not lead to significant organ dys- functions. The most important mechanism that monoter- functions. For this reason, the activity, toxicity, and penes influence is post-translational isoprenylation of pharmacokinetics of D-limonene are currently in phase proteins regulating the growth of cells. In general, preny- I clinical trials [92]. lated proteins regulate cell growth and transformation; D-limonene serves as a precursor of other oxygenat- therefore, disturbance of prenylation of one (especially ed monocyclic monoterpenes, e.g. perillyl alcohol and Ras-regulated small GTP-binding proteins) or more of carvone, which have also been shown to have anticancer these proteins may be responsible for the antitumor activities [23]. Perillyl alcohol is a naturally occurring activity of monoterpenes [23]. monocyclic monoterpene which has preventive and The activity of D-limonene and its oxygenated deriv- therapeutic activity against a variety of pre-clinical atives may be associated with selective inhibition of the tumor models. It has been shown that perillyl alcohol post-translational isoprenylation oncoprotein p21ras reg- induces apoptosis in many kinds of cancer cells (pancre- ulating signal transduction and cell growth. This inhibi- atic, mammary, colon, and liver) both in in vitro and in tion may also alter gene expression, leading to apopto- vivo tests. Its activity led to complete regression of sis, cellular re-differentiation and, consequently, tumor chemically induced and animal transplanted tumors. regression [25, 92]. In animal experiments the predomi- Perillyl alcohol was also tested as an inhibitor of car- nant blood-circulating metabolites of D-limonene were cinogenesis induced by ultraviolet light. It was revealed perillic acid, dihydroperillic acid, and limonene-1,2-diol. that suntan lotions enriched with perillyl alcohol might They were found to have greater pharmacological activ- limit melanoma induction. This monoterpene is, there- ity in inhibiting protein isoprenylation and cellular pro- fore, postulated to be an effective agent against skin car- liferation than the initial compound. These data suggest cinoma development [37]. The basis of the antitumor that the antitumor activity of D-limonene in in vivo con- effects of perillyl alcohol, similarly to D-limonene, is the ditions is not direct, but mediated via its metabolites [26, inhibition of posttranslational isoprenylation of small 92]. The most important advantage of D-limonene is its GTP-binding proteins. Another mechanism of the good tolerance in human volunteers at doses which may chemotherapeutic effects of perillyl alcohol is activation 318 R. Paduch et al.: Terpenes useful in healthcare

of transforming growth factor (TGF)-β signaling. TGF-β mals by inducing nitric oxide (NO) and tumor necrosis is produced in a latent form, which needs to be activat- factor (TNF) production [59, 70]. These triterpenoids ed. Perillyl alcohol mediates TGF-β activation and leads and their derivatives act at various stages of tumor to increased mRNA synthesis encoding its receptors. development, inhibiting initiation and promotion as well Activation of TGF-β signaling by perillyl alcohol is as inducing tumor cell differentiation and apoptosis. closely associated with elevated synthesis of pro-apop- Moreover, they are effective inhibitors of angiogenesis, totic proteins (Bax, Bak, and Bad) without influencing invasion, and metastasis of tumor cells [60]. p53 or Bcl-2 expression [2]. Moreover, through TGF-β, Terpenes are easily available and make up a promis- perillyl alcohol down-regulates the cell cycle, influencing new class of agents which may be approved as sup- ing the production of cyclin and cyclin-dependent kinas- plementary drugs in contemporary oncology. es or their reciprocal interactions. In consequence, it leads to G1-phase arrest and cell apoptosis [2, 86]. Another mechanism of perillyl alcohol action on tumor ANTIMICROBIAL cells is inhibition of the synthesis of coenzyme Q (CoQ) AND ANTIFUNGAL ACTIVITIES [2, 36], an important element of mitochondrial respiratory metabolism. In the plasma membrane, CoQ partic- Many terpenes have been found to be active against ipates in the transmembrane electron transport to stabi- a variety of microorganisms. Tests have been performed lize extracellular ascorbate [7]. The reduction of CoQ in on Gram-positive and Gram-negative bacteria and also cell membranes may, therefore, limit cellular signal on fungi [90]. It has been shown that microorganisms transduction and metabolism and induce apoptosis of express a differentiated sensitivity to plant-derived tumor cells. agents. In general, Gram-positive bacteria are more sen- During phase I clinical trials, perillyl alcohol at doses sitive to terpenes than Gram-negative [54]. This is main- which may have clinical activity was well tolerated by ly determined by differences in the permeability, com- patients and had relatively low normal-tissue and sys- position, and charge of the outer structures of the temic toxicity [2, 5]. D-limonene and perillyl alcohol microorganisms. The mechanism of antimicrobial may therefore be considered as pharmaceuticals or pro- action of terpenes is closely associated with their -drugs, which after administration are converted in the lipophilic character. Monoterpenes preferentially influ- organism into pharmacologically active derivatives with ence membrane structures which increase membrane antitumor activity. However, it should be noted that fluidity and permeability, changing the topology of enantiomeric derivatives of these monoterpenes do not membrane proteins and inducing disturbances in the influence the metabolism, growth, and differentiation of respiration chain [90]. A mixture of terpinen-4-ol, α-ter- tumor cells [33]. Therefore, during the preparation of pineol, 1,8-cyneole, and linalool (monoterpenes) has natural chemotherapeutic agents, their stereoisomeric been shown to possess antibacterial activity against configuration should be taken into consideration. Gram-positive and Gram-negative bacteria isolated Chemotherapeutic activities towards human pancre- from the oral cavity, skin, and respiratory tract (Fig. 3). atic cancers have also been shown for other terpenes, Moreover, promising results were obtained in tests such as farnesol and geraniol [10]. Moreover, monoter- against the Gram-positive bacteria Staphylococcus penes such as carveol, uroterpenol and sobrerol have aureus. The rank order of the antibacterial activities of been tested against mammary carcinomas. Additionally, terpenes against S. aureus was: farnesol>(+)-neroli- carvone has been analyzed as an agent reducing pul- dol>plaunotol>monoterpenes such as (–)-citronellol, monary adenoma and fore-stomach tumor formation geraniol, nerol, and linalool. Thymol and (+)-menthol [13, 75, 93]. A stevioside mixture from Stevia rebaudiana (monoterpenes) also expressed high toxicity when ana- was found to suppress the tumor-promotion effect of lyzed with S. aureus and additionally (+)-menthol was 12-O-tetradecanoylphorbol-13-acetate on skin tumor toxic against Escherichia coli [39, 90]. formation in mouse skin [34, 97]. Moreover, several Kubo et al. [58] suggested that the activity of ter- plant triterpenes exhibited in vitro antitumor activity. penes against S. aureus may be closely dependent on the Betulinic acid has been shown to induce apoptosis of number of carbon atoms in the hydrophobic chain from several human tumor cells, among others melanoma hydrophilic hydroxyl groups. However, this suggestion and glioma. Apoptosis was induced via changes in the has not been fully confirmed. Recently it was proposed permeability transition potential in mitochondria and that the antibacterial activity against S. aureus depends up-regulation of pro-apoptotic proteins (Bax) and on the lengths of the aliphatic chains of terpene alcohols decreasing bcl-2 expression. It was also shown that and the presence of double bonds [47]. In turn, the betulinic acid is an inhibitor of topoisomerase I, sesquiterpenoids nerolidol, farnesol, bisabolol, and apri- a nuclear enzyme that catalyses changes in DNA topol- tone enhanced bacterial permeability and susceptibility ogy [18, 30] and, in consequence, leads to apoptosis of to antibiotics [8]. The most important terpene that can cells. Other plant triterpenes, such as ursolic acid and be used in antimicrobial therapy is (4R)-(+)-carvone oleanolic acid, found in natural wax on apples and other (monoterpene), which was effective against Listeria fruits, reduced leukemia cell growth [19] and inhibited monocytogenes and showed activity towards Entero- the proliferation of several transplantable tumors in ani- coccus faecium and Escherichia coli [13]. R. Paduch et al.: Terpenes useful in healthcare 319

CH3 CH3 CH3 CH3 HO H

CH2 H C H C CH 3 CH3 3 3 O CH3 OH OH OH H3C CH H C CH H3C CH3 3 3 3 H3C CH3 CH CH H3C CH3 3 2

α-terpineol linalool (+)-terpinen-4-ol 1,8-cineole citronellol α-pinene β-pinene

OH CH CH CH CH 3 3 3 3 CH O H C 3 H3C H 3 H HOH CH3 OH CH3 H

OH OH H3C H H CH H3C CH3 H3C 3 H C CH H3C CH3 H C CH H C CH 3 3 H3C CH3 3 3 3 3

l-menthol α-terpinene thymol nerol ferruginol bisabolol apritone

H C 3 H C H 3 OH CH3 H H3C CH3 CH 3 CH CH CH 2 3 CH3 H 3 H HO H3C CH3 O CH 2 H CH O 3 H3C O H2C OH H H3C CH3 H C O 3 H C CH CH3 O 3 3

elisapterosin B parthenolide zeorin nerolidol

Fig. 3. Structures of selected terpenes with antimicrobial and antifungal activity.

Terpenoid derivatives have been reported to possess a composition of monoterpenes, which included ter- antimycobacterial activity, as well. Several metabolites pinen-4-ol, α-pinene, β-pinene, 1,8-cineole, linalool, have been tested, where the most active was ferruginol and α-terpineol [40, 54]. They inhibited the develop- (diterpene), which exhibited inhibitory activity towards ment of dermatophytes such Trichophyton mentagro- Mycobacterium smegmatis, M. intracellulare, and M. che- phytes, T. rubrum, and Microsporum gypseum, as well. α- lonei. On the other hand, benzoxazole-containing diter- terpinene also exhibited antifungal activity similar to penes, tetracyclic diterpene elisapterosin B, and triter- that of commonly used antifungal drugs [69]. In general, penoid zeorin were shown to reduce growth of M. tuber- antifungal therapy utilizing terpenes and their deriva- culosis [20]. An extensive array of sesquiterpenes and tives is very promising but may be difficult to apply their lactones also revealed activity against Myco- because high doses of terpenes or terpenoids have to be bacteria. Moreover, such sesquiterpene lactones as cos- used. For that reason, such therapy might result in seri- tunolide, parthenolide, and others exhibited antimyco- ous side effects. These substances may nevertheless baterial activity [20]. Among the triterpenes, oleanolic serve as supplementary agents that could improve stan- acid and ursolic acid were also active against M. intra- dard, conventional antifungal therapies. cellulare [20] and Gram-positive and Gram-negative bacteria [61]. Terpenes also display antifungal activity. Experi- ANTIVIRAL ACTIVITY ments have been performed in two groups of fungi: Saccharomycetes and mildew fungi, that are potentially Currently, the antiviral activity of terpenoids is pathogenic to humans. Both optical isomers of carvone rather poorly understood. Therefore, there is a lot of were found to be active towards many kinds of human research aimed at discovering agents, also from natural pathogenic fungi. Carvone and perillaldehyde inhibited sources, which could have potent antiviral activity. The the transformation of Candida albicans from the coccal new antiviral compounds should specifically inhibit viral to the filamentous form, which is responsible for the functions and should not influence normal eukaryotic pathogenicity of the fungus [13]. The development of C. cell metabolism. The search for natural antiviral com- albicans, C. krusei, and C. tropicalis was also limited by pounds has led to the isolation of isoborneol (Fig. 4). 320 R. Paduch et al.: Terpenes useful in healthcare

CH2 H3C CH3

H3C

H CH H3C 3 H3C CH3 O CH OH 3 CH3 CH H C H OH 3 3 CH 3 CH3 H CH H 3 H H HO CH3 O H HO OH H H3C CH3 H3C CH3

borneol isoborneol moronic acid betulin

HOHOO HOH H3C O CH O 3 CH HO OH 3 H3C OH O O CH3 O O O OH O O H H3C OH O O H3C CH3 O OH O lucialdehyde D O OH OO H H CH H O CH H 3 HO 3 CH3

O OH H CH3 O OH O O OH H O OH O H C CH3 HO 3 HO O O O

OH OH putranjivain A OH glycyrrhizin HO O OH OH Fig. 4. Structures of selected terpenes with antiviral activity.

This monoterpene has been shown to exhibit low cyto- It also modulated the fluidity of human immunodefi- toxicity and relatively strong anti-herpes simplex virus-1 ciency virus (HIV) envelope [41]. In recent years, the (anti-HSV-1) action. The mechanism of isoborneol antiviral activities of several triterpene compounds have activity relies on interactions of its hydroxyl groups with also been described. Moronic and betulinic acids have virus envelope lipids. Furthermore, isoborneol may been found to possess anti-HSV-1 activity. Moreover, inhibit virus replication and the glycosylation of viral betulin and betulinic acid, as well as several of their proteins. As a result, HSV-1 loses its infectivity [4]. derivatives, have been described as very active anti-HIV Potent anti-HSV-1 activities have also been reported for agents affecting virus-cell fusion, reverse transcriptase monoterpenes such as cineol and borneol, a stereoiso- activity, and virion assembly and/or budding. Betulin, mer of isoborneol. Moreover, an analysis of diterpenes betulinic acid, and oleanolic acid have also been shown has revealed that putranjivain A, isolated from to inhibit the replication of vesicular stomatitis virus and Euphorbia jolkini (Euphorbiaceae), may inhibit viral encephalomyocarditis virus [51]. The terpenoid con- attachment and cell penetration and may also affect late stituents of Ganoderma pfeifferi oil lucialdehyde D and stages of HSV-2 replication [55]. ganoderon A and C were also potent inhibitors of HSV In a group of triterpenes, moronic acid from Rhus [66]. To conclude, terpenoids are an interesting group of javanica and meliacine from Melia azeolarch exhibited natural agents with both specific and wide-ranging anti-HSV-1 effects. They inhibited infected-cell antiviral activities that could be used to improve the polypeptides produced in late stages of infection or therapeutic efficacy of standard antiviral therapy. diminished viral DNA synthesis. Lupenone and its saponin also showed antiviral activities against HSV-1 and -2. They influenced HSV-1 DNA synthesis and ANTIHYPERGLYCEMIC ACTIVITY exhibited inhibitory effects on viral plaque formation [55]. Triterpenoid saponins such as glycyrrhizin and Type 2 diabetes mellitus is a chronic metabolic dis- oleanan-type triterpenoid saponins, including gly- order that results from reduced first-phase insulin secre- cyrrhetic acid, had anti-HSV-1 activity. Interestingly, tion, β cell dysfunction with relative glucagon excess, glycyrrhizin also effectively inhibited replication of and defects in insulin action [48, 50]. Glucose is the most severe acute respiratory syndrome-associated virus [46]. powerful physiological stimuli of the β cell. However, R. Paduch et al.: Terpenes useful in healthcare 321 chronic elevation of blood glucose concentration the typical sweet taste [32]. Rebaudioside A, similarly to impairs β cell function. At early stages in type 2 dia- stevioside, possesses insulinotropic effects but does not betes, diet and exercise are sufficient to maintain glu- cause a stimulation of insulin release at near-normal cose homeostasis [15]. With time, however, oral antidia- glucose levels [1]. betic drugs and insulin replacement often become nec- Stevioside enjoys dual-positive effects by acting not essary. Long-time use of the oral hypoglycemic agents only as an antihyperglycemic agent, but also as a blood may, however, decrease their pharmacological action, pressure-lowering substance. It has been shown that ste- a phenomenon described as desensitization [15, 16]. vioside induces blood pressure reduction and diuresis in Therefore there is increasing scientific and clinical rats. The antihypertensive effect of the plant glycoside is endorsement for the search and use of natural antidia- therefore closely associated with cardiovascular risk fac- betic agents. Stevioside is a diterpene steviol glycoside tor reduction, which appears through a calcium-antago- extracted from leaves of the plant Stevia rebaudiana nist mechanism [14, 45]. It has also been shown that which possesses insulinotropic, glucagonostatic, and isosteviol inhibits angiotensin-II-induced cell prolifera- antihyperglycemic effects. It has been shown that stevio- tion and endothelin-1 secretion. These results may sug- side and the aglucon steviol both potentiate insulin gest that isosteviol possesses substantial positive effects secretion from isolated mouse islets in a dose- and glu- on the cardiovascular system [96]. cose-dependent way [49]. The antihyperglycemic action of stevioside and steviol may be associated in part with the induction of genes involved in glycolysis or inhibito- ANTI−INFLAMMATORY ACTIVITY ry action on ATP phosphorylation and NADH-oxidase activity in liver mitochondria, leading to an increase in Peana et al. [71, 72] have shown that (–)-linalool, glycolysis and suppression of gluconeogenesis [17, 49]. a naturally occurring enantiomer, possesses anti-inflam- Stevia leaves contain, beside stevioside, also other matory activity. Moreover, (–)-linalool and its ester, diterpene glycosides, such as rebaudioside A–F, steviol- linalyl acetate, demonstrated analgesic and edema- bioside, and dulcoside A, which all are responsible for reducing effects [71] (Fig. 5). Arachidonic acid metabo-

OH H3C

HO CH3 CH3 OH O H

H3C H3C CH3 H O H H C H 3 H CH2 O O H H2C O CH H C CH H3C 3 3 3 H C O 3 CH3 O H CH2 O O linalyl acetate artemisolide celaphanol A costunolide

O CH CH3 2 H3C OH H C 3 H3C

CH3 H O

H C H CH CH H CH CH H 3 3 3 CH 3 3 CH3 CH3 O 3 O CH3 CH3 H H CH3

HO H3C O HO H3C CH3 H3C celastrol H3C COOH lupeol

acetyl-11-keto-β-boswellic acid O

O O OH CH3 CH H3C 3

CH3 O CH H O O H3C 3 CH HH 3 OH O CH H OH 3 O HO OH O O CH3 CH3 CH3 O

H3C CH3 O H3C cucurbitacin B oleandrin Fig. 5. Structures of selected terpenes with anti-inflammatory activity. 322 R. Paduch et al.: Terpenes useful in healthcare

lism and pro-inflammatory cytokine production in acti- Carapa guianensis can be useful in attenuating allergen- vated human monocytes were suppressed by 1,8-cineole -induced eosinophilia [73]. Moreover, they inhibited

(eucalyptol), a monoterpene isolated from eucalyptus NO and PGE2 production in LPS-stimulated macro- oil. 1,8-cineole was easily transported into tissues, but phages in vitro [52]. was rather slowly released into plasma. It also had a long Other terpenes exhibiting in vitro and in vivo anti- terminal half-life, so it remained inside the tissues at -inflammatory action, mainly by inhibition of phospholi-

high concentrations even after the dosing was over. pase A2 (PLA2) activity, have also been detected. PLA2 Therefore, this monoterpene was found to be especially is strongly associated with the control and regulation of useful in curing chronic ailments such as bronchitis inflammatory processes involving arachidonic acid sinusitis and steroid-dependent asthma or as a preven- metabolism and phospholipids turnover. Among the tive agent in returning respiratory infections [71]. The most active, betulin and betulinic acid [6] and cucur- sesquiterpene-monoterpene lactone artemisolide, iso- bitacins isolated from Cayaponia tayuya [78] have been

lated from Artemisia asiatica (Compositae), was shown described. Also, PLA2 was inhibited by oleanic and to be an nuclear factor (NF)-κB inhibitor. Artemisolide morolic acids [35] and a triterpene known as isomastica- attenuated lipopolysaccharide (LPS)-induced produc- dienonalic acid and its derivative tirucallane-type lanos-

tion of prostaglandin E2 (PGE2) and NO in macro- tanoids (masticadienonic and masticadienolic acids), phages cultured in vitro [79]. Terpinen-4-ol, the main isolated from Schinus molle [98]. On the other hand, component of the oil of Melaleuca alternifolia (tea tree phospholipase Cβ was inhibited by several sesquiter- oil), and cineole derivatives present in many plant oils penes, among which petasin was the most active [89]. also suppressed the production of several proinflamma- Betulin, betulinic acid, and ursolic acid isolated from α tory substances such as PGE2, TNF- , and interleukin Diospyros leucomelas also inhibited inflammation in the 1β [38, 42, 85]. Escandell et al. [29] have shown that carrageenan and serotonin paw edema tests [76]. cucurbitacin R reduce inducible nitric oxide synthetase Several lupane, oleane, and ursane triterpenoids and α (iNOS), cyclooxygenase 2 (COX-2), TNF- , and PGE2 their natural and synthetic derivatives exhibited anti- in paw homogenates of rats with adjuvant-induced -inflammatory effects in vitro and in vivo [77]. They inhib-

arthritis. Moreover, the naturally occurring diterpene ited NO production or interacted with PLA2 or peroxi- pepluanone, isolated from Euphorbia peplus, was shown some proliferator-activated receptor γ, a regulator of α to reduce NO, PGE2, and TNF- production by inhibit- the expression of genes expression involved in fatty-acid ing COX-2 and iNOS activity and down-regulating NF- β-oxidation and energy homeostasis [27, 44, 59, 67, 94]. -κB [21]. NF-κB is a well-characterized protein respon- Moreover, oleanolic and ursolic acids at low doses exert sible for the regulation of complex phenomena with an hepatoprotective effect which can be due to their a pivotal role in controlling cell signaling, especially the anti-oxidant and anti-inflammatory actions. These expression of gene-encoding pro-inflammatory cyto- triterpenoids are also effective inducers of metalloth- kines, chemokines, adhesion molecules, growth factors, ionein, a small cysteine-rich protein acting like glu- COX-2, and iNOS or immune receptors. All of these tathione in the body’s defense against many natural and play critical roles in inflammatory processes. Naturally chemical insults that could induce liver injury [60]. occurring NF-κB inhibitors have also been detected A pentacyclic terpene, α-amarin, also exhibited anti- among the diterpenes (excisanin, kamebakaurin), triter- -inflammatory activity in vivo (ear edema) and in vitro penes (avicin, oleandrin), sesquiterpenes and sesquiter- inhibiting pro-inflammatory cytokine production [68]. pene lactones (costunolide, parthenolide), pentacyclic triterpenes (celastrol, celaphanol A), and pentacyclic triterpenes such as aglycones of saponins [64, 74, 83]. ANTIPARASITIC ACTIVITY Among the pentacyclic terpenoids, acetyl-11-keto-β- -boswellic acid (AKBA), isolated from Boswellia serrata, A variety of natural products have been described as also exhibited pronounced anti-inflammatory activity. It antiparasitic agents with high efficacy and selectivity. causes selective blockade of the 5-lipooxygenase The antiparasitic activity of terpenoids is explained by through a pentacyclic structure-binding site which is dif- their interaction with heme and Fe(II) groups where ferent from the substrate binding site. In consequence, free radicals are released and kill parasites. Clinically, AKBA is considered to be an anti-inflammatory remedy their effects are rather immediate, but lead to a rapid [62]. It is also an inhibitor of NF-κB function and has reduction of parasitemia. In a group of monoterpenes, several biological effects, such as activation of cytokines espintanol and piquerol A have been found to have production and enhancement of the activity of some antiprotozoan parasite activity (Fig. 6). Thymol chemotherapeutic agents which induce apoptosis of and its structural derivatives also possess an anti-leish- tumor cells or suppress osteoclastogenesis. Therefore, manial potential [81]. Menthol derivatives have, in turn, AKBA may be active against a number of diseases, been described to possess trypanocidal activity [56]. including cancer, arthritis, chronic colitis, ulcerative col- Diterpenes and their lactones, e.g. dehydroabietinol iso- itis, and bronchial asthma [3, 87]. NF-κB-activated lated from Hyptis suaveolens, have been shown to have genes are also involved in allergic reactions. It has been antimalarial activity [91, 99]. Diterpenes with a nor-abi- indicated that several tetranorterpenoids isolated from etane skeleton had leishmanicidal and antiplasmodial R. Paduch et al.: Terpenes useful in healthcare 323

CH3 H OH CH CH3 3 O O OH OH H3C CH3 O H H H CO OCH HO CH 3 3 2 O

CH3 H3C

H3C CH3 H2C CH3 CH O 3 espinatol piquerol A artemisinin norabietane skeleton

CH3 OH H3C

HO H3C O CH H C 3 3 O H3C CH3 dehydroabietinol yingzhaosu A

Fig. 6. Structures of selected terpenes with antiparasitic activity.

action [84]. Betulinic acid has been described to have can be administered transdermally. It has been suggest- antimalarial activity [9]. Among the sesquiterpenes, ed that skin penetration enhancers such as terpenes may artemisinin and its derivatives, especially in combination increase the permeability of the stratum corneum with synthetic antimalarial substances, have been shown through intercellular lipid disruption, interaction with to be effective agents in the treatment of persons infect- proteins, or improved access of agents into the stratum ed with drug-resistant Plasmodium [43]. Other ses- corneum [63]. Such enhancers facilitate the diffusion of quiterpene peroxides, such as yingzhaosu A and drugs through the skin, increasing their therapeutic yingzhaosu C, also showed antiparasitic activity, espe- value. Terpene compounds possess several advantages, cially against Plasmodium berghei [53]. such as good penetration-enhancing abilities, low skin irritation effects, and low systemic toxicity. The greatest enhancement activity has been shown for oxide terpenes TERPENOIDS and other terpenoids compared with hydrocarbon or AS SKIN PENETRATION ENHANCERS even alcohol or ketone group-containing terpenes [95]. However, hydrocarbon terpenes, e.g. D-limonene, has Terpenes are used in numerous areas of medicine. already been approved as an active enhancer for There are many reports indicating that terpenes are skin steroids. Terpenes were also effective as skin perme- penetration-enhancing agents. Currently, terpenes are ability enhancers for the lipophilic molecule being analyzed as supplementary agents in topical der- indomethacin and for hydrophilic diazepam and propra- mal preparations, cosmetics, and toiletries. Moreover, it nolol [95]. Moreover, monoterpenes such as linalool, has been demonstrated that the transdermal pathway carvone, and thymol were also demonstrated to enhance may be suitable as an alternative route in, for example, the permeability of a number of agents, e.g. 5-fluo- antitumor drug administration. This is especially benefi- rouracil (5-FU), through skin and mucous membranes. cial when relatively long-term therapy is required [31]. Terpenes, however, vary in their enhancing activity In anticancer therapy, terpenes may serve as safe and towards 5-FU. It has been shown that D-limonene, clinically acceptable accelerants for the application of nerolidol, and 1,8-cineole increase drug permeability 2-, drugs with both lipophilic and hydrophilic features [63]. 23-, and 95-fold, respectively [22]. Sesquiterpenes, larg- In dermatology and cosmetology, lipophilic, hydro- er terpene molecules, also function as skin penetration philic, and multiphase vehicles are used. Among theses, enhancers. It has been shown that nerolidol enhances hydrogel solutions and oil-in-water emulsions are often the permeability of the hydrophilic drug 5-FU through applied. The activity of terpenes as transdermal human skin. enhancers is based on a reversible disturbance of the Terpenes have also been shown to significantly lipid arrangement in the intercellular region of the stra- increase transdermal flux of zidovudine (AZT) com- tum corneum [11]. The stratum corneum is the thin, out- pared with vehicle. AZT is the first anti-HIV compound ermost layer of the skin, which generally limits the approved for clinical use; however, its dose-dependent amount of different agents, drugs among others, that hematological toxicity limits its therapeutic effective- 324 R. Paduch et al.: Terpenes useful in healthcare

ness. Therefore, to maintain a stable, non-toxic, and cells by modulating cell cycle-related protein expression. plasma-effective concentration of AZT, a route of Cancer Lett., 181, 187–194. administration other than the peroral route has to be 6. Bernard P., Scior T., Didier B., Hibert M. and Berthon J. Y. (2001): Ethnopharmacology and bioinformatic combi- found. AZT is a polar molecule, so its transdermal per- nation for leads discovery: application to phospholipase A2 meability is rather poor and its concentration in plasma inhibitors. Phytochemistry, 58, 865–874. after transdermal application is low. Therefore, 7. Brea-Calvo G., Rodriguez-Hernandez A., Fernandez- enhancers allowing the drug molecule to pass through -Ayala D. J., Navas P. and Sanchez-Alcazar J. A. (2006):

the skin, especially the stratum corneum barrier, should Chemotherapy induces an increase in coenzyme Q10 levels be applied. The effectiveness of terpenes’ enhancement in cancer cell lines. Free Radic. Biol. Med., 40, 1293–1302. activity has been established as follows: cineole>men- 8. Brehm-Stecher B. F. and Johnson E. A. (2003): thol>menthone≈pulgeone≈α-terpineol>carvone>ve- Sensitization of Staphylococcus aureus and Escherichia coli hicle water [65]. Terpenes express low toxicity and are, to antibiotics by the sesquiterpenoids nerolidol, farnesol, therefore, regarded as safe agents, especially when used bisabolol, and apritone. Antimicrob. Agents Chemother., in humans with a weakened immunological system. 47, 3357–3360. 9. Bringmann G., Saeb W., Assi L. A., Francois G., Sankara It is generally assumed that small terpene molecules Narayanan A. S., Peters K. and Peters E. M. (1997): are better enhancers than larger ones. However, it Betulinic acid: isolation from Triphyophyllum peltatum and appears that non-polar terpenes such as D-limonene Ancistrocladus heyneanus, antimalarial activity, and crystal provide better enhancement for lipophilic agents than structure of the benzyl ester. Planta Med., 63, 255–257. polar terpenes. On the other hand, terpenes containing 10. Burke Y. D., Ayoubi A. S., Werner S. R., McFarland B. C., polar groups, e.g. menthol and 1,8-cineole, enable Heilman D. K., Ruggeri B. A. and Crowell P. L. (2002): hydrophobic permeants to traverse the human skin Effects of the isoprenoids perillyl alcohol and farnesol on much more easily than terpenes without polar groups. apoptosis biomarkers in pancreatic cancer chemopreven- This is the general mechanism on which the enhancing tion. Anticancer Res., 22, 3127–3134. activities of terpenes are based [65]. 11. Cal K., Kupiec K. and Sznitowska M. 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