Potential role of organic sulfur compounds from Allium ... - Springer Link

Phytochem Rev (2009) 8:349–368 DOI 10.1007/s11101-009-9122-z

Potential role of organic sulfur compounds from Allium species in cancer prevention and therapy C. Scherer Æ C. Jacob Æ M. Dicato Æ M. Diederich

Received: 22 September 2008 / Accepted: 29 January 2009 / Published online: 17 February 2009 Springer Science+Business Media B.V. 2009

Abstract Phytochemical research has revealed that organic sulfur-containing compounds (OSCs) from Allium species exert biological effects, that might be beneficial in the treatment or prevention of a range of diseases, such as infections, cardiovascular and metabolic affections, cancers and related indispositions. Focusing physiological activities of these compounds in the context of cancer, it became clear from both epidemiological studies in men and experimental studies in diverse models, that the OSCs have a strong potential to prevent or to treat cancers even with selectivity against non-neoplastic cells. Though underlying mechanisms are not yet fully understood, several parts of their modes and mechanisms of action were elucidated: Pivotal molecular targets of as well chemoprevention as chemotherapy are metabolic, transporter or repair enzymes strongly affecting cell death, proliferation and formation of metastases. Accordingly effects are not restricted to the run of cell death programs, but they moreover comprise the strongly interdepending immune and inflammatory systems. Respectively, C. Scherer M. Dicato M. Diederich (&) Laboratoire de Biologie Mole´culaire et Cellulaire du Cancer, Hoˆpital Kirchberg, 9, Rue Edward Steichen, Luxembourg, Luxemburg e-mail: [email protected] C. Scherer C. Jacob Bioorganic Chemistry, Saarland University, Saarbru¨cken, Germany

several hypotheses exist which are based on chemical properties of sulfur as the ‘‘pharmacophor’’ of the compounds appearing in up to ten different oxidation states (-2 to ?6). Hence compounds can undergo redox-reactions and electrostatic interactions, making reactive oxygen species (ROS) a key feature of their mechanisms of action. Keywords Organic sulfur compounds from Allium species Chemoprevention Chemotherapy Modes and mechanisms of action Abbreviations (A)GE (Aged) garlic extract AHQR Agency for Healthcare Research and Quality Akt Member of the protein kinase B-family AML Acute myeloid leukemia AMS Allyl methyl sulfide AMTS MATS allyl methyl trisulfide ARE Anti-oxidant response element ATR Ataxia-telangiectasia mutated and Rad3 related Bcl-2 B-cell lymphoma 2 BPH Benign prostatic hyperplasia Cdk1 Cyclin dependent kinase1 Chk1 Checkpoint kinase1 COX Cyclooxygenase CYP450 Cytochrome P450 DADS Diallyl disulfide DAS Diallyl sulfide

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DATS DATTS DMTS DPDS DPS DPTS DPTTS DU145 ERK Ets-1 c-GCS G(P)E GO GP GST HDAC HEK HIF HL60 HO1 HUVEC IAP ICAM IL iNOS JNK LDL LPS MAPK MDR NCI NFjB NK Nox NQO1 Nrf2 OO OSC(s) p53 PBMCs PC-3 P-gp PI3 PMS QR Ref

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Phytochem Rev (2009) 8:349–368

Diallyl trisulfide Diallyl tetrasulfide Dimethyl trisulfide Dipropyl disulfide Dipropyl sulfide Dipropyl trisulfide Dipropyl tetrasulfide Human prostate cancer cells Extracellular signal-regulated kinases Erythroblastosis virus E26 oncogene homolog 1 c-Glutamylcysteine synthetase Garlic (powder) extract Garlic oil Garlic powder Glutathione-S-transferase Histone deacetylase Human embryonic kidney cells Hypoxia-inducible factors Human leukemia cells Heme oxygenase 1 Human umbilical vein endothelial cells Inhibitor of apoptosis protein family Intercellular adhesion molecule Interleukin Inducible nitric oxide synthase c-Jun-terminal kinases Low density proteins lipopolysaccharide Mitogen-activated protein kinases Multidrug resistance National Cancer Institute Nuclear factor kappa B Natural killer cells NADPH-oxidases NAD(P)H:quinone oxidoreductase 1 Nuclear factor E2-related factor 2 Onion oil Organic sulfur compound(s) Tumor suppressor protein (mass 53 kDa) Peripheral blood mononuclear cells Human prostate cancer cells Glycoprotein P Phosphatidylinositol Propyl methyl sulfide Quinone reductase Redox-factors

RNS ROS SAC SAMC SH-SY5Y SOD SW480 TNF UK VEGF

Reactive nitrogen species Reactive oxygen species S-Allyl cysteine S-Allyl mercaptocysteine Human neuroblastoma cells Superoxide dismutase Human colon adenocarcinoma cells Tumor necrosis factor United Kingdom Vascular endothelial growth factor

Introduction Scientific search for new therapeutic agents is strongly supported by epidemiological studies about medicinal plants. Hence if beneficial effects on human health have been found, detailed studies are performed to identify active ingredients of plants in order to develop new drugs. In this context organic sulfur compounds (OSCs) of the genus Allium (Table 1) (Block 1992), especially allyl sulfides from garlic were elucidated to be the main class of compounds of those species responsible for anticancer and chemopreventive activities (Ariga and Seki 2006; Jacob 2006; Shukla and Kalra 2007). In this respect, potency of garlic formulations and of different OSCs was shown in epidemiological studies in men as well as in extensive preclinical studies in vitro and in vivo. Plant ingredients were active against a huge set of diverse cancers derived from different human tissues, such as prostate gland, gastrointestinal tract, liver, breast, lung, skin, brain and blood (Shukla and Kalra 2007; Wu et al. 2005). The compounds exert effects by different mechanisms affecting various cellular pathways and being strongly based on interactions with cellular proteins, DNA or oxidative stressors (Munchberg et al. 2007) finally leading to induction of cell death, e.g. via apoptosis or inhibition of proliferation. Mode of action of these OSCs, however, is not yet fully understood and can therefore only be explained in part by their chemical reactivity, comprising both chemical reactions, such as redox-reactions, and other types of interactions with cellular contents.


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Table 1 Selection of OSCs from Allium species known to exert beneficial effects on human health Compound name (abbreviation)

Chemical structure

References

Diallyl sulfide (DAS)

CH2=CH–CH2–S–CH2–CH=CH2

Shukla and Kalra (2007) and Wu et al. (2005)

Diallyl disulfide (DADS)

CH2=CH–CH2–S–S–CH2–CH=CH2


Diallyl trisulfide (DATS)

CH2=CH–CH2–S–S–S–CH2–CH=CH2


Diallyl tetrasulfide (DATTS)

CH2=CH–CH2–S–S–S–S–CH2–CH=CH2

Munday et al. (2003)

Allyl methyl sulfide (AMS) CH2=CH–CH2–S–CH3

Davenport and Wargovich (2005)

Allyl methyl trisulfide (AMTS, MATS)

Ariga and Seki (2006)

CH2=CH–CH2–S–S–S–CH3

Dimethyl trisulfide (DMTS) CH3–S–S–S–CH3


Propyl methyl sulfide (PMS)

CH3–CH2–CH2–S–CH3


Dipropyl sulfide (DPS)

CH3–CH2–CH2–S–CH2–CH2–CH3


Dipropyl disulfide (DPDS)

CH3–CH2–CH2–S–S–CH2–CH2–CH3


Dipropyl trisulfide (DPTS)

CH3–CH2–CH2–S–S–S–CH2–CH2–CH3

Chen et al. (2004)

Dipropyl tetrasulfide (DPTTS)

CH3–CH2–CH2–S–S–S–S–CH2–CH2–CH3

Munday et al. (2003)

Allicin

CH2=CH–CH2–S(O)–S–CH2–CH=CH2

Wu et al. (2005)

Ajoene

CH2=CH–CH2–S(O)–CH2–CH=CH–S–S–CH2–CH=CH2 Shukla and Kalra (2007) and Wu et al. (2005)

S-Allyl cysteine (SAC)

CH2=CH–CH2–S–CH2–CH(NH2)–COOH

Shukla and Kalra (2007), Wu et al. (2005) and Davenport and Wargovich (2005)

S-Allyl mercaptocysteine (SAMC)

CH2=CH–CH2–S–S–CH2–CH(NH2)–COOH


For some of the listed compounds biological effects have to be attributed in part to metabolites formed inside the body. Apart from the depicted compounds, further chemically related (a) symmetrical methyl-, ethyl-, and propyl-based polysulfides (S3–S6) can be isolated from Allium species. Some compounds of this class also occur in trees or were not yet shown to have pharmacological effects (Jacob 2006; Munday et al. 2003; Benkeblia and Lanzotti 2007). Remarks: chemical structures according to Shukla and Kalra (2007), Davenport and Wargovich (2005) and Chen et al. (2004); in order to facilitate inspection, exclusively selected reviews or experimental papers are indicated as references

Besides, some OSCs were shown to possess selective activity against cancer cells in comparison with their healthy analogues (Munchberg et al. 2007; Dirsch et al. 1998; Jacob and Anwar 2008). This is quite surprising due to the widespread activity/reactivity of the compounds and could be explained by different levels and patterns of protein expression, by different surviving mechanisms or by different redoxlevels of healthy and cancer cells (Jacob et al. 2003; Finkel and Holbrook 2000; Winyard et al. 2005). Overall, properties of the compounds are quite favourable for ongoing drug development studies. Besides plants containing OSCs could be considered as functional food due to their beneficial effects on health (Dashwood and Ho 2007; Jastrzebski et al. 2007).

Modes and mechanisms of action of organic sulfur compounds (OSCs) from Allium species with potential therapeutic use focusing cancer diseases Epidemiological studies and records The inverse association between the consumption of garlic (and other Allium-species) and the risk of diverse human diseases or the use of the plant as remedy have been widely reported throughout recorded history (Wu et al. 2005). In this regard the plants’ beneficial effects on human health were observed in connection with both cardiovascular diseases and cancers (chemoprevention, chemotherapy) (Agarwal 1996). Besides favourable activities of the plant constituents were

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revealed for pathophysiological imbalances often described to be linked with cancers, i.e. immune function, diabetes, blood pressure, blood glucose or lipid level, atherosclerosis, thrombosis, diverse infections and aging (Shukla and Kalra 2007; Wu et al. 2005; Ngo et al. 2007; Hassan 2004; Devrim and Durak 2007; Herman-Antosiewicz and Singh 2004). Pharmacological efficacy was especially evident, however, in cardiovascular diseases and in intestinal cancers considering population-based studies and clinical trials; accordingly, garlic is one of the plants recognised by the National Cancer Institute (NCI) of the UK as one of several vegetables with potential anticancer properties (http://www.cancer.gov/cancer topics/factsheet/Prevention/garlic-and-cancer-preven tion) (Ariga 2006). In this respect case-control or cohort studies demonstrated, that elastic properties of the aorta were ameliorated after garlic consumption (Barrett 2004). Furthermore the Agency for Healthcare Research and Quality (AHQR) recorded several population based studies on beneficial effects of garlic preparations on blood level of cholesterol (low-density lipoprotein (LDL) and triglycerides), on hypertension and on atherosclerosis. Moreover, several population based studies and clinical trials suggest a preventive effect of garlic consumption against gastrointestinal cancers (Barrett 2004; Fleischauer and Arab 2001; Gonzalez et al. 2006; Steinmetz et al. 1994; Gao et al. 1999; Setiawan et al. 2005; Chan et al. 2005), the plant’s potency could even be correlated with the dose of intake (Tanaka et al. 2004; Garlic and 2008). Accordingly strong prevention of death from stomach cancer by consumption of Allium vegetables (improvement of around factor 10 of cases per controls) could be shown comparing two different provinces in China (high intake (20 g per day) versus low intake (1 g per day)) (Shukla 2007). Concordantly reciprocal correlations were found for garlic intake in other countries (e.g. Sweden, Italy, USA, Japan) all reporting a reduced risk of stomach, esophageal and colorectal cancers (Shukla 2007). Less often garlic’s efficacy against other tumors, such as prostate cancer or benign prostatic hyperplasia (BPH), cancers of head, neck, breast, skin or lung, were elucidated (Devrim and Durak 2007; Fleischauer and Arab 2001; Garlic and 2008; Tilli et al. 2003; Hsing et al. 2002; Challier et al. 1998), suggesting that effects are not restricted to topical

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applications, but also occur systemically. For example population based diet studies in England revealed a decreased risk of prostate cancer in elderly men caused by a high total fat intake when consuming garlic. This was indicated by an odds ratio of 0.65 of subjects (adapted by social class) ingesting garlic as a food to the ones consuming none (Devrim 2007). Additionally clinical trials could show an improvement of disease parameters of patients suffering from prostate cancer or BPH after treatment with aqueous garlic extracts (Devrim 2007). Experimental studies Cancer-related modes of activity of OSCs from Allium species Based on information provided by epidemiological data, a huge amount of experimental studies was performed confirming a broad spectrum of beneficial biological activities of Allium species in vitro and in vivo, mainly of garlic (Shukla and Kalra 2007; Wu et al. 2005; Herman-Antosiewicz et al. 2007). In this respect, OSCs were identified to be the compound class responsible for most of the pharmacological effects of the plant family (Ariga and Seki 2006; Agarwal 1996; Davis 2005). Most of the effects described can be attributed to cancers and related diseases, cardiovascular affections and infections with viruses, bacteria, fungi or parasites (Agarwal 1996; Davis 2005). This review will focus, however, on the biological activities of OSCs related with cancer. The activity profile in the area of chemoprevention and/or chemotherapy comprises stimulation of the immune function, induction of apoptosis, inhibition of proliferation and formation of metastases, anti-inflammatory effects, reversal of multidrug resistance (MDR), modulation of metabolism Phase I and Phase II, and the modulation of most redox-sensitive cellular processes. All these modes of action yield a protection of the body against initiation, promotion and progression of cancers due to different causes (Tables 2, 3). Hence extensive experimental studies of garlic formulations and OSCs, naturally occurring in the plant, were performed in order to elucidate mechanisms of action. Nonetheless it is not always possible to make a clear cut between different ‘‘targets’’ and pathways affected, e.g. in the case of reactive oxygen species


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Table 2 Anti-cancer effects of different OSCs from Allium clearly attributed to interactions with ROS OSC

Models

Influence on ROS-level

Biological effects

DAS

Human cancer cells

;

Cytoprotective

Chen et al. (2004)

Human cancer cells

:

Chemotherapeutic

Das et al. (2007)

Mice

;

Chemopreventive, cytoprotective

Devrim and Durak (2007) and Prasad et al. (2008)

Human cancer cells

:

Chemotherapeutic

Shukla and Kalra (2007), Wu et al. (2005), Dashwood and Ho (2007), Herman-Antosiewicz and Singh (2004), Das et al. (2007), Karmakar et al. (2007), Kwon et al. (2002), Filomeni et al. (2003), Liu et al. (2006) and Lu et al. (2004)

Human cancer cells

;

Cytoprotective, chemopreventive

Shukla and Kalra (2007), Dashwood and Ho (2007) and Chen et al. (2004)

Human cancer cells

;

Cytoprotective

Chen et al. (2004)

Human cancer cells

:

Chemotherapeutic, chemopreventive

Shukla and Kalra (2007), Herman-Antosiewicz et al. (2007), Das et al. (2007), Herman-Antosiewicz et al. (2007), Hosono et al. (2005), Xiao et al. (2005)), Antosiewicz et al. (2006), Kim et al. (2007), Xiao et al. (2004) and Xiao and Singh (2006)

DADS

DATS

References

Normal human cells

:

Anti-angiogenic

(Devrim and Durak 2007; Xiao et al. 2006)

Macrophages

;

iNOS;, NFjB;

Liu et al. (2006)

Rats

;


Ariga and Seki (2006) and Fukao et al. (2004a, b)

DATTS

Rats

;

Cytoprotective

Murugavel and Pari (2007a, b)

DPTS

Human cancer cells, mice

;

Cytoprotective

Chen et al. (2004) and Nishimura et al. (2006)

Allicin

Human cancer cells

:, ;

Chemopreventive, chemotherapeutic

Oommen et al. (2004)

Mice

:

Immune-stimulatory, chemotherapeutic

Patya et al. (2004)

(Z)-Ajoene

Human cancer cells, human leukemic blood

:

Chemotherapeutic

Shukla and Kalra (2007), Dirsch et al. (1998), HermanAntosiewicz and Singh (2004), Dirsch et al. (2002) and Li et al. (2002)

SAC

Normal human cells, human cancer cells, macrophages, rats

;


Ariga and Seki (2006), Aggarwal and Shishodia (2004), Ide and Lau (2001), Geng et al. (1997), Balasenthil et al. (2001, 2002), Ho et al. (2001) and Sundaresan and Subramanian 2008)

AGE

Human cancer cells, macrophages

;


Ide and Lau (2001)

GE GO

Rats

;

Anti-inflammatory

Sankaranarayanan et al. (2007)

Hamster

;

Chemopreventive

Wu et al. (2005)

Rats

;

Chemoprevention, cytoprotection

Agarwal et al. (2007)

Mice

;

Cytoprotection

Liu and Xu (2007)

Potency of OSCs in the field of cancer research was extensively shown by experimental studies in vitro and in vivo. Moreover, it was proven in several models that ROS are a key factor of the different triggered events. Remarks: Effects of extracts have partially to be attributed to other compound classes of the plant family, such as saponins (Lanzotti 2005), sapogenins and phenolic compounds or flavonoids (Lanzotti 2006). The compound class primarily responsible for anti-oxidant effects are organosulfur compounds (Siegers et al. 1999), but other endogenous components, such as phenolics, also contribute to this effect (Benkeblia 2005; Yin and Cheng 1998). OSC Organic sulfur compound, ROS reactive oxygen species, DAS diallyl sulfide, DADS diallyl disulfide, DATS diallyl trisulfide, DATTS diallyl tetrasulfide, DPTS dipropyl trisulfide, SAC S-allyl-cysteine, AGE aged garlic extract, GE fresh garlic extract, GO garlic oil

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Table 3 Direct and indirect anti-cancer effects of different OSCs not elucidated to be linked with the cellular redox-system OSC

Models

Biological effects

References

DAS


Modulation of MDR

Shukla and Kalra (2007) and Arora et al. (2004)

Human cancer cells

Chemotherapeutic

Wu et al. (2005) and Karmakar et al. (2007)

Rodents

Modulation of Phase I- and Phase IImetabolism (CYP450)

Davenport and Wargovich (2005) and Yang et al. (2001)

Anti-inflammatory, immunomodulatory (NFjB;)

Aggarwal and Shishodia (2004), Davenport and Wargovich (2005) and Keiss et al. (2003)

Human cancer cells


Shukla and Kalra (2007), Wu et al. (2005), Herman-Antosiewicz and Singh (2004), Karmakar et al. (2007), Xiao et al. (2005), Wen et al. (2004) and Tsai et al. (2007)

Rats

Modulation of Phase I- metabolism (CYP450)


DADS Normal human blood

DADS Rats

Chemopreventive

Devrim and Durak (2007) and Arunkumar et al. (2006)

Mice

Chemotherapeutic (inhibition of p21H-ras membrane association)

(Singh et al. 1996; Singh 2001)

DATS Human cancer cells

Cytoprotective (MAPKs, calcium)

(Chen et al. 2004)

Human cancer cells


Shukla and Kalra (2007), Wu et al. (2005), Herman-Antosiewicz and Singh (2004) and Tsai et al. (2007)

Rats

Modulation of Phase I- metabolism (CYP450)


AMS

MATS In vitro, in vivo Anti-thrombotic


Allicin Normal human cells

Anti-inflammatory, immunomodulatory (NFjB;, ICAM-1;)

Aggarwal and Shishodia (2004), Keiss et al. (2003) and Son et al. (2006)

Allicin Human cancer cells

Chemotherapeutic

Wu et al. (2005) and Hassan (2004)

Ajoene Human cancer cells

Chemotherapeutic, anti-thrombotic, cholesterol lowering

Wu et al. (2005), Hassan (2004), Herman-Antosiewicz and Singh (2004) Park et al. (2005) and Li et al. (2002)

SAC

Anti-invasive, anti-metastatic (E-cadherin:, Devrim and Durak (2007), Chu et al. (2006) and Sundaresan c-catenin:)) and Subramanian (2008)

Human cancer cells

SAMC Human cancer cells, mice

Anti-invasive, anti-metastatic (E-cadherin:) Devrim and Durak (2007), Howard et al. (2007), Chu et al. (2006) and Sigounas et al. (1997a, b)

Human cancer cells

Chemotherapeutic

Wu et al. (2005), Herman-Antosiewicz and Singh (2004), Xiao et al. (2005) and Sigounas et al. (1997a, b)

GE


Immunomodulatory (NK-activation): chemotherapeutic

Hassan et al. (2003)

GPE

Normal human blood

Anti-inflammatory, immunomodulatory (NFjB;), chemotherapeutic

Shukla and Kalra (2007), Aggarwal and Shishodia (2004) and Keiss et al. (2003)

GO

Human cancer cells

Chemotherapeutic, induction of differentiation

Seki et al. (2000)

OO

Human cancer cells

Chemotherapeutic, induction of differentiation

Seki et al. (2000)

GP

Rats

Chemopreventive

Park et al. (2002)

Though manifold studies show clearly, that ROS is an important part of signaling pathways affected by OSCs (see Table 2), it seems not always to be targeted. Hence its contribution to different activities of OSCs remains a matter of discussion. Remarks: Biological activities of DAS have partially to be attributed to the metabolites diallyl sulfoxide (DASO) and the diallylsulfon (DASO2) (Yang et al. 2001). OSC Organic sulfur compound, ROS reactive oxygen species, DAS diallyl sulfide, DADS diallyl disulfide, DATS diallyl trisulfide, AMS allyl methyl sulfide, MATS allyl methyl trisulfide, SAC S-allyl cysteine, SAMC S-allyl-mercaptocysteine, GE fresh garlic extract, GPE garlic powder extract, GO garlic oil, OO onion oil, GP garlic powder, MDR multidrug resistance, CYP450 cytochrome P450, NFjB nuclear factor kappa B, MAPK mitogen activated protein kinases, ICAM intercellular adhesion molecule, NK natural killer cells

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(ROS), since intra- and inter-cellular crosstalks are very strong. Less attention has so far been payed for pharmacokinetic studies, but bioavailability is nonetheless obvious by manifold systemic effects in vivo after peroral application (in men and in animals) (Shukla and Kalra 2007). Furthermore, the ability of several OSCs to cross biological barriers was shown in particular studies (Miron et al. 2000). Hypotheses and studies on mechanisms of anti-cancer-activities of OSCs Overall, it was shown that compounds reduce the transformation of normal to neoplastic cells at different phases (initiation, promotion, progression (Tapiero et al. 2004) and that they do kill cancer cells. While mechanisms of activities of the different OSCs are not yet fully understood, some molecular targets have been clearly identified in diverse models. Overview of molecular targets affected by OSCs Modulation of metabolic and transporter enzymes: chemoprevention, enhancement of chemotherapies One part of the impact of OSCs on cellular metabolism is the modulation of Phase I enzymes, what can result in an inhibition of procarcinogen activation (Guengerich 1988). For example, diallyl sulfide, diallyl disulfide, and diallyl trisulfide were found to prevent cancer in rats by inhibition of cytochrome (CYP) P450 2E1, in that this isoform is an important factor in carcinogen activation (Aggarwal and Shishodia 2004; Wu et al. 2002). Nonetheless, one has to bear in mind the interspecies differences of CYP450s (rodents versus men). Moreover some CYP450enzymes are overexpressed in human cancers, and this could make them attractive therapeutic targets (McFadyen et al. 2004; Davenport and Wargovich 2005). On the other hand, activity or level (of proteins or mRNA) of some CYP450-enzymes in rats, such as 1A1, 2B1, 3A1 or 2B10 were increased by garlic oil, diallyl sulfide, diallyl disulfide and diallyl trisulfide (Wu et al. 2002; Fisher et al. 2007). This might be beneficial if these enzymes would metabolise cytotoxic agents, or if they would activate procytotoxic agents selectively in cancer cells (due to different

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enzyme expression patterns of healthy and cancer cells) (McFadyen et al. 2004); but this process might otherwise be a disadvantage if triggering carcinogen activation in all cells. Besides, inhibition of several enzymes, such as adenosine deaminase or cyclic AMP-phosphodiesterase, can directly result in physiological effects, i.e. inhibition of platelet aggregation and vasodilatation (Agarwal 1996), that might also contribute to the antimetastatic activity (and cardiovascular effects) described for several garlic compounds (Ariga and Seki 2006; Hassan 2004; Devrim and Durak 2007; Howard et al. 2007). Apart from the fact that diverse OSCs interact with different CYP450s, this effect is additionally dependent on the model, the dose and the scheme of application (Agarwal 1996; Herman-Antosiewicz and Singh 2004; Davenport and Wargovich 2005). Another important aspect of the effects of OSCs on cellular metabolism is the induction of Phase II enzymes conjugating metabolic intermediates with glutathione, glucuronic acid or some amino acids. In consequence, carcinogen detoxification and elimination are activated (Ariga and Seki 2006; Sheweita et al. 2001), i.e. diallyl trisulfide was reported to increase activities of glutathione-S-transferase (GST) and quinone reductase (QR) in rat liver (Ariga and Seki 2006; Fukao et al. 2004a; 2004b); besides garlic oil and diallyl disulfide elevate GST-activity in rats (Wu et al. 2002). Accordingly GST-activity was elevated in human glioblastoma cells after treatment with diallyl sulfide, diallyl disulfide and diallyl trisulfide (Das et al. 2007). Additionally, GST-gene expression levels were enhanced, mediated by the anti-oxidant response element (ARE) (Chen et al. 2004); Moreover, ARE was shown to play an important role for detoxifying enzymes linked with nuclear factor E2-related factor 2 (Nrf2), such as NAD(P)H:quinone oxidoreductase 1 (NQO1), c-glutamylcysteine synthetase (c-GCS), heme oxygenase 1 (HO1) and superoxide dismutase (SOD) (Chen et al. 2004; Chan and Kan 1999). Other studies report beneficial effects of OSCs on H- and L-ferritin in animal and cellular models (Chen et al. 2004; Thomas et al. 2002). The latter observations reveal that the connection of OSCs with the cellular redoxsystem is in part due to the modulation of antioxidative or pro-oxidative enzymes irrespective of direct chemical interactions with redox-species.

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Concordantly with the modulation of Phase II enzymes, post-translational modifications can be inhibited, e.g. the growth of H-ras oncogene transformed tumor xenografts in mice was inhibited by diallyl disulfide (Herman-Antosiewicz et al. 2007; Tapiero et al. 2004; Singh et al. 1996). Apart from these effects on key enzymes of metabolism, OSCs can also affect other enzymes. In the context of cancer, the modulation of multidrug resistance enzymes, such as efflux pumps with a broad substrate spectrum (e.g. glycoprotein P (P-gp)) (Ambudkar et al. 1999; Arora et al. 2004), is very beneficial to improve response of cancers to chemotherapies. This was described for ajoene improving the efficiency of cytarabine and fludarabine against acute myeloid leukemia (AML) (Hassan 2004), or for diallyl sulfide attenuating resistance of leukemic K562 cells against vinca-alkaloids via P-gp-modulation (Arora et al. 2004).

Fig. 1 Molecular mechanisms of induction of apoptosis by DAS and DADS in human neuroblastoma cells (SH-SY5Y cells) (Mechanism modified according to Karmakar et al. (2007). As can be concluded from the schematic, both canonical pathways of apoptosis (mitochondrial and death receptor mediated) are targeted by OSCs in cancer cells. DAS Diallyl sulfide; DADS diallyl disulfide; Ca calcium; TNF tumor necrosis factor; casp caspase; cyt cytochrome c; (I)CAD

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Induction of programmed cell death, inhibition of proliferation and metastases: chemotherapeutic effects The most extensively described modes of action of OSCs from garlic in cancer cells are the induction of programmed cell death type I and the inhibition of cellular proliferation (Shukla and Kalra 2007; Wu et al. 2005; Herman-Antosiewicz and Singh 2004). Accordingly, theories about underlying mechanisms leading to apoptosis or to cell cycle arrest are manifold although they are not yet completely understood. Some very detailed hypotheses about these cellular signaling cascades affected by garlic compounds were established for diallyl sulfide or diallyl disulfide in SH-SY5Y cells (human neuroblastoma) (Karmakar et al. 2007) (Fig. 1), for diallyl trisulfide in PC-3 and DU145 cells (human prostate cancer) (Herman-Antosiewicz et al. 2007), or for

(inhibitor of) caspase-activated DNAse; Apaf 1 apoptotic peptidase activating factor 1; AIF apoptosis-inducing factor; IAP inhibitor of apoptosis proteins (e.g. BIRC-2, -3); Smac second mitochondrial activator of caspases; Diablo direct IAPbinding protein with low pI; Bcl-2-family members Bax, Bak, Bid, Bcl-2, Bcl-xL; CARD caspase recruitment domains; IP3 inositoltriphsosphate; IjBa inhibitor of nuclear factor kappa B alpha; NFjB nuclear factor kappa B


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Fig. 2 Molecular mechanisms of induction of apoptosis or cell cycle arrest by DADS and SAMC in human colon adenocarcinoma cells (SW480) and of DATS in human prostate cancer cells (PC-3, DU145) (Mechanisms modified according to Herman-Antosiewicz et al. (2007) or to Xiao et al. (2005) respectively). According to the scheme OSCs trigger cell cycle arrest and apoptosis in diverse cancer models which might be especially favourable for cancer treatments since two control points of cellular survival would be simultaneously affected. DATS Diallyl trisulfide; DADS diallyl disulfide; SAMC

S-allylmercaptocysteine; DNA-DSB DNA-double strand breaks; ATR ataxia-telangiectasia mutated and Rad3 related checkpoint; Chk1 checkpoint kinase 1; ROS reactive oxygen species; Cdc25C cell division cycle 25 homolog C (S. pombe); Chk1 cyclin-dependent kinase; Cdk1 cyclin-dependent kinase; APC/C anaphase-promoting complex/cyclosome; Bcl-2-family members Bax, Bad, Bcl-2 (and phosphorylated proteins); IGFR insulin-like growth factor receptor; JNK c-Jun-terminal kinases; ERK extracellular signal-related kinases; AIF apoptosis inducing factor

diallyl disulfide and S-allyl-mercaptocysteine in SW480 cells (human colon adenocarcinoma) (Xiao et al. 2005) (Fig. 2). Respectively, treatment of SHSY5Y cells with DAS or DADS mediated a caspasedependent run of three different apoptotic cell death programs, i.e. an increase of the Bax/Bcl-2-ratio, an increase of free intracellular calcium, or an inhibition of cell survival signals. In the first case, mitochondrial release of proapototic molecules was promoted, whereas the increase of calcium led to an activation of calpain and caspase 3. On the other hand cell survival was inhibited by a down regulation of NFjB and of IAPs triggering an over activation of caspase 3. Treatment of the human prostate cancer cells PC-3 and DU145 with DATS resulted in a G2 and M phase arrest of the cell cycle. The underlying mechanism is supposed to start with a degradation of ferritin, leading to an increase of free intracellular iron and of ROS hence promoting the destruction of Cdc25C;

besides, however, a downregulation of the protein level of Cdk1 was observed. Moreover the prometaphase arrest seems to be partially controlled by a novel ATR/Chk1 checkpoint. Application of SAMC or DADS to human colon adenocarcinoma cells induced apoptosis via both a caspase-dependent pathway and an independent one. The caspasedependent one resulted from a microtubule depolymerisation and a consecutive mitotic arrest; the mechanism of the other pathway remains elusive. Based on information and theories developed from experimental data, it becomes obvious that physiological effects are strongly dose-, time-, and modeldependent for each test compound. Nevertheless, some observations were repeatedly made when comparing diverse test systems: promotion of apoptosis of cancer cells occurs via both, the extrinsic and the intrinsic pathway, the latter one being much more prominent (Wu et al. 2005). Respectively, common

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markers of apoptosis are modulation of the Bcl-2family (Wu et al. 2005), mitochondrial membrane permeabilisation and release of cytochrome c into the cytoplasm (Wu et al. 2005; Dirsch et al. 2002), activation of caspases (3, 8, 9) (Wu et al. 2005; Kwon et al. 2002; Oommen et al. 2004) (not mandatory, Park et al. 2005), increase of free intracellular calcium (Wu et al. 2005; Park et al. 2002), modulation of diverse kinases (e.g. extracellular signal-regulated kinases (ERK) (Sriram et al. 2008; Antlsperger et al. 2003), mitogen-activated protein kinases (MAPK) (Chen et al. 2004; Park et al. 2005; Wen et al. 2004), c-Jun-terminal kinases (JNK) (Antlsperger et al. 2003), influence on transcription factors (e.g. nuclear factor kappa B (NFjB) (Dirsch et al. 1998, p. 53; Hong et al. 2000; Bottone et al. 2002) or the inhibitor of apoptosis family (IAP) (Park et al. 2005). Regarding arrest of cell cycle by OSCs, it may— likewise apoptosis—occur via different checkpoints (Shukla and Kalra 2007; Wu et al. 2005; HermanAntosiewicz and Singh 2004; Hartwell and Weinert 1989); one main point is the G2/M-phase (HermanAntosiewicz and Singh 2004; Wu et al. 2004; Robert et al. 2001; Knowles and Milner 2000; Druesne et al. 2004), another one is the direct interaction with microtubules (e.g. inhibition of tubulin polymerisation) (Hosono et al. 2005; Xiao et al. 2003). Moreover, there are other studies about anti-proliferative effects of OSCs concerning DNA-repair that presume that histone deacetylase (HDAC)-inhibition (Dashwood and Ho 2007; Filomeni et al. 2003) or suppression of membrane association of tumoral p21H-ras (Singh 2001) contribute to the induction of cell death. Accordingly, OSCs are also able to decrease or prevent formation of metastases, which is additionally attributed to other targets. For instance, S-allylmercaptocysteine was shown to suppress invasion and motility of PC-3 cells via up-regulation of the cell-adhesion molecule E-cadherin in mice (Howard et al. 2007). In a similar model Chu et al. (2006) demonstrated that S-allylmercaptocysteine and S-allylcysteine restored E-cadherin expression, while down-regulating the molecule’s suppressor Snail; it was assumed that this observation may also valid for other cancer types. Further studies confirmed this anti-metastatic effect of OSCs by inhibition of angiogenic features of normal endothelial cells, i.e. formation of capillary-like tube

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structures and migration by human umbilical vein endothelial cells (HUVECs) after treatment with diallyl trisulfide, an effect which was mainly associated with a suppression of vascular endothelial growth factor (VEGF)-secretion, down-regulation of VEGF receptor 2 and inactivation of Akt (member of the protein kinase B-family) (Xiao et al. 2006). Modulation of physiological pathways with potential use for cancer therapies Other biological pathways that might be implicated in anti-cancer approaches are related with the immune and the inflammatory system. Since both are strongly interdependent, OSCs affect both of them. Accordingly, garlic contents were described to possess immunomodulatory and anti-inflammatory properties, by modulating lipopolysaccharide (LPS)induced cytokine levels (e.g. decrease of proinflammatory interleukin (IL)-1b and tumor necrosis factor (TNFa)) in human blood (Keiss et al. 2003), which resulted moreover in a reduction of the activity of the transcription factor NFjB—which is strongly linked with inflammatory diseases like cancers (Aggarwal and Shishodia 2004; Delhalle et al. 2004)—in human embryonic kidney (HEK 293) cells, when exposed to the treated blood (Keiss et al. 2003). Anti-inflammatory effects were also observed by prevention of a radiotherapy-induced up-regulation of the intercellular adhesion molecule-1 (ICAM-1) by allicin (Son et al. 2006), or by a decrease of the level of cyclooxygenase 2 (COX-2), an enzyme responsible for the biosynthesis of prostaglandins and known to be induced in several cancers. The latter effect appeared to be correlated with an anti-neoplastic activity in vitro (Elango et al. 2004). In addition, stimulation of the immune defense (lymphocytes) by allicin was demonstrated in vitro and supposed to be contributing to the compounds anti-tumoral potency in mice (Patya et al. 2004). Furthermore, apart from interactions with the immune system or inflammatory processes, induction of differentiation of cancer cells was shown for human leukemia cells (HL-60) leading to a growth inhibition (Seki et al. 2000). Pivotal role of ROS, cancer-related activities of OSCs Many of the observed activities of several of the OSCs are strongly linked with the cellular redoxsystem. On the other hand it is even not always


possible to distinguish between biological effects linked with this system or occurring independently from it. ROS seems to play, however, an important role for many biological activities of OSCs (Shukla and Kalra 2007; Wu et al. 2005), but it does not appear to be mandatory for all chemopreventive and chemotherapeutic effects; for example, apoptosis can be initiated by ROS, but ROS is not a precondition for cellular run of apoptotic programs (Shukla and Kalra 2007; Sriram et al. 2008). Links between oxidative stress, cancer and organic sulfur-species The intracellular balance between oxidising and reducing species is one of the preconditions of health of most living organisms. Hence cells have to monitor and to regulate their redox-level in order to maintain this equilibrium against disturbances (Winyard et al. 2005). Imbalances of this state—called ‘‘oxidative stress’’ (Finkel and Holbrook 2000; McCord 1998, 2002; Sies 1985)—can be initiated by increased intracellular concentrations of ‘‘reactive oxygen species’’ (ROS), ‘‘reactive nitrogen species’’ (RNS) (Betteridge 2000) or ‘‘free’’ adventitious transition metal ions (Bush 2000). These highly reactive species interfere with diverse cellular constituents, like nucleic acids, proteins, lipids, sugars or metal ions (Jacob 2006; Takahashi and Niki 1998; Panayiotidis 2008) thus affecting a wide and diverse range of cellular pathways and signaling cascades, finally leading to biological effects. In order to avoid unwanted processes, most organisms (e.g. animals, plants, fungi, bacteria) possess anti-oxidant defensemechanisms, that are mainly mediated by thiols together with their corresponding disulfides, making up an intracellular redox-buffer (Jacob 2006). Nevertheless, defense capacity is not always sufficient to prevent damage, which then results in several pathologies, such as rheumatoid arthritis, neurodegenerative diseases, diabetes or cancer (Winyard et al. 2005). ROS-triggered carcinogenesis and cancer promotion/survival Endogenous and exogenous oxidants (mostly free radical species, e.g. superoxide (O•2 ), hydroxyl radical (•OH), singlet oxygen, alcoxyl- and peroxylradicals or hydrogen peroxide (H2O2) (Galaris et al.

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2008), peroxynitrite, hypochlorous acid (Hawkins and Davies 2002; Kawai et al. 2004; Doulias et al. 2001)), at certain concentrations are known to induce cytotoxicity or mutagenesis (Ushio-Fukai and Nakamura 2008), which is mainly attributed to the species’ high reactivity with the cellular macromolecules mentioned above (Panayiotidis 2008). Hence it is not surprising that ROS-species have been reported to be involved in over 150 human pathologies, amongst them cancer as a very important one (Nishikawa 2008; Halliwell et al. 1992). In this respect ROS can also induce carcinogenesis fostering the conversion of normal cells to a malignant state (Tapiero et al. 2004; Loft and Poulsen 1996; Feig et al. 1994). Bearing this in mind one might assume that drug research in the related fields might be limited to antioxidative agents excluding pro-oxidative compounds, but this is not the case since basic endogenous redoxlevels of healthy cells differ in the majority of cases from those of cancer cells (Panayiotidis 2008). In general tumor cells have an inherently increased metabolic activity when compared to their healthy analogues (Clerkin et al. 2008). Under normoxic or hypoxic conditions (Galanis et al. 2008), this often leads to an increase of intracellular ROS-levels in cancer cells (e.g. superoxide radical and hydrogen peroxide) involving production by mitochondria (Pelicano et al. 2004) and NADPH-oxidases (Nox, diverse isoforms); expression pattern of these enzymes differs moreover from healthy cells (Cheng et al. 2001). In consequence, ROS activate several pathways, such as those associated with phosphatidylinositol (PI3)-kinase/protein kinase B, (Clerkin et al. 2008), hypoxia-inducible factors (HIF-1a), redox-factors (Ref-1), tumor proteins (p53), NFjB, erythroblastosis virus E26 oncogene homolog 1 (Ets-1) (Ushio-Fukai and Nakamura 2008); all of these signaling cascades have pivotal influence on cellular metabolism, angiogenesis, formation of metastases, cell cycle regulation, cell survival and inhibition of apoptosis (Nishikawa 2008; Clerkin et al. 2008; Galanis et al. 2008). Moreover, cancer cells can hardly buffer elevated ROS levels, since their level/activity of anti-oxidant enzymes (e.g. copper, zinc-superoxide dismutase (SOD)), manganese-SOD, catalase, glutathione peroxidase) is generally low, which is often linked to changes in three types of genes, i.e. oncogenes, tumor-suppressor genes and stability genes (Nishikawa 2008). As a

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matter of course the down-regulation of this antioxidant defense favours cancer initiation, promotion and progression (Klaunig and Kamendulis 2004) in the healthy environment of the cancer cells, since total physiological oxidative load is increasing and cancer cells strongly interact with surrounding tissue, extracellular matrix, immune cells, blood cells and endothelial cells (Nishikawa 2008). Nevertheless, many details of the mechanisms of ROS-triggered events still remain elusive. Therapeutic options for the different courses/ patterns of ROS-triggered carcinogenesis or cancer survival Though both cancerous and non-cancerous cells naturally produce oxidative species—mostly ROS— during aerobic metabolism (Clerkin et al. 2008), the levels of different cells differ due to their different potency of generating endogeneous and in removing/ buffer endogenous as well as exogenous oxidative species (Galaris et al. 2008). Generally the ROScontent of healthy cells is lower than the one of their cancer-counterparts (Ushio-Fukai and Nakamura 2008), indicating that cancer cells are harder to kill by this kind of stress (Ushio-Fukai and Nakamura 2008). Nonetheless this difference is also an important feature to reach selectivity in therapeutic anti-cancer approaches in this field, what is additionally accomplished by some bottlenecks: strong interspecies/ intertissue-variations of ROS (Szatrowski and Nathan 1991), differing spectra of anti-oxidant defense (Galaris et al. 2008; Wiese et al. 1995), and adverse effects/functions of different levels of ROS (UshioFukai and Nakamura 2008; Nishikawa 2008). Under certain circumstances ROS has even important physiological functions, such as in the immune defensesystem (Nishikawa 2008; Fidler and Schroit 1988; Mytar et al. 1999). Cancer treatment by ROS-production A common thesis is, that the redox-level of tumor cells has to be pushed above their oxidative threshold to induce cell death, what is assumed to be one of the active principles of several chemo- and radiotherapies (Nishikawa 2008; Clerkin et al. 2008). The theoretical background of this approach is the weak defense system of cancer cells against oxidative stress (Laurent et al. 2005), what might at first glance seem

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inconsistent with the fact that cancer cells survive with higher intracellular ROS-levels than healthy ones (Ushio-Fukai and Nakamura 2008). Nonetheless all available theories about mechanisms/principles of action in this field have always to be put in relation to and are strongly limited by the respective model. Again, cellular equipment with ‘‘factors’’ counterbalancing disturbances of the intracellular equilibrium play a key role in this regard. Thus cancer cells might in general survive at higher ROS-levels, but their tolerance against changes/increase above a certain threshold might be lower than the one of healthy cells. Nonetheless, there are some restrictions to the ROS-generating anti-cancer approach. Though one mode of cell death induced in this way is apoptosis, an other mode is still necrosis, thus being harmful for the physiological environment, e.g. by induction of inflammation (Galaris et al. 2008). Moreover, high ROS-levels could lead to other severe side effects, like initiation of tumors or killing of the more stress-sensitive healthy cells, because the reactive species damage unselectively all cells (Nishikawa 2008). Nevertheless, radiotherapy and various pro-oxidative anti-cancer agents (i.e. anthracyclines, platinum-containing complexes, alkylating agents, cytotoxic antibiotics) are clinically used as standards (Pelicano et al. 2004; Serrano et al. 1999; Moeller et al. 2004; Lawenda et al. 2008; Ratnam et al. 2006), due to the absence of comparably effective therapies simultaneously exerting less adverse effects. Cancer treatment by ROS-decrease In contrast to the pro-oxidant approaches depicted above, other avenues try to fight cancer cells by applying anti-oxidative agents (mostly defined as radical scavengers (Lawenda et al. 2008)) in order to decrease ROS levels (Clerkin et al. 2008). The main underlying theory is that after lowering ROS levels, susceptibility of cancer cells to pro-apoptotic stimuli might be increased, based on the fact that antiapoptotic pathways are generally activated by increased ROS-concentrations in cancer cells (Clerkin et al. 2008). Hence application of multiple anti-oxidant vitamins (individually or in combination) is widely described since the 1980s to enhance efficiency of several standard chemotherapies and radiotherapies against


cancer cells. Additionally, anti-oxidants have been shown to reduce toxicity of some of these prooxidative anti-cancer therapies on normal cells (Prasad et al. 1999). Nevertheless, safety and efficacy of the supplemental treatments is a matter of discussion (Lawenda et al. 2008). In this context randomised clinical studies demonstrated that although concurrent administration of anti-oxidants to chemotherapeutics or radiations lowers adverse effects on healthy tissue (in regard of chemoprevention), co-treatments might also protect tumor cells from oxidative damage, thus attenuating efficiency of anti-cancer therapies and potentially decreasing patients’ survival (Lawenda et al. 2008). In essence no general conclusions can be drawn yet with regard to dietary supplementation of cancer therapies with anti-oxidants as adversarial or beneficial, since effects are always strongly case-dependent. In this regard not only the variety of diverse cancers and their properties have to be considered, but also the broad chemical spectrum of anti-oxidants (e.g. carotenoids, polyphenols, triterpenes, vitamin C, vitamin E, thiols), comprising a huge amount of biological properties associated with ROS, that are moreover dose- and bioavailability-dependent (Chen et al. 2004; Lawenda et al. 2008; Blumberg and Milbury 2006). Potential role of OSCs from Allium species in chemoprevention/chemotherapy targeting ROS Being aware of the complexity and strong modeldependence of physiological events influenced by different levels of ROS and the controversial (pro- or anti-oxidative) anti-cancer approaches in this field, the complexity of problems in related drug development studies is obvious. Nonetheless, ROS remain an attractive target, since ROS are generally not harmful at physiological concentrations, and modulation of ROS levels is highly effective in clinical radio- and chemo-therapies. Hence it would be desirable to find drugs affecting ROS in a distinct manner by combining pro-and anti-oxidant qualities—each depending on/determined by the physiological microenvironment. In this way compounds might be oxidised at elevated intracellular levels of oxidants yielding even more- or more reactive-ROS, finally provoking cell death. This process might occur selectively in cancer cells mostly containing elevated ROS-levels without

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affecting the healthy environment. Correspondingly the same compounds, when being exposed to a reducing physiological environment, could be transformed generating a kind of redox-buffer, thus attenuating reductively generated oxidative stress (Winyard et al. 2005) and finally preventing carcinogenesis (Tapiero et al. 2004). This multifaceted range of compound properties (Fig. 3) is met rather well by several OSCs from Allium species (Table 1) (Jacob 2006; Jacob et al. 2003, 2006), and although many mechanistic details of their modes of action remain elusive/are not yet fully understood, it has already been demonstrated as part of various experimental anti-cancer studies, that these compounds are very potent in chemoprevention and chemotherapy, in large part affecting ROS (Table 2). Selectivity against healthy cells, safety of application Though underlying mechanisms, however, are not yet fully understood, cytotoxic effects of garlic compounds are widely selective for cancer cells if compared to their healthy counterparts. This becomes obvious from historical records and epidemiological studies using diverse formulations of the plant as a remedy, mainly against cardiovascular diseases and tumors (Shukla and Kalra 2007; Wu et al. 2005; Ngo et al. 2007). Selectivity could also be confirmed by experimental studies, such as induction of apoptosis in primary leukemic blood cells and in HL-60 cells with selectivity compared to peripheral blood mononuclear cells (PBMCs) (Dirsch et al. 1998), or the higher resistance of normal prostate epithelial cells against cell cycle- and growth-arrest triggered by diallyl trisulfide in comparison with the prostate cancer cell lines PC-3 and DU145 (Xiao et al. 2005). Even human primary neurons remained unaffected by OSCs under conditions killing human malignant neuroblastoma cells (Karmakar et al. 2007). Safety of application of garlic compounds can also be concluded from manifold anti-cancer studies in vivo rarely describing any harmful side effects (Shukla and Kalra 2007; Wu et al. 2004). On the other hand, there were some studies revealing harmful effects of OSCs, on occasion even higher cytotoxicity against normal cells than cancer cells (Li et al. 2002). Nonetheless, ‘‘toxicity’’ against normal cells can also be beneficial from the therapeutic point of view if being selective against certain

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cell types, such as endothelial cells (e.g. HUVECs), an effect which might be used for the prevention of metastases (Xiao et al. 2006). Furthermore, there are reports about adverse effects in animals (Agarwal 1996; Munday et al. 2003), but this is not a knock-out criterion for ongoing drug development, since the observation might be dose-dependent and modeldependent. In any case, toxicity in animals does not mandatory implicate toxicity in men, as can be proven by epidemiological data and even by several drugs for men on the market (e.g. Aspirin is quite toxic in several mammals).

Summary and conclusions Summarising results obtained from experimental studies so far, OSCs from Allium species clearly target widespread physiological pathways and are very potent against a variety of diseases, especially those of the cardiovascular system and several types of cancer. Moreover, this beneficial spectrum of activity could be confirmed by several studies in men,

Fig. 3 Simplified overview of possible series of reactions of OSCs starting from a disulfide (or rather a thiosulfonate) as a model. The scheme briefly depicts possible transformations of simple OSCs in a simplified physiological environment occurring as multiple-step-reactions leading to other highly

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simultaneously proving safety of applied plant formulations/contents. Interestingly, safety is also assumed in advance based on medicinal reports throughout recorded history. Nonetheless due to the high complexity of possible reactions, that the compounds might undergo under physiological conditions, chemical and biochemical mechanisms of action are not yet fully elucidated, e.g. the indispensability of ROS for diverse cellular signaling pathways remains a matter of discussion. Furthermore, the reasons for selectivity against cancer cells if compared to their healthy counterparts are still ambiguous in most models. Nevertheless, OSCs from Allium (garlic, onion) combine beneficial effects/therapeutic potency with low adverse effects. Hence one of the most interesting fields of medicinal application would be cancer—both in chemotherapy and chemoprevention—because compounds might be able to kill cancer cells in men by targeting at the same time diverse control points of cellular growth, survival or proliferation (e.g. by apoptosis, cell cycle arrest) without affecting the ‘‘cancer-environment’’ in a damaging manner, thus avoiding harm of patients being a main problem of

reactive species (Jacob 2006; Jacob et al. 2006). R allyl-, or alkyl-group; arabic numbers oxidation states; ox oxidation; red reduction; e-: electron; H• hydrogen atom; GST glutathione-Stransferase; ATP adenosine triphosphate


current chemotherapies. Further advantages would be the capability of the compounds to modulate drug resistance of cancer cells and to target simultaneously cancer-related affections of the immune system, the inflammatory system or even infections (e.g. with viruses, bacteria). On the other hand compounds might be useful to prevent formation of metastases and the development of cancers, e.g. for elderly people. In any case, experimental studies should be extended in order to consider safety and to establish adequate application schemes (e.g. dose optimisation by drug metabolism and pharmacokinetic (DMPK)-studies), since such studies are quite rare so far and compounds seem to have a very promising profile for ongoing drug development. Moreover adequate drug formulations of compound mixtures or of single compounds from garlic are needed to enable tailored population based studies and clinical trials using clearly specified dosages of known constituents. Additionally drug formulations would improve compliance of patients and enable an intake of higher doses of the compounds by masking their strong odour and by reducing their irritant effect. Apart from that, those formulations might improve reproducibility or comparability of diverse studies of diverse institutions if considering high variations between diverse models so far. Acknowledgement CS thanks the ‘‘Ministe`re de la Culture, de l’Enseignement supe´rieur et de la Recherche of Luxembourg’’ for financial support by providing a ‘‘Bourse de formationrecherche’’. Moreover researchers are indebted to ‘‘Te´le´vie’’, the ‘‘Fondation de Recherche Cancer et Sang’’ and ‘‘Recherches Scientifiques’’ Luxembourg association. Likewise the authors thank ‘‘Een Ha¨erz fir Kriibskrank Kanner’’ association, the Action Lions ‘‘Vaincre le Cancer’’, the Foundation for Scientific Cooperation between Germany and Luxemburg, and the Saarland University for additional support.

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