Phytochemical therapy - Phytochemicals Dithiolthiones (isothiocyanates)

Kyle J. Norton

Dithiolthiones are phytochemicals in the class of Organosulfides, found abundantly in cruciferous vegetables, garden sorrel, horseradish, etc.

The study of the hepatoprotective drug anisyldithiolthione was showed to be effective  in acting as hepoprotective agent in inhibited lipid peroxidation induced in rat liver microsomes either chemically by FeSO4 and reducing agents (cysteine or ascorbate) or enzymatically, probably through the presence of its dithiolthione function(1) Other medication such as Anethol dithiolthione (ADT), usually prescribed as a choleretic drug, also exhibited an hepatoprotective potency at doses as low as 10 mg/kg relative to serum aminotransferase activities and hepatic glutathione related enzyme system in in Swiss female mice(2)

References
(1) A new potent inhibitor of lipid peroxidation in vitro and in vivo, the hepatoprotective drug anisyldithiolthione by Mansuy D, Sassi A, Dansette PM, Plat M.(PubMed)
(2) Protective effect of anethol dithiolthione against acetaminophen hepatotoxicity in mice by Warnet JM¹, Christen MO, Thevenin M, Biard D, Jacqueson A, Claude JR.(PubMed).

2. Isothiocyanates and cancers
Cancer is a class of diseases in which a group of cells growing and multiplying disordered and uncontrollable way in our body, have become progressively worse and damaged other healthy tissues, sometimes spreads to other organs in the body via lymph or blood and results may be in death.
In a case-control study conducted in urban Shanghai. The cases (from December 2006 to December 2008, ITC consumption from cruciferous vegetables intake showed a positive effect in reduce risk of pancreatic cancer after adjusting for possible confounding factors such as age, sex, history of diabetes and pancreatitis(1). Thiazolo, the synthesis of a novel class of quinazoline, produced by the reaction of 4,6-dichloro-5-aminopyrimidine with isothiocyanates in presence of 20 mol% KF/alumina, showed to exhibit antiproliferative activity in lung (NCI-H322 and A549), epidermal (A431) and glioblastoma (T98G), HL-60 cell lines at 20 μM. The effect of compound 4a on mitochondrial potential loss in HL-60 cells probably through cleavage of PARP-1 and procaspase-3 inhibition(2).
The study by Campus Morro do Cruzeiro suggested that the phytochemical  inhibited the cell viability of human cervical cancer cells, human pancreatic cancer cells, human hepatocellular carcinoma cells, human ovarian cancer cells, and have antiinflammatory properties in the treatment of human T-cell leukemia cells(3).

References
(1) [A case-control study on the association between urinary levels of isothiocyanates and the risk of pancreatic cancer].[Article in Chinese] by Wang J¹, Han L, Zhang W, Wang J, Ni Q, Shen M, Gao Y².(PubMed)
(2) Synthesis, antiproliferative and apoptosis-inducing activity of thiazolo[5,4-d]pyrimidines by Singh B¹, Guru SK, Kour S, Jain SK, Sharma R, Sharma PR, Singh SK, Bhushan S, Bharate SB, Vishwakarma RA.(PubMed) 
(3) The anti-oxidant properties of isothiocyanates: a review by de Figueiredo SM¹, Filho SA, Nogueira-Machado JA, Caligiorne RB.(PubMed)

3. Isothiocyanates as Antioxidants
Free radicals are atoms, molecules, or ions with unpaired electrons through chemical bonds with other atoms or molecules during a chemical reaction. They may have positive, negative or zero charge. The unpaired electrons cause radicals to be highly chemically reactive in the human body, leading to aging and cancers.
In Fuchs endothelial corneal dystrophy (FECD), an oxidative stress disorder, treatment with Sulforaphane, a molecule within the isothiocyanate group, decreased CEC apoptosis by 55% in unstressed group and by 43% in tBHP-treated specimens, through inhibition of oxidative stress(1).
The Universidade Federal de Ouro Preto study also indicated the similar result of sulforaphane in improvement of antioxidant status in the testing of number of cancer cell lines(2). Other study suggested that isothiocyanates (ITCs), found abundantly in cruciferous vegetables, may be effective as a cancer chemopreventive agent through modulation of phase II detoxifying/antioxidant enzyme activities(3).

Reference
(1) Sulforaphane decreases endothelial cell apoptosis in fuchs endothelial corneal dystrophy: a novel treatment by Ziaei A¹, Schmedt T, Chen Y, Jurkunas UV.(PubMed)
(2) The anti-oxidant properties of isothiocyanates: a review by de Figueiredo SM¹, Filho SA, Nogueira-Machado JA, Caligiorne RB.(PubMed)
(3) Structural influence of isothiocyanates on the antioxidant response element (ARE)-mediated heme oxygenase-1 (HO-1) expression by Prawan A¹, Keum YS, Khor TO, Yu S, Nair S, Li W, Hu L, Kong AN.(PubMed)

4. Isothiocyanates and heart diseases
Beside cancer, heart disease kills more than 2,000 Americans everyday. Approximately 60 million Americans have heart disease.
There are many causes of heart diseases. Most of heart diseases are caused by high blood pressure contributes to hardening of the arteries. High levels of bad cholesterol (LDL) build up in the arteries as a result of uncontrolled diet with high levels of saturated fat and trans fat.
In human immunodeficiency virus (HIV) patients, showed to improve AIDS-related heart dysfunction through inhibition of apoptosis by decreasing iNOS and Bax expression through suppression of NF-κB.(1). In ischemic injury of hearts patients, showed to inhibit reactive oxygen species mediators in exerting a toxic effect during ischemia-reperfusion through mitochondrial K(ATP) channels and antioxidant pathway(2). On ischaemia-reperfusion-induced cardiac injury. steamed broccoli  showed a superior cardioprotective properties over cooked broccoli, probably through through the redox signalling of sulphoraphane(3). the phytochemical also found to trduce risk of vascular disease due to aging by inhibiting oxidative stress (4).

References
(1) Isothiocyanates ameliorate the symptom of heart dysfunction and mortality in a murine AIDS model by inhibiting apoptosis in the left ventricle. by Ho JN¹, Yoon HG, Park CS, Kim S, Jun W, Choue R, Lee J.(PubMed)
(2) Sulforaphane protects ischemic injury of hearts through antioxidant pathway and mitochondrial K(ATP) channels.by Piao CS¹, Gao S, Lee GH, Kim do S, Park BH, Chae SW, Chae HJ, Kim SH.(PubMed)
(3) Comparison of the protective effects of steamed and cooked broccolis on ischaemia-reperfusion-induced cardiac injury. by Mukherjee S¹, Lekli I, Ray D, Gangopadhyay H, Raychaudhuri U, Das DK.(PubMed)
(4) Crosstalk between Nrf2 and the proteasome: therapeutic potential of Nrf2 inducers in vascular disease and aging by Chapple SJ¹, Siow RC, Mann GE.(PubMed)

5. Isothiocyanates and neuroprotective effect
Sulforaphane, a naturally organosulfur compound found in broccoli, showed to exert its neuroprotective effects through significantly attenuated the scopolamine-induced memory impairment and improved cholinergic system reactivity, as indicated by an increased ACh level, decreased AChE activity, and increased choline acetyltransferase (ChAT) expression in the hippocampus and frontal cortex(1). in a variety of acute and chronic neurodegenerative diseases, phytochemicals, isothiocyanate sulforaphane, derived from the hydrolysis of the glucosinolate glucoraphanin mainly present in Brassica vegetables, demonstrated its neuroprotective effects in several in vitro and in vivo studies, may be mainly ascribed to its peculiar ability to activate the Nrf2/ARE pathway(2). In dopaminergic neurotoxicity in mice induced by 6-hydroxydopamine (6-OHDA), the phytochemical showed the neuroprotective effect through its ability to enhance glutathione levels and its dependent enzymes (glutathione-S-transferase and glutathione reductase) and to modulate neuronal survival pathways(3).

References
(1) Sulforaphane alleviates scopolamine-induced memory impairment in mice by Lee S¹, Kim J¹, Seo SG², Choi BR³, Han JS³, Lee KW⁴, Kim J⁵.(PubMed)
(2) Sulforaphane as a potential protective phytochemical against neurodegenerative diseases byTarozzi A¹, Angeloni C, Malaguti M, Morroni F, Hrelia S, Hrelia P.(PubMed)
(3) Neuroprotective effect of sulforaphane in 6-hydroxydopamine-lesioned mouse model of Parkinson's disease byMorroni F¹, Tarozzi A, Sita G, Bolondi C, Zolezzi Moraga JM, Cantelli-Forti G, Hrelia P.(PubMed)

6. Sulforaphane and Obesity
Obesity is defined as a medical condition of excess body fat has accumulated overtime, while overweight is a condition of excess body weight relatively to the height. According to the Body Mass Index(BMI), a BMI between 25 to 29.9 is considered over weight, while a BMI of over 30 is an indication of obesity. According to the statistic, 68% of American population are either overweight or obese.
Taking foods containing sulforaphane may be effective in managing weight loss for obese patients accompanied with change of lifestyle with more vegetables and fruits into diet. Sulforaphane,  a molecule within the isothiocyanate group, according to Chungbuk National University, showed to prevent high-fat diet (HFD)-induced obesity in C57BL/6N mice. through inhibiting adipogenesis( the cells differentiation for a vital role in energy homeostasis and process the largest energy reserve  in the body of animals). via down-regulation of PPARγ(regulation of metabolism) and C/EBPα (inflammatory process) and by suppressing lipogenesis( protein as an intermediate stage in metabolism of simple sugars) through activation of the AMPK(in cellular energy homeostasis) pathway(1). Chronic oral administration of sulforaphane, on obesity and insulin resistance induced by a highly palatable (HP) diet in male Wistar rats, at the specific dose was able to accentuate glucose intolerance and may affect GLUT3 expression involed neuronal glucose transport in the cerebral cortex and hypothalamus(2). The  Chonbuk National University also suggested that Sulforaphane suppressed AMPK phosphorylation(cellular energy homeostasis) at Thr-172 in a dose-dependent manner(3).

References
(1) Sulforaphane attenuates obesity by inhibiting adipogenesis and activating the AMPK pathway in obese mice by Choi KM¹, Lee YS¹, Kim W¹, Kim SJ², Shin KO¹, Yu JY³, Lee MK¹, Lee YM¹, Hong JT¹, Yun YP¹, Yoo HS⁴.(PubMed)(2) Chronic sulforaphane oral treatment accentuates blood glucose impairment and may affect GLUT3 expression in the cerebral cortex and hypothalamus of rats fed with a highly palatable diet by Souza CG¹, Riboldi BP, Hansen F, Moreira JD, Souza DG, de Assis AM, Brum LM, Perry ML, Souza DO.(PubMed)
(3) Sulforaphane induced adipolysis via hormone sensitive lipase activation, regulated by AMPK signaling pathway by Lee JH¹, Moon MH, Jeong JK, Park YG, Lee YJ, Seol JW, Park SY.(PubMed)

7. Sulforaphane and Lung diseases
Lung diseases is defined as a condition, affecting  the upper respiratory tract, trachea, bronchi, bronchioles, alveoli, pleura and pleural cavity, and the nerves and muscles of breathing.
Sulforaphane may be used as a preventive chemical constituent of  pulmonary damage for patient who exposure to arsenic. According to China Medical University, arsenic-containing dust resulted in ; all of which were blocked by sulforaphane (SF) blocked pathological alterations, oxidative DNA damage, and mild apoptotic cell death in the lung caused by 2 weeks of exposure to arsenic through activation of Nrf2(master regulator of the total antioxidant system)(1). In wildtype neonatal mice exposed to hyperoxia. SF also found to activated Nrf2 activation through induced expression of anti-oxidant genes,(2). In the lungs of the arrhythmic Clock(Δ19) mice, SF also activated  it anti ovidative damage effect through activation of NRF2/glutathione defense pathway in combating oxidative/fibrotic lung damage(3).

References
(1) Sulforaphane prevents pulmonary damage in response to inhaled arsenic by activating the Nrf2-defense response. by Zheng Y¹, Tao S, Lian F, Chau BT, Chen J, Sun G, Fang D, Lantz RC, Zhang DD.(PubMed)
(2) Transcriptional responses of neonatal mouse lung to hyperoxia by Nrf2 status by McGrath-Morrow SA¹, Lauer T, Collaco JM, Lopez A, Malhotra D, Alekseyev YO, Neptune E, Wise R, Biswal S.(PubMed)
(3) The circadian clock regulates rhythmic activation of the NRF2/glutathione-mediated antioxidant defense pathway to modulate pulmonary fibrosis by Pekovic-Vaughan V¹, Gibbs J, Yoshitane H, Yang N, Pathiranage D, Guo B, Sagami A, Taguchi K, Bechtold D, Loudon A, Yamamoto M, Chan J, van der Horst GT, Fukada Y, Meng QJ.(PubMed)


8. Sulforaphane and Liver disease
Liver disease in most cases are linked to alcohol or drugs. In fact, it can be caused by a variety of factors and affecting everyone from infants to older adults.
In CYP2E1-dependent binge alcohol-induced liver steatosis, oral treatment of sulforphane sulforaphane showed to  activated Nrf2, increased levels of the Nrf2 target heme oxygenase-1 and subsequently lowered oxidant stress as shown by the decline in lipid peroxidation and 3-nitrotyrosine protein adducts and an increase in GSH levels(1). In  the comparison of the effectiveness of Sulforaphane and glucoraphanin in modulating carcinogen-metabolising enzymes in Hep G2 cells, Dr Abdull Razis AF¹, and Noor NM found that sulforphane is superior to glucoraphanin in modulators of various phase I and phase II enzymes involved in carcinogen-metabolising enzyme systems in vitro(2). The University of Rhode Island, Kingston study also insisted that SF activate  Nrf2 activation in inhibited lipid accumulation in white adipose tissue, suppressed adipogenesis, induced insulin resistance and glucose intolerance, and increased hepatic steatosis in Lep(ob/ob) mice(3)..

References
(1) Sulforaphane induces Nrf2 and protects against CYP2E1-dependent binge alcohol-induced liver steatosis by Zhou R¹, Lin J, Wu D.(PubMed)
(2) Sulforaphane is superior to glucoraphanin in modulating carcinogen-metabolising enzymes in Hep G2 cells by Abdull Razis AF¹, Noor NM.(PubMed)
(3) Enhanced Nrf2 activity worsens insulin resistance, impairs lipid accumulation in adipose tissue, and increases hepatic steatosis in leptin-deficient mice by Xu J¹, Kulkarni SR, Donepudi AC, More VR, Slitt AL.(PubMed)


9. Sulforaphane and Breast cancer
Breast cancer (malignant breast neoplasm) is a cancer that starts in the tissues of the breast either from the inner lining of milk ducts (Ductal carcinoma) or the lobules (Lobular carcinoma) that supply the ducts with milk. there is also rare cases that breast cancer starts in other areas of the breast. In 2010, over 250,000 new cases of breast cancer were expected to be diagnosed in women in the U.S. alone and the risk of getting invasive breast cancer during life time of a women is 1/8.
The University of Michigan, also insisted that ingestion of sulforaphane at a dose of 50 mg/kg  for 2 weeks inhibited breast cancer stem cells(1). According to Manipal University, Sulforaphane inhibited growth of human breast cancer cell line MCF-7 cells, through induces apoptosis and anti-inflammatory effects on MCF-7 cells via downregulation of Bcl-2 (anti-apoptotic protein) and COX-2 (inlvoved inflammatory process) respectively(2). Also in testing of MCF-7 breast cancer cells, researchers at the The Catholic University of Korea, showed that sulforaphane induced the inhibition of 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced MMP-9 expression(involved in keratinocyte migration and granulation tissue remodeling during wound healing) and cell invasion by via the suppression of the NF-κB (nvolved in cellular responses)pathway in MCF-7 cells(3).

References
(1) Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells by Li Y¹, Zhang T, Korkaya H, Liu S, Lee HF, Newman B, Yu Y, Clouthier SG, Schwartz SJ, Wicha MS, Sun D.(PubMed)
(2) Sulforaphane inhibits growth of human breast cancer cells and augments the therapeutic index of the chemotherapeutic drug, gemcitabine by Hussain A¹, Mohsin J, Prabhu SA, Begum S, Nusri Qel-A, Harish G, Javed E, Khan MA, Sharma C.(PubMed)
(3) Sulforaphane controls TPA-induced MMP-9 expression through the NF-κB signaling pathway, but not AP-1, in MCF-7 breast cancer cells by Lee YR¹, Noh EM, Han JH, Kim JM, Hwang BM, Kim BS, Lee SH, Jung SH, Youn HJ, Chung EY, Kim JS.(PubMed)

10. Sulforaphane and Prostate cancer
Prostate cancer is defined as a condition in which the cells of prostate has become cancerous, causing abnormal cell growth which spread to the distant parts of the body. Most prostate cancers are slow growing and enlarged prostate and prostate cancer may be detected during the Physical (rectum) exams.
Oral administration of d,l-sulforaphane (SFN) can decrease the incidence or burden of early-stage prostate cancer [prostatic intraepithelial neoplasia (PIN)] and well-differentiated cancer (WDC) but not late-stage poorly differentiated cancer (PDC)., according to the University of Pittsburgh Cancer Institute and  University of Pittsburgh School of Medicine(1)
In advanced prostate cancer stem-like cells, sulforaphane showed to inhibit tumor engraftment and tumor growth, without the induction of liver necrosis or other obvious side effects, In vivo(2).
In the comparison of the effect of sulforaphane(SFN) and 3,3'-diindolylmethane(DIM) in normal prostate epithelial cells and prostate cancer cells, researchers at the Oregon State University found that SFN and DIM reversed many of the cancer-associated methylation alterations, including aberrantly methylated genes that are dysregulated or are highly involved in cancer progression(3).


References
(1) Chemoprevention of prostate cancer by d,l-sulforaphane is augmented by pharmacological inhibition of autophagy by Vyas AR¹, Hahm ER, Arlotti JA, Watkins S, Stolz DB, Desai D, Amin S, Singh SV.(PubMed)
(2) Sulforaphane and TRAIL induce a synergistic elimination of advanced prostate cancer stem-like cells by Labsch S, Liu L, Bauer N, Zhang Y, Aleksandrowicz E, Gladkich J, Schönsiegel F, Herr I.(PubMed)
(3) Effects of sulforaphane and 3,3'-diindolylmethane on genome-wide promoter methylation in normal prostate epithelial cells and prostate cancer cells by Wong CP¹, Hsu A¹, Buchanan A², Palomera-Sanchez Z¹, Beaver LM¹, Houseman EA², Williams DE³, Dashwood RH³, Ho E⁴.(PubMed)


11. Sulforaphane and colon cancer
Bowel cancer is relatively very common and slowly growing and progress cancer and in predictable way. Bowel cancer is the third most commonly diagnosed cancer in developed countries, including US and Canada.
According to ¹INRA, Laboratoire des Xénobiotiques, sulforaphane inhibited colon cancer cell line (HT29) through cell cycle arrest via an apoptotic process(1). GE132+Natural, a novel supplement consisting  Resveratrol, Ganoderma lucidum, Sulforaphane, Lycopene and Royal jelly, in the testing of tested cancer cell lines (PC3, MCF7 and SW480), is found to be effective in inhibiting all tested cancer cell proliferation, the University of Belgrade insisted(2). Other study also showed the effective of sulforaphane and related dietary isothiocyanates in treating colon cancer cells via included cell growth arrest, autophagy and apoptosis depending to Depending on the isothiocyanates (ITCs)  and treatment conditions(3).

References
(1) Sulforaphane, a naturally occurring isothiocyanate, induces cell cycle arrest and apoptosis in HT29 human colon cancer cells by Gamet-Payrastre L¹, Li P, Lumeau S, Cassar G, Dupont MA, Chevolleau S, Gasc N, Tulliez J, Tercé F.(PubMed)
(2) GE132+Natural: Novel promising dietetic supplement with antiproliferative influence on prostate, colon, and breast cancer cells by Okic-Djordjevic I¹, Trivanovic D, Krstic J, Jaukovic A, Mojsilovic S, Santibanez JF, Terzic M, Vesovic D, Bugarski D.(PubMed)
(3) HDAC turnover, CtIP acetylation and dysregulated DNA damage signaling in colon cancer cells treated with sulforaphane and related dietary isothiocyanates by Rajendran P¹, Kidane AI, Yu TW, Dashwood WM, Bisson WH, Löhr CV, Ho E, Williams DE, Dashwood RH.(PubMed)


12. Sulforaphane and cervical cancer
Cervix is the lower part of uterus that opens at the top of the vagina. Cervix acts an transition area for vaginal lining (squamous epithelium) change to uterus type (columnar epithelium) through the transitional area (squamous columnar epithelium) to host the development of the fetus. Cervical cancer is malignant neoplasm of the cervix uteri or cervical area caused by abnormal cells growth with alternation of cells DNA.
According to the Manipal University in the study of the effect of sulforaphane and eugenol effects on human cervical cancer cells, found that combined treatment with variable dose combinations resulted in differential effects with an antagonistic effect at lower and synergistic at higher sub-lethal doses as reflected in cell cytotoxicity and apoptosis induction(1). The Manipal University  also showed that application of SFN inhibited human cervical cancer cell lines through  apoptosis induction and anti-inflammatory properties(2). In human cervical carcinoma HeLa, treatment with SFN  inhibit the cancer cell through down-regulation of anti-apoptotic Bcl-2 and Bcl-XL, and the up-regulation of pro-apoptotic Bax expression(3).

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References
(1) Concurrent sulforaphane and eugenol induces differential effects on human cervical cancer cells by Hussain A¹, Priyani A, Sadrieh L, Brahmbhatt K, Ahmed M, Sharma C.(PubMed)
(2) Anti-carcinogenic effects of sulforaphane in association with its apoptosis-inducing and anti-inflammatory properties in human cervical cancer cells by Sharma C¹, Sadrieh L, Priyani A, Ahmed M, Hassan AH, Hussain A.(PubNed)
(3) Induction of apoptosis by isothiocyanate sulforaphane in human cervical carcinoma HeLa and hepatocarcinoma HepG2 cells through activation of caspase-3 by Park SY¹, Kim GY, Bae SJ, Yoo YH, Choi YH.(PubMed)