Diallyl polysulfanes, such as diallyl trisulfide and diallyl tetrasulfide, are regarded as a group of potential chemopreventive compounds as they have been proven to be effective inhibitors of cancer cells. These agents have been implicated in signal transductions, including the generation of Reactive Oxygen Species (ROS), Endoplasmic Reticulum (ER) stress, mitogen-activated protein kinase (MAPK) signaling, regulation of cell cycle progression, and induction of apoptosis. Nonetheless, certain aspects of the diallyl polysulfane triggered inhibitory effects on cancer cells are still not clear. Understanding the targeted signaling pathways may help to develop new strategies to treat cancer and other diseases. This review is therefore aimed at addressing the targeting of specific intracellular signal transduction cascades by these diallyl polysulfanes in order to shed some light on possible mechanisms of action of these compounds.
Corzo-MartinezM, CorzoN, VillamielM. (2007) Biological properties of onions and garlic. Trends in Food Science and Technology, 18, 609–625.
2.
BlockE. (1992) Die Organoschwefelchemie der Gattung Allium und ihre Bedeutung für die organische Chemie des Schwefels. Angewandte Chemie International Edition England., 104, 1158–1203.
3.
MunchbergU, AnwarA, MecklenburgS, JacobC. (2007) Polysulfides as biologically active ingredients of garlic. Organic and Biomolecular Chemistry, 5, 1505–1518.
4.
JacobC, AnwarA, BurkholzT. (2008) Perspective on recent developments on sulfur-containing agents and hydrogen sulfide signaling. Planta Medica, 74, 1580–1592.
5.
PowolnyAA, SinghSV. (2008) Multitargeted prevention and therapy of cancer by diallyl trisulfide and related Allium vegetable-derived organosulfur compounds. Cancer Letter, 269, 305–314.
6.
StanSD, KarS, StonerGD, SinghSV. (2008) Bioactive food components and cancer risk reduction. Journal of Cellular Biochemistry, 104, 339–356.
7.
MilnerJA. (1996) Garlic: its anticarcinogenic and antitumorigenic properties. Nutrion Reviews, 54, S82–S86.
8.
MilnerJA. (2001) Mechanisms by which garlic and allyl sulfur compounds suppress carcinogen bioactivation. Garlic and carcinogenesis. Advances in Experimental Medicine and Biology, 492, 69–81.
9.
MundayR, MundayJS, MundayCM. (2003) Comparative effects of mono-, di-, tri-, and tetrasulfides derived from plants of the Allium family: redox cycling in vitro and hemolytic activity and Phase 2 enzyme induction in vivo. Free Radical Biology and Medicine, 34, 1200–1211.
10.
IciekM, KwiecienI, WlodekL. (2009) Biological properties of garlic and garlic-derived organosulfur compounds. Environmental and Molecular Mutagenesis, 50, 247–265.
11.
HaberJE. (1999) DNA recombination: the replication connection. Trends in Biochemical Sciences, 24, 271–275.
12.
FilomeniG, AquilanoK, RotilioG, CirioloMR. (2003) Reactive oxygen species-dependent c-Jun NH2-terminal kinase/c-Jun signaling cascade mediates neuroblastoma cell death induced by diallyl disulfide. Cancer Research, 63, 5940–5949.
13.
FilomeniG, AquilanoK, RotilioG, CirioloMR. (2005) Glutathione-related systems and modulation of extracellular signal-regulated kinases are involved in the resistance of AGS adenocarcinoma gastric cells to diallyl disulfide-induced apoptosis. Cancer Research, 65, 11735–11742.
14.
XiaoD, Herman-AntosiewiczA, AntosiewiczJ, XiaoH, BrissonM, LazoJS, SinghSV. (2005) Diallyl trisulfide-induced G(2)-M phase cell cycle arrest in human prostate cancer cells is caused by reactive oxygen species-dependent destruction and hyperphosphorylation of Cdc25C. Oncogene, 24, 6256- 6268.
DasA, BanikNL, RaySK. (2007) Garlic compounds generate reactive oxygen species leading to activation of stress kinases and cysteine proteases for apoptosis in human glioblastoma T98G and U87MG cells. Cancer, 110, 1083–1095.
17.
YangJS, ChenGW, HsiaTC, HoHC, HoCC, LinMW, LinSS, YehRD, IpSW, LuHF, ChungJG. (2009) Diallyl disulfide induces apoptosis in human colon cancer cell line (COLO 205) through the induction of reactive oxygen species, endoplasmic reticulum stress, caspases casade and mitochondrial-dependent pathways. Food and Chemical Toxicology, 47, 171–179.
18.
LinHL, YangJS, YangJH, FanSS, ChangWC, LiYC, ChungJG. (2006) The role of Ca2+ on the DADS-induced apoptosis in mouse-rat hybrid retina ganglion cells (N18). Neurochemical Research, 31, 383–393.
19.
ChenC, PungD, LeongV, HebbarV, ShenG, NairS, LiW, KongAN. (2004) Induction of detoxifying enzymes by garlic organosulfur compounds through transcription factor Nrf2: effect of chemical structure and stress signals. Free Radical Biology and Medicine, 37, 1578–1590.
20.
BottoneFGJr., MoonY, KimJS, Alston-MillsB, IshibashiM, ElingTE. (2005) The anti-invasive activity of cyclooxygenase inhibitors is regulated by the transcription factor ATF3 (activating transcription factor 3). Molecular Cancer Therpeutics, 4, 693–703.
21.
KnightJA. (1995) Diseases related to oxygen-derived free radicals. Ann. Clin. Lab Sci., 25, 111–121.
22.
XiaoD, PintoJT, SohJW, DeguchiA, GundersenGG, PalazzoAF, YoonJT, ShirinH, WeinsteinIB. (2003) Induction of apoptosis by the garlic-derived compound S-allylmercaptocysteine (SAMC) is associated with microtubule depolymerization and c-Jun NH(2)-terminal kinase 1 activation. Cancer Research, 63, 6825–6837.
23.
HosonoT, Hosono-FukaoT, InadaK, TanakaR, YamadaH, IitsukaY, SekiT, HasegawaI, ArigaT. (2008) Alkenyl group is responsible for the disruption of microtubule network formation in human colon cancer cell line HT-29 cells. Carcinogenesis, 29, 1400–1406.
24.
LinYT, YangJS, LinSY, TanTW, HoCC, HsiaTC, ChiuTH, YuCS, LuHF, WengYS, ChungJG. (2008) Diallyl disulfide (DADS) induces apoptosis in human cervical cancer Ca Ski cells via reactive oxygen species and Ca2+-dependent mitochondria-dependent pathway. Anticancer Research, 28, 2791–2799.
25.
AquilanoK, VigilanzaP, FilomeniG, RotilioG, CirioloMR. (2010) Tau dephosphorylation and microfilaments disruption are upstream events of the anti-proliferative effects of DADS in SH-SY5Y cells. Journal of Cellular and Molecular Medicine, 14, 564–577.
26.
BuschC, JacobC, AnwarA, BurkholzT, BaLA, CerellaC, DiederichM, BrandtW, WessjohannL, MontenarhM. (2010) Diallylpolysulfides induce growth arrest and apoptosis. Intnational Journal of Oncology., 36, 743–749.
27.
AntosiewiczJ, Herman-AntosiewiczA, MarynowskiSW, SinghSV. (2006) c-Jun NH(2)-terminal kinase signaling axis regulates diallyl trisulfide-induced generation of reactive oxygen species and cell cycle arrest in human prostate cancer cells. Cancer Research, 66, 5379–5386.
28.
DattaSR, DudekH, TaoX, MastersS, FuH, GotohY, GreenbergME. (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell, 91, 231–241.
FernandezJ, BodeB, KoromilasA, DiehlJA, KrukovetsI, SniderMD, HatzoglouM. (2002) Translation mediated by the internal ribosome entry site of the cat-1 mRNA is regulated by glucose availability in a PERK kinase-dependent manner. Journal of Biological Chemistry, 277, 11780–11787.
31.
RonD, WalterP. (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nature Reviews Molecular Cell Biology, 8, 519–529.
32.
HardingHP, ZhangY, RonD. (1999) Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature, 397, 271–274.
33.
VenugopalR, JaiswalAK. (1998) Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes. Oncogene, 17, 3145–3156.
34.
CullinanSB, DiehlJA. (2006) Coordination of ER and oxidative stress signaling: the PERK/Nrf2 signaling pathway. International Journal of Biochemistry and Cell Biology, 38, 317–332.
35.
OyadomariS, MoriM. (2004) Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death and Differentition, 11, 381–389.
36.
NakamuraK, Bossy-WetzelE, BurnsK, FadelMP, LozykM, GopingIS, OpasM, BleackleyRC, GreenDR, MichalakM. (2000) Changes in endoplasmic reticulum luminal environment affect cell sensitivity to apoptosis. Journal of Cell Biology, 150, 731–740.
37.
HitomiJ, KatayamaT, EguchiY, KudoT, TaniguchiM, KoyamaY, ManabeT, YamagishiS, BandoY, ImaizumiK, TsujimotoY, TohyamaM. (2004) Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death. Journal of Cell Biology, 165, 347–356.
38.
KostenkoS, DumitriuG, LaegreidKJ, MoensU. (2011) Physiological roles of mitogen-activated-protein-kinase-activated p38-regulated/activated protein kinase. The World Journal of Biological Chemistry, 2, 73–89.
39.
CargnelloM, RouxPP. (2011) Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiology and Molecular Biology Reviews, 75, 50–83.
40.
PlotnikovA, ZehoraiE, ProcacciaS, SegerR. (2011) The MAPK cascades: Signaling components, nuclear roles and mechanisms of nuclear translocation. Biochimica et Biophysica Acta, 1813, 1619–1633.
41.
WortzelI, SegerR. (2011) The ERK cascade: Distinct functions within various subcellular organelles. Genes and Cancer, 2, 195–209.
42.
WhelanJT, HollisSE, ChaDS, AschAS, LeeMH. (2011) Post-transcriptional regulation of the Ras-ERK/MAPK signaling pathway. Journal of Cellular Physiology, doi: 10.1002/jcp.22899. [Epub ahead of print]
WuXJ, HuY, LamyE, Mersch-SundermannV. (2009) Apoptosis induction in human lung adenocarcinoma cells by oil-soluble allyl sulfides: triggers, pathways, and modulators. Environmental and Molecular Mutagenesis, 50, 266–275.
45.
XiaoD, ChoiS, JohnsonDE, VogelVG, JohnsonCS, TrumpDL, LeeYJ, SinghSV. (2004) Diallyl trisulfide-induced apoptosis in human prostate cancer cells involves c-Jun N-terminal kinase and extracellular-signal regulated kinase-mediated phosphorylation of Bcl-2. Oncogene, 23, 5594–5606.
46.
KnowlesLM, MilnerJA. (2003) Diallyl disulfide induces ERK phosphorylation and alters gene expression profiles in human colon tumor cells. Journal of Nutrition, 133, 2901–2906.
47.
SriramN, KalayarasanS, AshokkumarP, SureshkumarA, SudhandiranG. (2008) Diallyl sulfide induces apoptosis in Colo 320 DM human colon cancer cells: involvement of caspase-3, NF-kappaB, and ERK-2. Molecular and Cellular Biochemistry, 311, 157–165.
48.
ShrotriyaS, KunduJK, NaHK, SurhYJ. (2010) Diallyl trisulfide inhibits phorbol ester-induced tumor promotion, activation of AP-1, and expression of COX-2 in mouse skin by blocking JNK and Akt signaling. Cancer Research, 70, 1932–1940.
49.
LeiXY, YaoSQ, ZuXY, HuangZX, LiuLJ, ZhongM, ZhuBY, TangSS, LiaoDF. (2008) Apoptosis induced by diallyl disulfide in human breast cancer cell line MCF-7. Acta Pharmacologica Sinica., 29, 1233–1239.
50.
ArellanoM, MorenoS. (1997) Regulation of CDK/cyclin complexes during the cell cycle. International Journal of Biochemistry and Cell Biology, 29, 559–573.
FerrellJEJr., TsaiTY, YangQ. (2011) Modeling the cell cycle: why do certain circuits oscillate?Cell, 144, 874–885.
57.
JohnsonDG, WalkerCL. (1999) Cyclins and cell cycle checkpoints. Annual Review of Pharmacology and Toxicology, 39, 295–312.
58.
LingH, WenL, JiXX, TangYL, HeJ, TanH, XiaH, ZhouJG, SuQ. (2010) Growth inhibitory effect and Chk1-dependent signaling involved in G2/M arrest on human gastric cancer cells induced by diallyl disulfide. Brazilian Journal of Medical and Biological Research, 43, 271–278.
59.
CerellaC, SchererC, CristofanonS, HenryE, AnwarA, BuschC, MontenarhM, DicatoM, JacobC, DiederichM. (2009) Cell cycle arrest in early mitosis and induction of caspase-dependent apoptosis in U937 cells by diallyltetrasulfide (Al2S4). Apoptosis, 297, 641- 6.
60.
WangHC, YangJH, HsiehSC, SheenLY. (2010) Allyl sulfides inhibit cell growth of skin cancer cells through induction of DNA damage mediated G2/M arrest and apoptosis. Journal of Agricultural and Food Chemistry, 58, 7096–7103.
61.
ViryE, AnwarA, KirschG, JacobC, DiederichM, BagrelD. (2011) Antiproliferative effect of natural tetrasulfides in human breast cancer cells is mediated through the inhibition of the cell division cycle 25 phosphatases. International Journal of Oncology, 38, 1103–1111.
62.
SohnJ, RudolphJ. (2003) Catalytic and chemical competence of regulation of cdc25 phosphatase by oxidation/reduction. Biochemistry, 42, 10060–10070.
63.
IndranIR, TufoG, PervaizS, BrennerC. (2011) Recent advances in apoptosis, mitochondria and drug resistance in cancer cells. Biochimica et Biophysica Acta, 1807, 735–745.
64.
HauptS, BergerM, GoldbergZ, HauptY. (2003) Apoptosis - the p53 network. Journal of Cell Science, 116, 4077–4085.
65.
SayersTJ. (2011) Targeting the extrinsic apoptosis signaling pathway for cancer therapy. Cancer Immunology, Immunotherapy, 60, 1173–1180.
NagataS. (2010) Apoptosis and autoimmune diseases. Annual New York Academy of Science, 1209, 10–16.
68.
XiaoD, ZengY, HahmER, KimYA, RamalingamS, SinghSV. (2009) Diallyl trisulfide selectively causes Bax- and Bak-mediated apoptosis in human lung cancer cells. Environmental and Molecular Mutagenesis, 50, 201–212.
69.
KarmakarS, BanikNL, PatelSJ, RaySK. (2007) Garlic compounds induced calpain and intrinsic caspase cascade for apoptosis in human malignant neuroblastoma SH-SY5Y cells. Apoptosis, 12, 671- 684.
70.
HongYS, HamYA, ChoiJH, KimJ. (2000) Effects of allyl sulfur compounds and garlic extract on the expression of Bcl-2, Bax, and p53 in non small cell lung cancer cell lines. Experimental and Molecular Medicine, 32, 127–134.
71.
PerriF, LorenzoGD, ScarpatiGD, BuonerbaC. (2011) Anaplastic thyroid carcinoma: A comprehensive review of current and future therapeutic options. The World Journal of Clinical Oncology, 2, 150–157.
72.
ShinHA, ChaYY, ParkMS, KimJM, LimYC. (2010) Diallyl sulfide induces growth inhibition and apoptosis of anaplastic thyroid cancer cells by mitochondrial signaling pathway. Oral Oncology, 46, e15–e18.
73.
KimYA, XiaoD, XiaoH, PowolnyAA, LewKL, ReillyML, ZengY, WangZ, SinghSV. (2007) Mitochondria-mediated apoptosis by diallyl trisulfide in human prostate cancer cells is associated with generation of reactive oxygen species and regulated by Bax/Bak. Molecular Cancer Therapeutics, 6, 1599- 1609.
74.
XiaoD, SinghSV. (2006) Diallyl trisulfide, a constituent of processed garlic, inactivates Akt to trigger mitochondrial translocation of BAD and caspase-mediated apoptosis in human prostate cancer cells. Carcinogenesis, 27, 533–540.
75.
XiaoD, LewKL, KimYA, ZengY, HahmER, DhirR, SinghSV. (2006) Diallyl trisulfide suppresses growth of PC-3 human prostate cancer xenograft in vivo in association with Bax and Bak induction. Clinical Cancer Research, 12, 6836–6843.
76.
AltieriDC. (2008) New wirings in the survivin networks. Oncogene, 297, 6276–6284.
77.
SongJD, LeeSK, KimKM, ParkSE, ParkSJ, KimKH, AhnSC, ParkYC. (2009) Molecular mechanism of diallyl disulfide in cell cycle arrest and apoptosis in HCT-116 colon cancer cells. Journal of Biochemical and Molecular Toxicology, 23, 71–79.
