Medicinal Properties of Fruits for Cancer

Medicinal Properties of Fruits for Cancer ABSTRACT Cancer a disease with high morbidity and mortality rates is a challenge to human life. The current therapeutic strategies are associated with adverse effects which necessitates alternate treatment with less adverse effects. In addition to this cancer prevention is desirable which has lead to a new concept called biochemoprevention. In this regard, medicinal properties of plants can be exploited for cancer prevention and management as they can be procured cost effectively and are less likely to produce adverse effects as they are diet derived. This article reviews the phytochemicals and evidence based preventive and therapeutic effects of some commonly used plants with medicinal properties against cancer. Key words: Cancer, phytochemicals, medicinal properties of plants, biochemoprevention. INTRODUCTION Cancer continues to be a challenge to human life as the disease has high morbidity and mortality rates. Though surgery, chemotherapy and radiotherapy remain the â€Å"Gold Standard† measures of cancer therapy they are associated with adverse effects. Despite the recent advances in therapeutic strategies, the five year survival rate of one of the most commonly occurring cancer like oral cancer is as low as 62% with no improvement in the quality of life of the affected individuals1. Hence a treatment modality with less adverse effects will be of great benefit to the affected patients. Also research in the field of oncology has lead to better understanding of the molecular mechanisms of carcinogenesis that has revealed that caner is a largely preventable disease. Hence a new concept called biochemoprevention has evolved not only to prevent but also combat the shortcomings of cancer therapy. Chemoprevention or biochemoprevention refers to pharmacological intervention with syntheti c or natural compounds that may prevent, inhibit or reverse carcinogenesis. The use of medicinal plants for the management of various diseases including cancer has been carried out several hundred years ago during the period of Charaka, the Father of Medicine and Susrutha, the Father of Surgery. With the advent of Modern medicine, traditional medicine has lost its importance. Hence the medicinal properties of plants which are our natural resources must be re- explored to prevent and treat cancer. The advantages of utilizing medicinal properties of plants for cancer prevention and management include easy availability, cost effective and less likely to produce side effects as most of these plants or plant parts are diet derived. This article highlights evidence based preventive and therapeutic effects of some commonly used plants with medicinal properties against cancer. REVIEW NEEM Azadirachta indica commonly known as neem in English and Vembu in Tamil is native to our country and is known for several medicinal properties including antimicrobial, antioxidant, antidiabetic. It also finds its use in preparation of cosmetics, tooth brush, fertilizer, and tooth brush. This could be attributed to more than 140 compounds present in various parts of the plant. Recently research has been carried out to demonstrate the antineoplastic effects of this plant. Ethanolic extract of neem leaves caused both reduction in tumor size and decrease in tumor progression even after cessation of treatment with neem extract in N methyl N nitrosurea induced mammary tumors in Sprague Drawley rats. Molecular analysis revealed upregulation of proapoptotic genes and proteins such as p53, Bcl2 (B cell lymphoma 2), Bax, Caspases, PTEN (Phosphatase and tensin homologe), JNK (c-Jun N-terminal kinases) and down regulation of oncogenes such as VEGF (Vascular endothelial growth factor), CDK1 (cycl in dependent kinase 1),Nuclear factor kappa B (NF kappa B), MAP 1 (mitogen activated protein kinase 1).2Glycoproteins present in neem leaves also exert anti- cancer effects by restricting tumor growth in murine, These proteins alter tumor microenvironment by increasing CD 8 T (cluster of differentiation ) cells, protect T cells from Anergy, decrease activation induced T cell death by decreasing expression of FAsR. (FAS receptor) Cytotoxicity of sarcoma cells were caused due to increased expression of performin, granzyme B in lymphocytes3. These results shed light on the fact that neem extracts posses immunomodulatory effects hence aid in targeted therapy against malignant cells, sparing normal cells. Hence these extracts are less likely to produce side effects. TULASI Oscimum sanctum commonly known as Tulasi in Tamil and Holy basil in English is a sacred plant of Hinduism. The aromatic plant has several medicinal properties and has been used several thousand years ago for the management of various diseases and ailments like common cold, fever, acne, headache, stress, aphthous ulcers, asthma, bronchitis, tuberculosis, ecema. It also has been used as an expectorant for management of cough, antimicrobial agent in preventing diarrhoea, analgesic for pain management. Other medicinal properties include immunomoduation, hypolipidemic and hepatoprotective. Phytochemical constituents that confer these properties are oleanic acid, urosolic acid, rosmatinic acid, eugenol, carvacol, linalool, beta carophyllene, beta elemene, germaserene. Oscimum sanctum possesses cancer preventive and therapeutic properties. Important phytochemicals such as eugenol, rosmarinic acid, apigenin, silosterol, carnosic acid, lutrolen, myrtenal present in tulasi prevent chemical ind uced cancers of skin, lung, oral cavity, liver by induction of apoptosis, prevention of angiogenesis and metastasis, antioxidant activity and alteration of genes4. Flavonoids such as ornitine, vicenin, protect normal tissue from therapeutic radiation and prevent radiation induced mortality in mice. Eugenol, rosmarinic acid and apigenin present in Holy basil prevent radiation induced DNA (deoxy ribonucleic acid) damage thereby acting as chemopreventive agent. Tulasi exerts radioprotective effects in oral cancer by causing significant reduction of glutathione in erythrocytes of oral cancer patients who were treated with radiotherapy and flavonoids of Oscimum sanctum in comparison with oral cancer patients who received only radiotherapy.5 ALLIUM VEGETABLES Allium vegetables like onion are used as flavouring and seasoning agent for food in many countries6. Interestingly two species of onion viz red onion (Allium cepa) and yellow onion (Allium flavum) possess medicinal properties. Bulb of Allium cepa contains flavonoids such as anthrocyanins and dihydroflavonols7. The sulphur containing active constituent of onion bulb occur mainly in the form of s alkaline cysteine sulfoxides which decompose into thiosulfinates and polysulfides8. Thiosulfinates are volatile sulphur compounds responsible for the pungent odour and medicinal properties9. Onion exerts chemopreventive activity. The ethyl acetate extract of onion has been shown to induce apoptosis in human breast cancer cell lines10. It also inhibits fatty acid synthase and lipid accumulation in adipocytes, thereby preventing obesity, one of the predisposing factors for breast cancer11. Yellow onion (Allium flavum) also has anticancer activity Allium flavum extract has significant phenolic content, antioxidant, antibacterial activity against Staphylococcus aureus, Bacillius subtilis and antiproliferative activity against HCT cell lines (Homo sapiens colorectal carcinoma cell lines)12. PINEAPPLE Annamas cosmous or pineapple is a tropical plant of Bromadiaceae family. Edible portion of this plant is the fruit which is made of coalesced berries. Pineapple has been used in South America, China, South East Asia for the management of various ailments like inflammation, burns as it exerts medicinal properties like anti-inflammatory, antithrombotic, fibrinolytic, inhibition of platelet aggregation and skin debridement. In 1957, Bromelain was identified as the active principle present in the stem and unripe fruits of pineapple exerting the above mentioned activities. Bromelain, is a mixture of proteases13. Bromelain alters molecular pathways of carcinogenesis, tumor microenvironment hence could be used as an anticancer agent. Bromelain also exerts anticancer effects by immunomodulation and hemostatic mechasnism14. Pineapple extract in stage 2 mouse skin tumorigenesis model cause reduction in tumor size (65%) and volume. Molecular analysis revealed upregulation of p53,Bax,, caspase 3 ,9 and downregulation of Bcl2, inhibition of COX 2( cyclooxygenase 2), inactivation of NF kappa B (nuclear factor kappa B), MAP(mitogen activated protein linase) kinase, Erk (extracellular-signal-regulated kinases ) and Akt (protein kinase B)15,16. CRUCIFEROUS VEGETABLES Brassica oleracea belongs to the family Brassiaceae which are commonly known as cruciferous vegetables. In uncultivated form it is called as wild cabbage and is native to Europe. Cabbage (Brassica oleracea capita), Cauliflower (Brassica oleracea botrytis), Brocoli (Brassica oleraceaitalica) are some of the varieties of wild cabbage developed by various cultivars. These cruciferous vegetables are a part of diet in many countries including India. Recently research has been carried out to assess the phytochemical constituents and medicinal properties of these vegetables17. The leaves of Cabbage contain 2 pyrolidinone which has been isolated and identified by gas chromatography, mass spectrometry and High Performance liquid chromatography. This active constituent induces apoptosis and cell cycle arrest in GO/G1 phase in HeLa ( cervical cancer cell line taken from Henrietta Lacks) and BC-3 cell lines (body cavity-based lymphoma cell line ), hence possesses antitumor activity.18 Brassica o leracea also contains glucosinoates which on hydrolysis yields isothicyanates that exerts antineoplastic effects. Surforaphane is one such isothiocyanate that causes downregulation of Bcl2 and upregulation of p53, Bax, Caspase 3 in Hep 2 cell lines ( He La derivative )19. Isothicyanates has chemopreventive effects. These isothiocyanates modulate carcinogen metabolising enzymes, thereby limit formation of reactive intermediates that from DNA adducts. Both intact glucosinolates and isothiocyantes modulate Phase II detoxification enzymes such as Quinone reductases, GST,( Glutathione-S-transferases) EH (Epoxide hydrolase), UGT (Uridine 5-diphospho-glucuronosyltransferase). Intact glucosinolates modulate CYP cytochrome P450 enzymes line EROD (ethoxyresorufin-O-deethylase) , MROD (ethoxyresorufin O-deethylase). Isothicyanates and glucosinolates like Phenyl isothiocyanates, erucin, sulforaphone are antagonists of Aryl hydrocarcobon receptor hence aid in cancer prevention17. APPLE Apple, the pomaceous fruit of Malus domestica tree belongs to the family Rosaceae. Malas sieversi, ancestor of this species is native to the mountains of Central Asia. It is one of the oldest known fruit that prevents lung cancer, chronic obstructive pulmonary disease (COPD), cardiovascular disease (CVD), thrombosis and stroke. Polyphenols and flavonoids, the phytochemical constituents of apple fruit have antioxidant properties. The phytochemical components of apple can act as chemopreventive agent due to the antioxidant and antiproliferative property20. Triterpenoids of apple peel possesses antitumor activity. 2R-hydroxy-3à ¢-{[(2E)-3-phenyl-1-oxo-2-propenyl]oxy}olean-12-en-28-oic acid, 2R-hydroxyursolic acid and 3à ¢-trans-p-coumaroyloxy-2R-hydroxyolean-12-en-28-oic acid , the triterpenoids isolated from apple peel exerts higher antitumor activity against HepG2 cell lines. Ursolic acid, 3à ¢-transp-coumaroyloxy-2R-hydroxyolean-12-en-28-oic acid and 2R-hydroxyursolic acid are the terpenoids that has higher antineoplastic activity against MCF-7 (Michigan Cancer Foundation-7) cancer cells. Terpenoids such as 2R-hydroxy-3à ¢-{[(2E)-3-phenyl-1-oxo-2- propenyl]oxy}olean-12-en-28-oic acid, 2R-hydroxyursolic acid, maslinic acid, and 3à ¢-trans-p-coumaroyloxy-2R-hydroxyolean-12-en-28-oic acid has higher anticancer effects against heterogeneoushumanepithelialcolorectaladenocarcinomacells (Caco2) cancer cells. Apple peel extracts exert anticancer effects by causing Go/G1 cell cycle arrest, decreasing expression of Proliferating cell nuclear antigen, increasing the levels of the tumor suppressor protein mapsin in human prostrate and breast carcinoma cells21,22. PAPAYA Carcia papaya commonly known as papaya of the family Caricaceae is cultivated throughout India. Leaves of papaya have been used to treat diseases and aliments like jaundice, asthma, colic, fever, beri beri. Recent studies have demonstrated that papaya leaf extracts could be used for cancer management. Significant growth inhibitory activity of Carica papaya leaf extract on a couple of cell lines including Raji and Ramos (Burkitt’s lymphoma cell lines) , Jurkat (T cell Lymphoma cell line), HepG2 and Huh-7 (hepatocellular carcinoma cell lines), K562 (chronic myelogenous leukemia cell line) PC14 (lung adenocarcinoma cell line), HeLa (cervical carcinoma cell line, Panc-1 (pancreatic epithelioid carcinoma cell line), Capan1 (pancreatic adenocarcinoma cell line), ARH77 (plasma cell leukemia cell line), H2452 (mesothelioma cell line) , Karpas-299 (anaplastic large cell lymphoma cell line), MCF-7 (breast adenocarcinoma cell line). Treatment of peripheral blood mononuclear cells (PMBC) with the extract caused increased production of antitumour cytokines with no change in viability of the cells. In addition, the peipheral blood mononuclear cells treated with the extract had increased cytotoxic activity against chronic mylogenous lukemia cell line23. Thus Carcia papaya exterts antitumour activity through grwoth inhibitory and immmunomodulatory mechanisms. This property could be attributed to the active constituent carpaine present in papaya leaves. Papaya Leaf also contains a remarkable protein-dissolving enzyme called papain that degrades fibrin that makes up the protective layer of cancer cells, making the cancer cells more susceptible to immune response or chemotherapy. Studies have revealed that mice immunized with papain possess serum antibodies which cross-react with cathepsin-B- and cathepsin-H-like endopeptidases isolated from B16 melanoma cells along with inhibition of growth rate, invasion and metastasis in B16 melanoma and the Lewis lung carcinoma .Thus t he compound hinders tumor growth and prevents it from spreading to other parts of the body24. In addition, papaya leaf has antioxidants like beta-carotene, flavonols, and vitamin C that scavenge free radicals which are responsible for carcinogenesis, which act as adjuvant for cancer therapy. Papaya seed has been used for the management of worm infestations in the gastrointestinal tract due to its antihelminthic activity. Papaya seeds contain benzyl isothiocyanate which exhibits antineoplastic effects by inhibiting of carcinogen-activating cytochrome P450 mono-oxygenases and cell cycle progression; inducing carcinogen-detoxifying phase 2 enzyme and apoptosis. Higher concentration of BITC (benzylisothiocyanate) has a better inhibition rate of cell proliferation on H69 cell, with IC(50) value of 6.5 ÃŽ ¼mol/L25. TOMATO Lycopersecon ecsculentum or tomato belongs to the night shade family called Solanaceae. Fleshy fruit of this plant is red in colour which is classified based on size and shape as slicing or globe tomato, beefsteak, oxheart, plum, pear, cherri, carpari. Lycopene is the chief active constituent having antibiotic, anti-inflammatory, antioxidant, cardiovascular and immunomodulatory effects26. Lycopene is a better singlet oxygen scavenger than other carotenoids. Interestingly tomato leaves has anticancer activity. Extracts of tomato leaves have been shown to exert antineoplastic activity in MCF breast cancer cell lines by causing genetic alterations27. Lycopene promotes cell adhesion by increasing E cadherin expression, reduces cell proliferation by decreasing PCNA (proliferating cell nuclear antigen) expression and confines proliferating cells to the basal and parabasal layer in 4NQQ (4-nitroquinoline-1-oxide )induced tongue carcinogenesis model in mice. Thus Lycopene could be used as a chemopreventive agent28. Bifunctional nucelases from tomato RTBN1 also has antitumor activity29. CONCLUSION Along with attempts to improve cure rate of cancer, concerted efforts to prevent the disease continuity should be undertaken. This is particularly true for the high risk population and high risk individuals. A targeted prevention in high risk individuals with high risk lesions using agents targeted to key molecules in the carcinogenesis process should have an impact in lowering the disease morbidity and mortality. Advances in molecular biology have helped to define these high risk individuals with high risk lesions and novel chemopreventive targets. In this regard targeted approach using medicinal properties of plants should overcome some of the earlier setbacks observed in cancer prevention and therapeutic research.