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Natural Sulfur Products as Redox Modulators and Selective Inducers of Cell Death

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Abstract

Numerous plants, fungi and microorganisms contain organic sulfur compounds (OSCs), which during the last couple of decades have been associated increasingly with chemoprevention, antibacterial and anticancer activity. These compounds also play a particular role as intracellular redox modulators and inducers of apoptosis. Among the various OSCs, redox-active, reactive sulfur species, such as allicin and polysulfanes (RSxR, R ≠ H, x ≥ 3) from garlic and onion, show particularly interesting properties. These compounds are able to S-thiolate or oxidize a wide range of peptides and proteins, and hence modulate intracellular redox processes, either directly or by oxidizing GSH to GSSG, which shifts the intracellular redox balance to more oxidizing potentials. Such interference with the intracellular ‘thiolstat’ has widespread consequences, ranging from an activation of antioxidant defenses to induction of apoptosis. While S-thiolation may be the most prominent mode of action associated with OSCs, the chemistry of these compounds has many facets, including superoxide radical generation, binding to metal centres of metallo-proteins and hydrophobic interactions with various cellular membranes and proteins. Ultimately, many of these reactions also have the potential to trigger apoptotic pathways.

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Notes

  1. 1.

    In the biochemical literature, the use of electrochemical potentials attributed to cysteine residues is sometimes confusing. In essence, the oxidation potential E ox reflects the ease of oxidation of the cysteine thiol to an oxidized form, usually the disulfide. The reduction potential E red, on the other hand, reflects the ease of reduction of the disulfide to the thiol. The redox potential E 0’ is calculated mathematically as the midpoint between these potentials (essentially the ‘average’). Importantly, E 0’ requires full reversibility of the oxidation and reduction processes, and can only be used to describe the thiol/disulfide pair, but not processes involving other sulfur oxidation states, such as sulfenic or sulfinic acids. It may therefore be more adequate to discuss redox sensitivity of the thiol groups of cysteine proteins in terms of E ox rather than E 0’.

  2. 2.

    Polysulfanes have the chemical formula RSxR’ (R,R’  ≠  H and x  ≥  3). They should not be confused with polysulfides, which, strictly speaking, are charged, often inorganic species of the type RSxH or S 2−x (R  ≠  H and x  ≥  2). In the case of DATS and DATTS, the widely used ‘trisulfide’ and ‘tetrasulfide’ terminology is therefore somewhat misleading.

  3. 3.

    It is likely that other diallylpolysulfanes, such as the penta- and hexasulfane, exhibit similar biological activities. Those longer-chain analogues have hardly been studied so far, mostly due to their inherent chemical instability.

  4. 4.

    Most of these studies have been conducted with DAS, DADS and DATS. DATTS is chemically more unstable and, at least in the past, has been more difficult to obtain. As a consequence, less is known about the various activities of DATTS and higher polysulfanes. Nonetheless, it is likely that these agents will exhibit a similar biochemical behavior.

Abbreviations

AIF:

apoptosis-inducing factor

ALA:

α-lipoic acid

AM:

allylmercaptan

ANT:

adenine nucleotide translocase

AP-1:

activator protein-1

AR:

androgen receptor

ATC:

Human anaplastic thyroid carcinoma

Bad:

B-cell lymphoma protein 2 associated death promoter

Bak:

B-cell lymphoma protein 2 homologous antagonist/killer

Bax:

B-cell lymphoma protein 2 associated X protein

Bcl-2:

B-cell lymphoma protein 2

Bcl-xL :

B-cell lymphoma protein 2-extra large

cdk1:

cyclin dependent kinase 1

DADS:

diallyldisulfide

DAS:

diallylsulfide

DATS:

diallyltrisulfide

DATTS:

diallyltetrasulfide

DHLA:

dihydrolipoic acid

DPTTS:

dipropyltetrasulfide

1,2-DT:

3-vinyl-4H-1,2-dithiin

1,3-DT:

2-vinyl-4H-1,3-dithiin

ERK:

extracellular signal-regulated kinases

FACS:

Fluorescence activated cell sorting

ERK:

extracellular signal-regulated kinases

GSH:

glutathione

GSSG:

glutathione disulfide

HDACs:

histone deacetylases

HMG-CoA:

3-hydroxy-3-methyl-glutaryl coenzyme A

H2S:

hydrogen sulfide

JNK:

c-Jun N-terminal kinase

MAPKs:

mitogen-activated protein kinases

MCF-7:

human mammary carcinoma cells

MPTP:

mitochondrial permeability transition pore

NHE:

normal hydrogen electrode

OSCs:

organic sulfur compounds

OS:

oxidative stress

PARP-1:

poly(ADT-ribose) polymerase 1

PC-3:

human prostate cancer cells

PDIs:

protein disulfide isomerases

PFTase:

protein FTase

PKA:

protein kinase A

PKB:

protein kinase B

PrSH:

protein thiol

PrSSG:

S-glutathiolated protein thiol

PrSSPr:

protein disulfides

Rb:

human retinoblastoma protein

ROS:

reactive oxygen species.

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  1. Division of Bioorganic Chemistry, School of Pharmacy, Saarland University, Campus, D-66123, Saarbruecken, Germany

    Brigitte Czepukojc, Thomas Schneider, Torsten Burkholz, Vincent Jamier & Claus Jacob

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  1. Brigitte Czepukojc
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  2. Thomas Schneider
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  3. Torsten Burkholz
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  4. Vincent Jamier
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  5. Claus Jacob
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  1. , Laboratoire de Biologie Moléculaire et C, Hôpotal Kirchberg, Rue Edward Steichen 9, Steichen, L- 2540, Luxembourg

    Marc Diederich

  2. , Laboratoire de Biologie Moléculaire et C, Hôpotal Kirchberg, Rue Edward Steichen 9, Steichen, L- 2540, Luxembourg

    Karoline Noworyta

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Czepukojc, B., Schneider, T., Burkholz, T., Jamier, V., Jacob, C. (2012). Natural Sulfur Products as Redox Modulators and Selective Inducers of Cell Death. In: Diederich, M., Noworyta, K. (eds) Natural compounds as inducers of cell death. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4575-9_12

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