Isothiocyanate: Cancer Chemopreventive Agent

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Isothiocyanate: Cancer Chemopreventive Agent Research Article Mrunmayee P.Toraskar et al. / Journal of Pharmacy Research 2009, 2(10),1638-1641 ISSN: 0974-6943 Available online through http://jprsolutions.info Isothiocyanate: cancer chemopreventive agent Mrunmayee P.Toraskar*, Vithal M. Kulkarni , Shweta T.Dhanashire, Vilasarao J.Kadam Department of Pharmaceutical chemistry, Bharati Vidyapeeth’s College of Pharmacy, Sector 08, CBD Belapur, Navi-Mumbai – 400614, India.. Received on: 20-05-2009; Accepted on:15-07-2009 ABSTRACT Isothiocyanates- plant derived dietary compounds, are promising chemopreventive agents generally non-toxic substances that interfere with the process of cancer development. Several natural and synthetic isothiocyanates have demonstrated cancer-preventive properties in animals treated with chemical carcinogens, including polycyclic aromatic hydrocarbon nitrosamines. Some of these compounds, the isothiocyanates – particularly allyl isothiocyanate and phenethyl isothiocyanate, have anticancer activity. Epidemiologic and clinical studies indicate a positive correlation between the general consumption of cruciferous vegetables and the decreased incidence of some cancers including non-Hodgkin’s lymphoma, liver, prostate, cervical, ovarian, lung, gastrointestinal tract. Natural isothiocyanates such as sulforaphane and phenethyl isothiocyanate possess strong antitumor activities both in vitro and in vivo. It exerts strong anticarcinogenic effects in a number of animal models of cancer, presumably by modulation of xenobiotic-metabolizing enzymes, such as by inhibition of cytochrome P- 450 and/or by induction of phase II detoxifying enzymes. Keywords: Isothiocyanates, Cancer chemopreventive agent, Apoptosis INTRODUCTION Chemopreventive isothiocyanates Cancer chemoprevention is regarded as the use of synthetic zymatically and enzymatically by myrosinase (ß-thioglucoside or natural agents to inhibit, delay or reverse the process of carcino- glucohydrolase) during food preparation, cooking and chewing. genesis through intervention before the appearance of invasive dis- Antineoplastic effect of cruciferous vegetables is attributed to ease. Isothiocyanates, plant-derived dietary compounds, are isothiocyanates, which occur as thioglucoside conjugates chemopreventive agents. Suppression of cell proliferation and in- (glucosinolates) in a variety of edible plants, including broccoli, wa- duction of differentiation and apoptosis during the promotion and tercress and cabbage. (4) progression stages are ideal preventive devices1. Vegetables are a good source of trace non-nutrient com- pounds that contribute to the prevention of cancer. Some of these MECHANISM OF ACTION OF ISOTHIOCYANATES compounds, the isothiocyanates – particularly allyl isothiocyanate and phenethyl isothiocyanate, have both anti-carcinogenic and anti- cancer activity 2. Glucosinolates and myrosinase are compartmentalised in plants Isothiocyanates acts as chemopreventive by inducing apoptosis pro- but interact when tissue damage occurs. Myrosinase activity of in- cess i.e cell death The mechanism by which Phenyl ethyl testinal bacteria may also contribute to the degradation of isothiocyanates inhibits chemically induced cancer involves inhibi- glucosinolates in vivo. Two of the most prevalent glucosinolates are tion of carcinogen activation due to inhibition of cytochrome P-450 sinigrin and gluconasturtin. Myrosinase-catalysed hydrolysis of sini- dependent mono-oxygenases and increased carcinogen inactivation grin and gluconasturtin cleaves the thioglucoside linkage; yielding due to induction of phase II enzymes, including glutathione trans- 4 glucose and an unstable iohydroximate-O-sulphonate aglycone that ferase .Cytotoxicity was associated with an initial decrease in GSH spontaneously rearranges to form allyl isothiocyanate and phenethyl and GSSG, with a concomitant formation of the GSH adduct S-(N- isothiocyanate (PEITC), respectively, other products, nitriles and iso- phenethylthiocarbamoyl) glutathione inside cells which was then ex- cyanates, may also be formed3. Cruciferous vegetables such as broc- ported from cell.Then S-(N-phenethyl thiocarbamoyl) glutathione coli, cabbage and kale, are rich sources of sulfur containing com- spontaneously fragmented to GSH and phenethyl isothiocyanate,GSH pounds called glucosinolates. Glucosinolates are degraded non-en- oxidized to GSSG and glutathionyl-protein disulphides and phenethyl isothiocyanate hydrolyzed to phenylethy lamine5.Induction of apoptosis by dietary isothiocyanates due to activation of the stress- *Corresponding author. activated protein kinase JNK1( Junction N-terminal Kinase) with cleav- Tel.: + 91-022 27662973 age of p22 BID protein to p15, p13 and p11 fragments. Telefax: +91- E-mail: [email protected] Journal of Pharmacy Research Vol.2.Issue 10.October 2009 1638-1641 Mrunmayee P.Toraskar et al. / Journal of Pharmacy Research 2009, 2(10),1638-1641 Mechanism of induction of tumour cell apoptosis by dietary EXAMPLES OF ISOTHIOCYANATE ( 6) isothiocyanates(5) 1. Benzyl Isothiocyanate The mechanism of induction of apoptosis involves the entry of the isothiocyanate into cells and formation of the GSH conjugate, S-(N- CH2NCS alkyl or arylalkyl thiocarbamoyl) glutathione. Concurrently, there is a slow inactivation of phenyl ethyl isothiocyanates by spontaneous hydrolysis then expulsion of the GSH conjugate via the MRP protein channel, with a consequent depletion of cellular GSH.There is a tem- 2. Phenethyl Isothiocyanate porary, reversible modification of cellular protein thiols – protein thiocarbamoylation. N=C=S Event 3 triggers recruitment of adaptor protein FADD to apoptosis-mediating cell death receptors (tumour necrosis receptor 1 and/or the fas receptor) and activates caspase-8. After this there is cleavage of mitochondrial protein BID, then release of cytochrome c 3. Phenyl Methyl Isothiocyanate from mitochondria and activation of caspase-3. Activation of the stress activation protein kinase JNK (which induces increased expression of the fas receptor ligand – further potentiating apoptosis) via activa- tion of the mitogen activated kinase MEKK1. N=C=S All these events induces apoptosis, DNA fragmentation and cell death. Where the isothiocyanate (RN=C=S) is administered as the corre- sponding thiol conjugate (RNH(C=S)-SR’), this sequence of events is preceded by fragmentation of the thiol conjugate to the free 4. Phenylhexyl Isothiocyanate isothiocyanate (CH2)6NCS 5. Sulphoraphane O S NCS H3C ferases (GSTs), and further metabolized to mercapturic acids. These isothiocyanate metabolites can be measured in the urine, and are highly correlated with dietary intake of cruciferous vegetables . BIOLOGICAL ACTIVITIES (2,8) Effects on Biotransformation Enzymes Involved in Carcinogen Me- tabolism Biotransformation enzymes play important roles in the metabo- lism and elimination of a variety of chemicals, including drugs, toxins and carcinogens. In general, phase -I biotransformation enzymes cata- lyze reactions that increase the reactivity of hydrophobic (fat-soluble) compounds, preparing them for reactions catalyzed by phase -II Metabolism and Bioavailability: biotransformation enzymes. Myrosinase a class of enzymes that catalyzes the hydrolysis (break- down) of glucosinolates, is physically separated from glucosinolates Inhibition of Phase - I Biotransformation Enzymes when plant cells are intact.8When cruciferous vegetables are chopped Some procarcinogens (carcinogen precursors) require or chewed, myrosinase can interact with glucosinolates and release biotransformation by phase-I enzymes, such as those of the cyto- isothiocyanates from their precursors.During metabolism, chrome P450 (CYP) family, in order to become active carcinogens that isothiocyanates are conjugated (bound) to glutathione, an activity are capable of binding DNA and inducing mutations. Inhibition of that is promoted by a family of enzymes called glutathione-S-trans- specific CYP enzymes involved in carcinogen activation inhibits the Journal of Pharmacy Research Vol.2.Issue 10.October 2009 1638-1641 Mrunmayee P.Toraskar et al. / Journal of Pharmacy Research 2009, 2(10),1638-1641 Clinically, it is usually diagnosed in patients over 50 years old. Thus, development of cancer in animal models.Isothiocyanates,including there could be opportunity for intervention using cancer PEITC and BITC(Benzyl isothiocyanates), have been found to inhibit chemopreventive compounds that prevent or slow the progression carcinogen activation by CYP enzymes. of this disease. Recent studies have indicated that using dietary Induction of Phase - II Biotransformation Enzymes chemopreventive compounds, such as isothiocyanates, might be a Many isothiocyanates, particularly SFN (Sulphoraphane), promising strategy to decrease the incidence of prostate cancer. Some are potent inducers of phase -II enzymes in cultured human cells. isothiocyanates derived from cruciferous vegetables, such as Phase -II enzymes, including GSTs, UDP-glucuronosyl transferases sulforaphane (SFN), are highly effective in preventing or reducing (UGTs), quinone reductase and glutamate cysteine ligase, plays im- the risk of cancer11. portant roles in protecting cells from DNA damage by carcinogens and reactive oxygen species Curcumin (from turmeric) is one of the most well known naturally Anti-inflammatory Activity occurring compounds. It has cancer chemopreventive potential Inflammation promotes cellular proliferation and inhibits against many types of cancerous cells, including prostate cancer. It is apoptosis, increasing
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