effect of secondary metabolites of medicago sativa on lung cancer

Int J Pharm Bio Sci 2016 Oct ; 7(4): (P) 265 - 271 Review Article

Pharmacognocy

International Journal of Pharma and Bio Sciences

ISSN 0975-6299

EFFECT OF SECONDARY METABOLITES OF MEDICAGO SATIVA ON LUNG CANCER F.REHMAN*1, S.MAIRAJ1, AND U.K.JETLEY2 1

Cancer rehabilitation centre,Faiz-E-Aam Degree College,Meerut,U.P.India Department of Industrial Chemistry,L.R. College,Ghaziabad,U.P.India

2

ABSTRACT Cancer is a major health problem in both developed and developing countries, second only to cardiovascular disease. Lung cancer, in particular, is a disease with high morbidity and mortality, and is major cause of death among all type of cancers the world over( ˜ 18.2%), causing about 1.38 million deaths per year. The cause of such high mortality rate of lung cancer may be both internal ( genetic, mutative, hormonal, poor immune conditions, etc ) and external (such as food habits, heavy industrialization, population explosion, lifestyle, smoking, etc.) Due to high death rate and ill effects of chemotherapy and radiation therapy, many cancer patients seek alternative / complementary medical treatment with milder side effects. Some natural therapies such as direct use of certain medicinal plants or the use of active ingredients extracted from these plants are reported found beneficial in combating cancer. As such there exists a wide scope of deriving potential anticancer agents from these medicinal plants, which need extensive exploration in this area. Till date only a few medicinal plants have attracted the interest of concern therapist. In view of these facts, the objective of present article is to review the medicinal plants with antitumor potential against lung cancer, the status of lung cancer in specific territories of India and with comparison at Global level, and causes of lung cancer along with their remedial aspects, and mechanism of action. KEY WORDS : Cancer, Medicinal Plants, Diet, Smoke, Population explosion

F.REHMAN

Cancer rehabilitation centre,Faiz-E-Aam Degree College,Meerut,U.P.India

*Corresponding author

This article can be downloaded from www.ijpbs.net P- 265

Int J Pharm Bio Sci 2016 Oct ; 7(4): (P) 265 - 271

INTRODUCTION Cancer is a group of diseases caused by loss of cell cycle control and associated with abnormal uncontrolled 1 cell growth ,which may occur at any time, at any age, and in any part of the body. Cancer is the leading and sub leading cause of death in economically developed and developing countries, and is second most common 2 disease after heart disease , and would overtake 70% of cancer deaths, in the developing world. Literature revealed that 14.1 million cancer patients were diagnosed in 2012, and this number is expected to be 15 million by 2020, about 8 million people died of cancer 3 in 2012 , and this number would reach 13.1 million in 2030. In India, cancer has become one of the ten leading cause of death and their number is rising alarmingly and form the Year 2020 onwards more than two million new cancer patients will add every year. The most frequently observed cancer in Indian population 4 are of lungs, breast, colon, rectum, stomach and liver , and approximately 50-60% cancer patients die each year. According to Indian council of medical research (December 2011) 5,14,470 cancer deaths were noted in 2009, 5,24,911 in 2010 and 5,35,767 were reported in 2011 this number is expected to rise to 7,00,000 by 2015 and five fold by 2025. A majority of cancer patients in India are between 30 to 70 years of age, such a high incidence of cancer may be both internal like genetic , hormonal and poor immune condition as well as external environmental factors such as food habits, heavy industrialization, population explosion, smoking, 5 ultraviolet rays and life-style, smoking, etc . Lung cancer is the second most common cancer in world over which causes 19.4% (1.38 million) of the total deaths 6 annually .The incidence rates of lung cancer are generally higher among men then women, and 80% of all cancer cases are non-small cell lung carcinoma, while remaining cases are small cell lung carcinoma. Recently surgery, radiation, chemotherapy hormones, immunotherapy including STAT3 pathway inhibition, cell cycle arrest, Htert silencing, chitin inhibition and ALK(anaplastic lymphoma kinase) gene inhibitor technique are used to cure different type of cancers. Although chemotherapy is most frequently used, but they have side effects which prevent their extensive usage. Now-a-day approximately 70% of the world population is depending on medicinal herbs or traditional medicine. The use of traditional medicine has again 7 increased dramatically, in the last two decades .More than 50% of all modern drugs in clinical are use of 8 natural products . Cancer can be controlled by the intake of active ingredients of medicinal plants. There are at least 2,50,000 species of plants, out of which more than one thousand plants have been found to

possess significant anticancer properties, while a large number of plants products are still remains to studies in details. In India the medicinal plants have been used to treat different type of cancer and some plant products are marketed as anticancer drugs based on the traditional uses and scientific reports, which may promote host resistance against infection by restabilizing body equilibrium and conditioning the body tissues. These plants may contributed novel compounds for preventive and curative medicine to modern science. The secondary metabolites are of specific interest to scientist because of their unique pharmacophores and medicinal properties. secondary metabolites specially poly phenols are commonly used in treating or preventing specific ailments, such as atherosclerosis, diabetes mellitus, cancer and various type of communicable disease caused by different microbes. One of the reasons for these diseases could be the imbalance between reactive oxygen species and antioxidant defense systems, which may increase the oxidative burden over the body and lead to alter the metabolic activities of the cell and such processes are thought to play an important role in pathological processes of various diseases. Antioxidants neutralize the effect of free radicals through different ways and may provide defense towards various diseases. Plant and herb which exhibit antioxidant properties are therefore has widely been used for the treatment of various diseases. This paper high-lights the lung cancer context in specific territories of India, causes and their remedial aspects by specific medicinal plants and their active ingredients with a recent advances in understanding mechanism of action and structure function relationship of nature derived anticancer agents.

LUNG CANCER GLOBAL STATUS The lung cancer is most commonly diagnosed cancer world over, accounting for 12.7% or 1.61 million of the total cancer cases in 2008 and this number rose to 13% or 1.8 million in 2012, which causes 1.6 million or 19.4% casualties in 2012, while this number was 1.38 million and 18.2 % of the total in 2008. In contrast to the 5 year survival of 52 % in all cancers, the lung cancer survival 9 rates continue to be poor . The decline trend of ageadjusted lung cancer death rate in USA over a period of six decades has been noted in males whereas the same trend in female rising mainly because of the declining smoking habits in males & increasing smoking habits in females. The regional burden of lung cancer (cases and deaths) in the world is shown in Table-1 and figure 1and 2.

Table 1 The worldwide distribution 2008 of the incidence of lung cancer Region World More developed region Less developed regions WHO Africa region (AFRS) WHO Americas region (PAHO)

Male Cases Deaths 1095 951 482 411 612 539 12 11 172 144

Female Cases Deaths 513 427 241 188 271 239 4 4 134 101


Both Sexes Cases Deaths 1608 1378 723 599 883 778 16 15 306 245

Int J Pharm Bio Sci 2016 Oct ; 7(4): (P) 265 - 271 WHO East Mediterronean region (EURO) 21 WHO South-East Asia region (SEARD) 108 IARC Membership (21 countries) 456 United States of America 114 China 351 India 47 European Union ( Eu-27) 207 Estimated numbers in thousands- (GLOBACON)

19 97 386 90 304 41 182

5 42 233 100 170 11 80

4 37 180 71 148 10 70

26 150 689 214 521 58 287

23 134 566 161 452 51 252

Figure 1 Graphical Representation of Data Shown in Table-1 (Total No of Cases)

Figure 2 Graphical Representation of Data Shown in Table-1 (Total No. of Deaths) st

CAUSES OF CANCER It has been long established that inadequate diets represent a major risk factor related to cancer deaths ( 10 30%), only second to tobacco consumption (35%) , and estimated that 40-70% of all cancers can be 11 prevented by dietary measures and lifestyle only . So, an important mean to reduce the risk factor associated with cancer deaths is to promote healthier diets and 12 lifestyle habits . It was also estimated in recent study that overweight and obesity accounted for 14% of all 13 cancer deaths in men and 20% of those in women , exposure of radiation (10%), infection ( 15-20%). Lack of physical activity, and environmental pollutants also 14 causes lung cancer .These factor may directly damage the genes or combine with existing genetic faults within 15 the cell to cause cancerous mutations . Approximately 5-10% of cancers can be traced directly to inherited genetic defects [Retrieved 2013]

MAIN CAUSES OF LUNG CANCER IN INDIA Smoking and lung cancer th In India, tobacco caused 100 million deaths in 20 century if current trends continue, it may cause one

billion death in 21 century. In India Tobacco smoking ( mainly in the form of beedi, cigarettes & hukka ) is the major cause of lung cancer and 90% cases result from tobacco exposure, which include 87% active exposure and 3% passive exposure. The percentage of tobaccorelated products smoked in India are beedi [28.4- 79%], cigarettes [9 – 53.7%], hukka [3.4 -77.3%] and mixed 16-18 [7.5 – 13.6%] . According to National Family Health 19 Survey , ascendancy of tobacco use (all forms) was 57% in men & 10.8% in women. In India, one third of men (33.4%) and 1.4 % of women were beedi / cigarette smokers. The number of active adult smokers are higher in the rural areas (31.3%) as compared to urban 20 area (21.5%) . Tobacco is the most important identified cause of cancer and is responsible to 30 to 50% cancer in men and about 10-15% of cancer in women, in different registry area [NCRP 2008]. Cigarrate smoke has more than 60 carcinogenic molecules, out of these benzo-α-pyrene and N-Nitrosomine NNK are highly carcinogenic in nature and form adduct with DNA and protein which increase the chance of DNA mutation and 21 interfere with proper function of protein .The relative risk of developing lung cancer in 2.64 for beedi smokers, 2.23 for cigarette smokers and with 2.45 as the overall relative risk [18,21,19]. Hukka smoking has also been associated with lung cancer with an odds ratio 22 of 1.94 . It has been noted that beedi is more


Int J Pharm Bio Sci 2016 Oct ; 7(4): (P) 265 - 271 23

carcinogenic . Currently, It has been noted that 89 % of men & 33 % women ever smokers suffer lung cancer as compared to respectively 60% of men and 20% of women among control. The odds ratio (OR) for ever smoking was 5.0 ( C I 3.11 – 8.04) among men and 2.47 ( CI 0.79 – 7.75) among women. Smoking of beedi and hooka as well as cigarettes has similar ORs for cumulative consumption. The daily consumption of all forms of tobacco use was higher among the lower income quintile ( 41.8%) compared to higher income quintile ( 15.5%) and in the elderly population (43.9% among 65+ age group) compared to younger age group ( 14.7% among 18-24 age group). Environmental tobacco smoke carries a relative risk of developing lung cancer of 1.48 (1.13 – 1.92) in male and 1.2 in females ( 1.12 – 1.29), while the odds ratio of environmental tobacco smoke during childhood was found 3.9 (95% CI 1.9-8.2) and while OR in female is higher depend upon the number of smokers and duration of exposure is 24,25 higher 5.1) .

DIET AND LUNG CANCER Improper diet is one of the main reason of cancer causes. The role of dietary factor towards cancer varies 26,27 greatly according to the type of cancer . It has been noted that some dietary factor with lowest intake of food rich in β-carotene, Vitamin A and Vitamin E have highest 28-31 . The green vegetable, allium risk of lung cancer vegetable, cruciferous vegetable and bananas have 32 protective effect on development of lung cancer , while pumpkins and onion have most invariable shielding effect on lung cancer and on the other hand dietary cholesterol and animal fat increases the risk of lung 33 cancer . Carrots and tomatoes decrease the risk of lung cancer about 20 - 25% which is due to α- carotene 34 and lycopene . It has been found that flavonoids (found in apples) and iso-thiocynate (found in cruciferous 35 vegetables) also reduce risk of lung cancer . Beans, chik, peas, lentils, and pulses have been significantly 36-37 used to reduce cancer .Thus, overall protective effect of fruits and vegetables is due to the presence of dithiones ,isothiocyanates,indole-32-carbinol, alliums compounds, flavonoids isoflavones, protease inhibitors, saponins, phytosterols, inositol hexa phosphate, vitamin C, D-limonene, lutein, folic acid, -carotene, lycopene, 38 selenium, vitamin E, and dietary fiber , while, heavy consumption of red meat is the main cause of several 39 type of cancers , which is due the production of heterocyclamines at elevated temperature, and food store in plastic container may also become carcinogenic 40 due the bisphenol of plastic .

MEDICINAL PLANTS FOR TREATMENT OF LUNG CANCER

THE

Herbal medicines are more frequently used against various types of tumor such as sarcoma, lymphoma, carcinoma, and leukemia because they have proven to be useful and effective in sensitizing conventional agents, prolong potent survival time, preventing side effects of chemotherapy and improving quality of life in 41 lung cancer patients . The secondary metabolites of medicinal plants have also been extensively studied for

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their anti lung cancer activity , for example vinblastine, vincristine,and vinca alkaloids extracted from 42 Catharanthus roseus, paclitaxel from the leaves of various Taxus species, nimbolide from edible part of Azadiracta Indica, curcumin from curcuma longa, genistei, diadezein and anositol from Glycin max seeds, kaempferal-3-galactoside, kaempferal-3rhamnoglucoside, hentriocontane-β-sitasteral, lupcal, flavanone glucosides, peonidine glucoside from 43 Bauhinia variegiate, gingerol from Zingiber officinale , 44 embelin from Embelia ribes , carbazole alkaloid from 45 murraya koenigi , subamolide A from Cinnamomum 46 47 subavenium , davallic acid from Davallia divuricate , 46 daphnodorin-B from Daphne genkwa , β-elemene extracted from Curcume wenyujin (Zingiberaceae) rhizome, etc .

MEDICAGO SATIVA L Literature revealed that medicago sativa has antitumor, antimutagenic, antibacterial, antiinflamatory,antirheumetic, anodyne, depurative, emmenagogue, estrogenic, galatagogue, ant diuretic, 48 antioxidant activity and used to treate several type of cancer such as prostate, bladder, pancreatic, colon, leukaemia, fibrocystic breast, arthritis, urinary tract infection, diabetes, antihistaminic, osteoporosis, high 49-50 density Lipolipid . It also help to clean liver, blood stream and reduce hyperglycemias by stimulating insulin production. Medicinal value of this plant is due significant amount of vitamins ( such as A, B1,B6,B12,C, D, E , K, niacin, biotin, folic acid and pathogenic acid), Minerals like ( sodium, potassium, Calcium, Magnesium, Phosphorus, Zinc, Silicon, chloride), proteins, carbohydrate, and other secondary metabolites such as alkaloid, flavonoids, carotene, tannin, several saponine and steroids. Saponine, which on hydrolysis yield glycones medicagenic acid, soya sapogenols A, B,C,D , E,α- ederagonin glycones, glucose, arabinose, xylose, rhamnose, galactose and glucoronic acid. Sterols(βsitosterols , α-spinasterol, stigmasterol, cycloartenol and compesterol with β-sitosterol as the major component. ostacosonol,tri-acontanol, triacontane, flavones, isoflavones (tricin,geneistein, diadzein, biochanin A,farmononetin and 5’- methoxy sativan), Coumarin derivatives(coumesterol,medicagol,satival,trifolial, lucernol and daphnoretin)and pectin methylsterose. Medicage sativa sprouts have about 8% saponins which is non-systemic and have a direct stimulating effect on the immune system by increasing the activity of natural killer cells such as T-lymphocytes and interferon, and help to fight microbes, viruses and fungal infection. It reduce the production of inflammatory toxins in the alimentary canal, destroy some tumour cells particularly lung and blood cancers, helped to lower level of bad cholesterol, inflammation, which is believed to help prevent arthrosclerosis, stock, chronic inflammatory disorder, and other cardiovascular diseases. Estrogen found in medicago sativa may increase bone formation, bone density, and help to prevent osteoporosis. Canavanine( amino acid analog) found in this plant may fight leukemia, pancreatic cancer, colon cancer and fibrocystic breast cancer.



MECHANISM Secondary metabolites play a major role in arrest cell cycle at G1 phase and stimulate apoptosis at G0/G1 phase and GB( glioblastoma), AMN-3 and MEF-3 cell 51 line in tumour cell and cleaved the DNA by inhibit DNA 52 topoisomerase I activity . These secondary metabolites also help to prevent biomolecules damage caused by 53 free radical Several current studies revealed that the medicago sativa extract has the ability to induce cell cycle arrest in mammalian cells, the mode of action in target cell appears to involve induction of apoptosis by 54 mitochondrial perturbation , and able to alter 55 membrane activity and have strong haemolytic activity . Saponin , present in medicago sativa inhibit cancer cell in three different modes ,firstly it combine with cholesterol of cancer cell membrane and preventing them entering the body through intestinal track, secondary it combine with bile acid to prevent highly

carcinogenic substance formed in large intestine by the interaction of bacteria, thirdly it help to flush pathogens through the gut without allowing to be absorbed.

CONCLUSION Therapeutic effects of medicinal plants are due to the presence of secondary metabolites which might have some specificity in their toxicity towards cancer cells rather than normal cell, this is due to different mode of interaction with the cholesterol rich membranes of cell. It is reasonable to expect that diets containing antioxidants as chemo-preventive ingredients may interfere with the initiation of cancers.

CONFLICT OF INTEREST Conflict of interest declared none.

REFERENCES 1.

2.

3.

4.

5.

6.

Krishnamurthi K . Screening of natural products for anticancer and antidiabetic properties. Health administrator. 2007;122: 69-75. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA: a cancer journal for clinicians. 2007 Jan 1;57(1):43-66. Bray F, Møller B. Predicting the future burden of cancer. Nature Reviews Cancer. 2006 Jan 1;6(1):63-74. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. International journal of cancer. 2010 Dec 15;127(12):2893-917. Meurman JH, Uittamo J. Oral micro-organisms in the etiology of cancer. Acta Odontologica Scandinavica. 2008 Jan 1;66(6):321-6. 6.Murthy NS, Mathew A. Cancer epidemiology, prevention and control. Curr Sci. 2004 Feb 25;86(4):518-24.

7.

8.

9.

10.

11.

Goel RK, Sairam K. Anti-ulcer drugs from indigenous sources with emphasis on Musa sapientum, tamrahbasma, Asparagus racemosus and Zingiber officinale. Indian Journal of Pharmacology. 2002 Jan 1;34(2):100-10. Rao CV, Sairam K, Goel RK. Experimental evaluation of Bocopa monniera on rat gastric ulceration and secretion. Indian Journal of Physiology and Pharmacology. 2000 Oct 24;44(4):435-41. Zelicourt MD, Detournay B, Compte S, Stockemer V . Epidemiology cost of Lung Cancer in France. Bull Cancer. 2001; 88: 753-758. Doll R, Peto R. The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. Journal of the National Cancer Institute. 1981 Jun 1;66(6):1192-308. American Institute for Cancer Research, World Cancer Research Fund International. Food,



12.

13.

14.

15. 16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27. 28.

nutrition and the prevention of cancer: a global perspective. American Institute for Cancer Research; 1997. de Jong FA, Sparreboom A, Verweij J, Mathijssen RH. Lifestyle habits as a contributor to anti-cancer treatment failure. European Journal of Cancer. 2008 Feb 29;44(3):374-82. . Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of US adults. New England Journal of Medicine. 2003 Apr 24;348(17):1625-38. Anand P, Kunnumakara AB, Sundaram C, Harikumar KB, Tharakan ST, Lai OS, Sung B, Aggarwal BB. Cancer is a preventable disease that requires major lifestyle changes. Pharmaceutical research. 2008 Sep 1;25(9):2097116. Kinzler KW, Vogelstein B. The genetic basis of human cancer (2nd, illustrated, revised ed.). Ministry of health and family welfare Gol. Report of the expert committee on the economic of tobacco use . New Delhi ,Goverment of India ,2001. Bhonsle RB, Murti PR, Gupta PC. Tobacco habits in India. Control of tobacco-related cancers and other diseases. 1992:25-46. Notani P, Sanghvi LD. A retrospective study of lung cancer in Bombay. British journal of cancer. 1974 Jun 1;29(6):477-82. International Institute for population sciences, Macro International. National Family Health Survey (NFHS-3, 2005-2006) India,Mumbai,IIPS, “ 2007” International Institute for Population Sciences, World Healh Organization (WHO).India-WR Office. World Health Survey, 2003.India,Mumbai:IIPS:2006. Rehman F.,Mairaj S., Goel Sanjeev, Jetley U.K.Comparative study and remidal aspect on lung cancer of the active component(s) of medicinal plants in specific territories of India.Int. J. Pharm Bio Sci 2015 Jan 6(1):698-707 Gupta D, Boffetta P, Gaborieau V, Jindal SK. Risk factors of lung cancer in Chandigarh, India. Indian Journal of Medical Research. 2001 Apr 1;113:142. Jindal SK, Behera D. Clinical spectrum of primary lung cancer-review of Chandigarh experience of 10 years. Lung India. 1990 May 1;8(2):94. Zhong L, Goldberg MS, Parent ME, Hanley JA. Exposure to environmental tobacco smoke and the risk of lung cancer: a meta-analysis. Lung cancer. 2000 Jan 31;27(1):3-18 Rapiti E, Jindal SK, Gupta D, Boffetta P. Passive smoking and lung cancer in Chandigarh, India. Lung Cancer. 1999 Mar 31;23(3):183-9. Anand P, Kunnumakara AB, Sundaram C, Harikumar KB, Tharakan ST, Lai OS, Sung B, Aggarwal BB. Cancer is a preventable disease that requires major lifestyle changes. Pharmaceutical research. 2008 Sep 1;25(9):2097116. Willett WC. Diet and cancer. The oncologist. 2000 Oct 1;5(5):393-404. Shekelle R, Liu S, Raynor W, Lepper M, Maliza C, Rossof A, Paul O, Shryock A, Stamler J. Dietary

29.

30.

31.

32.

33.

34.

35. 36.

37.

38.

39.

40.

41.

vitamin A and risk of cancer in the Western Electric study. The lancet. 1981 Nov 28;318(8257):1185-90. Heinonen . The effect of vitamin E and β- carotene on the incidence of lung cancer and other cancer in male smokers, the α-tocopherol, β- carotene, cancer preventention study group. N England J Med. 1995, 330, 1029-65. Hennekens CH, Buring JE, Manson JE, Stampfer M, Rosner B, Cook NR, Belanger C, LaMotte F, Gaziano JM, Ridker PM, Willett W. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. New England Journal of Medicine. 1996 May 2;334(18):1145-9. Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, Keogh JP, Meyskens Jr FL, Valanis B, Williams Jr JH, Barnhart S. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. New England journal of medicine. 1996 May 2;334(18):1150-5. Sankaranarayanan R, Varghese C, Duffy SW, Padmakumary G, Day NE, Nair MK. A case‐control study of diet and lung cancer in Kerala, South India. International journal of cancer. 1994 Sep 1;58(5):644-9. Law M. Dietary fat and adult diseases and the implications for childhood nutrition: an epidemiologic approach. The American journal of clinical nutrition. 2000 Nov 1;72(5):1291s-6s. Michaud DS, Feskanich D, Rimm EB, Colditz GA, Speizer FE, Willett WC, Giovannucci E. Intake of specific carotenoids and risk of lung cancer in 2 prospective US cohorts. The American journal of clinical nutrition. 2000 Oct 1;72(4):990-7. Goodman G E. Prevention of lung cancer, Crit Rev and Hematol, 2000;33:187-97 Jain MG, Hislop GT, Howe GR, Ghadirian P. Plant foods, antioxidants, and prostate cancer risk: findings from case-control studies in Canada. Nutrition and cancer. 1999 Jul 1;34(2):173-84. Mills PK, Beeson WL, Phillips RL, Fraser GE. Cohort study of diet, lifestyle, and prostate cancer in Adventist men. Cancer. 1989 Aug 1;64(3):598604. Steinmetz KA, Potter JD. Vegetables, fruit, and cancer prevention: a review. Journal of the American Dietetic Association. 1996 Oct 31;96(10):1027-39. Chao A, Thun MJ, Connell CJ, McCullough ML, Jacobs EJ, Flanders WD, Rodriguez C, Sinha R, Calle EE. Meat consumption and risk of colorectal cancer. Jama. 2005 Jan 12;293(2):172-82. Durando M, Kass L, Piva J, Sonnenschein C, Soto AM, Luque EH, Muñoz-de-Toro M. Prenatal bisphenol A exposure induces preneoplastic lesions in the mammary gland in Wistar rats. Environmental Health Perspectives. 2007 Jan 1:80-6. Jeong SJ, Koh W, Kim B, Kim SH. Are there new therapeutic options for treating lung cancer based on herbal medicines and their metabolites?. Journal of ethnopharmacology. 2011 Dec 8;138(3):652-61.


Int J Pharm Bio Sci 2016 Oct ; 7(4): (P) 265 - 271 42.

43.

44.

45.

46.

47.

48.

Kim EC, Min JK, Kim TY, Lee SJ, Yang HO, Han S, Kim YM, Kwon YG. [6]-Gingerol, a pungent ingredient of ginger, inhibits angiogenesis in vitro and in vivo. Biochemical and biophysical research communications. 2005 Sep 23;335(2):300-8. Avisetti DR, Babu KS, Kalivendi SV. Activation of p38/JNK pathway is responsible for embelin induced apoptosis in lung cancer cells: transitional role of reactive oxygen species. PLoS One. 2014 Jan 22;9(1):e87050. Mohan S, Abdelwahab SI, Cheah SC, Sukari MA, Syam S, Shamsuddin N, Rais Mustafa M. Apoptosis effect of girinimbine isolated from Murraya koenigii on lung cancer cells in vitro. Evidence-Based Complementary and Alternative Medicine. 2013 Mar 13;2013. Hung JY, Wen CW, Hsu YL, Lin ES, Huang MS, Chen CY, Kuo PL. Subamolide a induces mitotic catastrophe accompanied by apoptosis in human lung cancer cells. Evidence-Based Complementary and Alternative Medicine. 2013 Feb 24;2013. Cheng AS, Chang WC, Cheng YH, Chen KY, Chen KH, Chang TL. The effects of Davallic acid from Davallia divaricata Blume on apoptosis induction in A549 lung cancer cells. Molecules. 2012 Nov 1;17(11):12938-49. Zheng W, Gao X, Chen C, Tan R. Total flavonoids of Daphne genkwa root significantly inhibit the growth and metastasis of Lewis lung carcinoma in C57BL6 mice. International immunopharmacology. 2007 Feb 28;7(2):117-27. Hwang J, Hodis HN, Sevanian A. Soy and alfalfa phytoestrogen extracts become potent low-density

49.

50.

51.

52.

53.

54.

55.

lipoprotein antioxidants in the presence of acerola cherry extract. Journal of agricultural and food chemistry. 2001 Jan 15;49(1):308-14. Sen S, Makkar HP, Becker K. Alfalfa saponins and their implication in animal nutrition. Journal of Agricultural and Food Chemistry. 1998 Jan 19;46(1):131-40. Deavours BE, Dixon RA. Metabolic engineering of isoflavonoid biosynthesis in alfalfa. Plant Physiology. 2005 Aug 1;138(4):2245-59. Pedro M, Ferreira MM, Cidade H, Kijjoa A, Bronze-da-Rocha E, Nascimento MS. Artelastin is a cytotoxic prenylated flavone that disturbs microtubules and interferes with DNA replication in MCF-7 human breast cancer cells. Life sciences. 2005 Jun 3;77(3):293-311. Darwanto A, Tanjung M, Darmadi MO. Cytotoxic mechanism of flavonoid from Temu Kunci (Kaempferia pandurata) in cell culture of human mammary carcinoma. Clinical hemorheology and microcirculation. 2000 Jan 1;23(2, 3, 4):185-90. Huryn DM, Wipf PE. Natural product chemistry and anticancer drug discovery. Cancer Drug Design and Discovery. 2008:107-30. Hirano T, Oka K, Mimaki Y, Kuroda M, Sashida Y. Potent growth inhibitory activity of a novel Ornithogalum cholestane glycoside on human cells: induction of apoptosis in promyelocytic leukemia HL-60 cells. Life sciences. 1996 Jan 26;58(9):789-98. Tusda H, Ohshima Y, Nomoto H, Fujita H, Matsudu E, ligo H,Takasuda N and Moore MA. Cancer Prevention by natural compounds. Drug Metab Pharmacokin 2004 ,19(4) : 245-63.
