|Year : 2016 | Volume
| Issue : 1 | Page : 24-27
Aqueous extracts of Rosmarinus officinalis, Urtica diocia, and soybean exert different effects on adenosine deaminase activity in cancerous and noncancerous human gastric and colon tissues
Zahide Esra Durak1, Hikmet Can Cubukcu2, Suleyman Buber2, Hilmi Kocaoglu3, Ilker Durak2
1 Turkish Ministry of Health, Public Health Institution, Ankara, Turkey
2 Department of Medical Biochemistry, Faculty of Medicine, Ankara University, Ankara, Turkey
3 Department of Surgical Oncology, Faculty of Medicine, Ankara University, Ankara, Turkey
|Date of Web Publication||25-Feb-2016|
Zahide Esra Durak
Turkish Ministry of Health, Public Health Institution, Ankara
Source of Support: None, Conflict of Interest: None
Objective: This study aimed to investigate effects of aqueous extracts of Rosmarinus officinalis, Urtica diocia, and soybean on adenosine deaminase (ADA) activity in cancerous and noncancerous gastric and colon tissues since it is key enzyme participating in DNA turn-over. Materials and Methods: In method, cancerous and noncancerous human gastric and colon tissues removed by surgical operations were studied. In the samples, ADA activities were measured with and without plant extract incubated for 1 h. Results: As a result, it has been observed that rosemary extract inhibits ADA enzyme in cancerous (P = 0.031) and noncancerous gastric tissues (P = 0.048), but not in colon tissues, and Urtica extract inhibits the enzyme only in the cancerous gastric tissue (P = 0.039). On contrast, soybean extract activates ADA enzyme in colon tissues significantly (P = 0.012). Conclusion: Inhibition of ADA enzyme might play a part in the proposed anti-cancer properties of rosemary and U. diocia. However, the finding of ADA activation in colon tissues by soybean extract is a new one which needs further verification.
Keywords: Adenosine deaminase, anti-cancer, Rosmarinus officinalis, soybean, Urtica diocia
|How to cite this article:|
Durak ZE, Cubukcu HC, Buber S, Kocaoglu H, Durak I. Aqueous extracts of Rosmarinus officinalis, Urtica diocia, and soybean exert different effects on adenosine deaminase activity in cancerous and noncancerous human gastric and colon tissues. J Health Res Rev 2016;3:24-7
|How to cite this URL:|
Durak ZE, Cubukcu HC, Buber S, Kocaoglu H, Durak I. Aqueous extracts of Rosmarinus officinalis, Urtica diocia, and soybean exert different effects on adenosine deaminase activity in cancerous and noncancerous human gastric and colon tissues. J Health Res Rev [serial online] 2016 [cited 2019 Jun 24];3:24-7. Available from: http://www.jhrr.org/text.asp?2016/3/1/24/177491
| Introduction|| |
It has long been investigated to find natural remedies for the treatment of cancer, and it has been observed that treatment of some types of cancers with plant sources may give rise to positive results. Most of the cancers are directly linked to the diet. While many dietary recommendations have been proposed to reduce the risk of cancer, unfortunately, few have significant supporting scientific evidence.
Adenosine deaminase (ADA) is an enzyme (EC 126.96.36.199) involved in purine metabolism. It is needed for the breakdown of adenosine and the turnover of nucleic acids. ADA is present virtually in all mammalian cells, and it is thought that its primary function in human beings is related to the immune system. However, the full physiological role of ADA is not completely understood. ADA association has also been observed with epithelial cell differentiation, neurotransmission, and gestation maintenance., It has also been proposed that ADA, in addition to its role in adenosine breakdown, stimulates the release of excitatory amino acids, and it is necessary to the coupling of A1 adenosine receptors and heterotrimeric G proteins.,
Some ADA inhibitors have been used for chemotherapeutic purposes in some types of cancers such as lyphoma and leukemia. From a scientific perspective of view, use of ADA inhibitors has helped much in understanding the mechanism of action of adenosine metabolites and analogs. ADA inhibitors have also led to the understanding of the regulatory processes associated with immunodeficiency characterized by a lack of ADA, and of maturation of the immune response. One of them, pentostatin (Nipent) is a nucleoside analog having the potential to inhibit ADA enzyme. Inhibition of ADA blocks the deamination reactions in the purine salvage pathway, the result of which is the inhibition of ribonucleotide reductase. As a result, this process depletes the nucleotide pool and limits DNA synthesis. ADA is selected for this study because it is a key enzyme in the DNA turnover, and therefore in the cancer process.
There are several biologically active components in rosemary, some of which are carnosol, rosmarinic acid, hesperetin, caffeic acid, ferulic acid, vanillic acid etc. This constituents have antioxidant properties.R. officinalis has been reported to possess many pharmacological activities,, some of which indicate a promising effect in controlling cancer development. This food has been shown to have significant antiproliferation activities against a variety of human cancer cell lines including breast, leukemia, prostate, lung, and liver.,
Urtica diocia is a herb that has a long tradition of use as an adjuvant remedy in the treatment of several diseases. Nettle leaf extract contains active compounds that reduce tumor necrosis factor-α (TNF-α) and other inflammatory cytokines., It has been demonstrated that nettle leaf lowers TNF-α levels by potently inhibiting the genetic transcription factor that activates TNF-α and interleukin-1B in the synovial tissue that lines the joint. Nettle root extracts have been studied in human clinical trials as a treatment for symptoms of benign prostatic hyperplasia. These extracts have been shown to help relieve symptoms compared to placebo both by themselves  and when combined with other herbal medicines.U. diocia is the most ferquently used herb in cancer therapy. Both roots and leaves of this plant were used traditionally. In a study, it has been observed that ADA activity in prostate tissue is inhibited by aqueous extract of U. dioica. ADA inhibition by U. dioica extract has been suggested as one of the mechanisms in the observed beneficial effect of U. dioica in prostate cancer.
There is much evidence suggesting that compounds present in soybeans can prevent cancer in many different organ systems. There is evidence that some compounds that may be able to suppress carcinogenesis in animals are the soybean isoflavones. Soybean compounds reported to have other types of anticarcinogenic activity include soybean trypsin inhibitor, saponins, and genistein. There is much evidence to suggest that diets containing large amounts of soybean products are associated with overall low cancer mortality rates, particularly for cancers of the colon, breast, and prostate. It is believed that supplementation of human diets with certain soybean products may markedly reduce human cancer mortality rates.
We aimed to investigate possible effects of aqueous extracts of R. officinalis, U. diocia and soybean on ADA activity which is one of the key enzymes participating in DNA turnover.
| Materials and Methods|| |
The study was approved by the Ethical Committee of Clinical Research in Ankara University Faculty of Medicine. Twenty-two cancerous gastric tissues and 22 noncancerous adjacent gastric tissues were obtained from patients with gastric cancer by surgical operation. Eleven cancer and 11 noncancer colon tissues were similarly obtained from patients with colon cancer. Tissues were first cleaned by saline solution and stored at −80°C until analysis. In the analysis process, they were first homogenized in saline solution (20%, w/v). After homogenization, samples were centrifuged at 5000 rpm for 30 min to remove debris and to obtain clear supernatant fraction. Analyses were performed in this fraction.
The extracts were prepared by soaking ground powder into the distilled water at the concentration of 10% (w/v) and waiting for 24 h at room temperature by continuously rotating. After the debris was removed, supernatants were centrifuged at 10.000 rpm for 20 min and upper clear part was removed to be used in the assays.
Protein concentrations of the tissues were measured by Lowry method  and ADA activity was measured by the method of Guisti. Lowry method is based on Cu-protein complex formation of phosphomolybdic and phosphotungstic acids with the formation of blue color. ADA activity measurements were performed with and without plant extract for 1 h. This method is based on the measurement of ammonia occurred after deamination reaction by the catalyzing effect of ADA. Statistical evaluations were made by using Wilcoxon test and values lower than 0.05 were evaluated significant. All statistical analyses were carried out using SPSS statistical software (SPSS for Windows, version 15.0, SPSS Inc., Chicago, IL, USA).
| Results|| |
Results are shown in [Table 1]. Rosemary extract inhibits ADA enzyme in cancerous and noncancerous gastric tissue but not in colon tissue. Urtica extract inhibits the enzyme only in cancerous gastric tissue. On contrast, soybean extract activates ADA enzyme in colon tissue.
|Table 1: Effects of rosemary leaf, soy bean and urtica diocia extracts on adenosine deaminase activities in gastric and colon tissues with and without cancer (mIU/mg)|
Click here to view
| Discussion|| |
Nutritional foods are important sources for the treatment of some types of cancers, leading to the development of potential novel agents.,, Several of the molecules such as curcumin, bullatacin, camptothecin, and triterpenic acid available from foods have been shown to exert anticancer effects on cancer cells. These effects have been observed through in vitro and in vivo animal studies.,,
Rosemary (R. officinalis L.) extract possesses antitumor properties against tumor cells from several organs. It has been observed that rosemary extract modulates estrogen and epidermal growth factor receptors in breast cancer cell lines, and that a standardized rosemary extract can disrupt the endoplasmic reticulum machinery to decrease the viability of prostate cancer cells and promote degradation of the androgen receptor. Two human prostate cancer cell lines, 22Rv1 and LNCaP, and prostate epithelial cells procured from two different patients undergoing radical prostatectomy were treated with standardized rosemary extract and evaluated by laboratory analyses. A significant modulation of endoplasmic reticulum stress proteins was observed in cancer cells while normal prostate epithelial cells did not undergo endoplasmic reticulum stress. This biphasic response suggests that rosemary extract may preferentially target cancer cells as opposed to normal cells.
It has been reported to possess anti-inflammatory and anticancer activities. However, the molecular mechanisms underlying the anticancer effects of carnosol remain poorly understood. It has been found that carnosol significantly reduced the viability of human colon cancer 116 cells in a concentration- and time-dependent manner. Treatment of cells with carnosol induced apoptosis, which was associated with activation of caspase-9 and -3 and the cleavage of poly-(ADP-ribose) polymerase.
Our results show that rosemary extract can significantly inhibit ADA enzyme in cancerous and noncancerous gastric tissues. This finding is of significance because of the fact that inhibition of ADA blocks the deamination of adenosine to inosine and deoxyadenosine to deoxyinosine in the purine salvage pathway. This accumulation of metabolites inhibits ribonucleotide reductase, which depletes the nucleotide pool and limits DNA synthesis.
In a study, antiproliferative activity of U. diocia extract on the human breast cancer cell line and fibroblasts isolated from foreskin tissue was evaluated. Mechanisms leading to apoptosis were also investigated at the molecular level by measuring the amount of anti- and pro-apoptotic proteins and at the cellular level by studying DNA fragmentation and annexin V staining by flow cytometry. The aqueous extract of U. dioica showed antioxidant and antiproliferative effects. The antiproliferative activity was found to be associated with an increase of apoptosis as demonstrated by DNA fragmentation. Study findings warrant further research on U. dioica as a potential chemotherapeutic agent for breast cancer.
A study investigated the hepatoprotective, nephroprotective, and antioxidant activity of U. dioica L methanolic extract (UDME) against cisplatin (CP) toxicity in Ehrlich ascites tumor (EAT)-bearing mice. In this investigation, levels of serum hepatic enzymes, renal function markers, and oxidant/antioxidant parameters of liver tissue were measured. Mice were inoculated with EAT on day 0 and treated with nothing else for 24 h. After a single dose of CP administration on day 1, the extract was given at the different doses daily during 6 days. Almost all doses of UDME performed a significant (P < 0.05) preventive role against CP toxicity. This suggests that UDME has a protective capacity and antioxidant activity against CP toxicity in EAT-bearing mice, probably by promoting antioxidative defense systems.
Our results show that U. diocia extract inhibits ADA enzyme only in malign gastric tissue. This finding may be also of importance like the action of rosemary leave extract on ADA enzyme relating to gastric cancer treatment.
In a soy food study, it has been reported that dietary soy consumption can lower the risk for breast cancer. Current human and animal data provide evidence for several anticancer properties of soy and its isoflavones. Although the specific quantities and constituents responsible for the observed anti-cancer effects have not been elucidated, it appears that soy isoflavones do not function as an estrogen, but rather exhibit anti-estrogenic properties. However, their metabolism differs between humans and animals and, therefore, the outcomes of animal studies may not be applicable to humans. The majority of breast cancer cases are hormone-receptor-positive; therefore, soy isoflavones should be considered as a potential anti-cancer therapeutic agent and warrant further investigation.
A study was conducted to examine the association between soy isoflavones consumption and risk of breast cancer incidence or recurrence. Soy isoflavones consumption was inversely associated with risk of breast cancer incidence. However, the protective effect of soy was only observed among studies conducted in Asian populations but not in Western populations. Soy isoflavones intake was also inversely associated with risk of breast cancer recurrence. Stratified analyses suggested that menopausal status may be an important effect modifier in these associations. They failed to identify a dose-response relationship between total isoflavones intake and risk of breast cancer incidence. This study suggests soy isoflavones intake is associated with a significantly reduced risk of breast cancer incidence in Asian populations, but not in Western populations.
In our study, we have however observed that soybean extract significantly activates ADA enzyme in cancerous and noncancerous colon tissues. As far as we know, these results are first ones showing activating effects of soybean extract on ADA enzyme. For the time being, what is the importance of this finding is not clear for us and needs further studies.
Studies in patients with breast, colorectal, or prostate cancer show that the influence of dietary factors on survival remains to be determined. Adiposity and a lack of physical activity, however, appear to influence cancer outcome negatively.
| Conclusion|| |
Rosemary leaf and U. diocia extracts inhibit ADA enzyme in cancerous gastric tissues significantly but does not affect the enzyme in colon tissue. It seems quite possible that accumulated adenosine due to the inhibition of ADA enzyme might play an important function in the anticancer properties of rosemary and U. diocia leaves, possibly through inhibition of ribonucleotide reductase and depletion of nucleotide pool for new DNA synthesis. However, soybean extract activates ADA enzyme in colon tissues, the significance of which is not known by us at the moment. Therefore, further researches including cell culture and animal studies are needed to obtain more information on the subject.
Financial support and sponsorship
Faculty of Medicine, Ankara University.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Abdulla M, Gruber P. Role of diet modification in cancer prevention. Biofactors 2000;12:45-51.
World Cancer Research Fund/American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective. Washington DC: AICR, 2007. p. 353.
Wilson DK, Rudolph FB, Quiocho FA. Atomic structure of adenosine deaminase complexed with a transition-state analog: Understanding catalysis and immunodeficiency mutations. Science 1991;252:1278-84.
Cristalli G, Costanzi S, Lambertucci C, Lupidi G, Vittori S, Volpini R, et al.
Adenosine deaminase: Functional implications and different classes of inhibitors. Med Res Rev 2001;21:105-28.
Aghaei M, Karami-Tehrani F, Salami S, Atri M. Adenosine deaminase activity in the serum and malignant tumors of breast cancer: The assessment of isoenzyme ADA1 and ADA2 activities. Clin Biochem 2005;38:887-91.
Glazer RI. Adenosine deaminase inhibitors: Their role in chemotherapy and immunosuppression. Cancer Chemother Pharmacol 1980;4:227-35.
Brown JB, Lee G, Grimm GR, Barrett TA. Therapeutic benefit of pentostatin in severe IL-10-/- colitis. Inflamm Bowel Dis 2008;14:880-7.
Cuvelier M-E, Richard H, Berset C. Antioxidative activity and phenolic composition of pilot-plant and commercial extracts of sage and rosemary. Journal of the American Oil Chemists' Society. 1996;73(5):645-52.
Nabekura T, Yamaki T, Hiroi T, Ueno K, Kitagawa S. Inhibition of anticancer drug efflux transporter P-glycoprotein by rosemary phytochemicals. Pharmacol Res 2010;61:259-63.
al-Sereiti MR, Abu-Amer KM, Sen P. Pharmacology of rosemary (Rosmarinus officinalis
Linn.) and its therapeutic potentials. Indian J Exp Biol 1999;37:124-30.
Cheung S, Tai J. Anti-proliferative and antioxidant properties of rosemary Rosmarinusofficinalis
. Oncol Rep 2007;17:1525-31.
Yesil-Celiktas O, Sevimli C, Bedir E, Vardar-Sukan F. Inhibitory effects of rosemary extracts, carnosic acid and rosmarinic acid on the growth of various human cancer cell lines. Plant Foods Hum Nutr 2010;65:158-63.
Teucher T, Obertreis B, Ruttkowski T, Schmitz H. Cytokine secretion in whole blood of healthy subjects following oral administration of Urtica dioica
L. plant extract. Arzneimittelforschung 1996;46:906-10.
Obertreis B, Ruttkowski T, Teucher T, Behnke B, Schmitz H. Ex-vivo in vitro
inhibition of lipopolysaccharide stimulated tumor necrosis factor-alpha and interleukin-1 beta secretion in human whole blood by extractum Urticae dioicae
foliorum. Arzneimittelforschung 1996;46:389-94.
Riehemann K, Behnke B, Schulze-Osthoff K. Plant extracts from stinging nettle (Urtica dioica
), an antirheumatic remedy, inhibit the proinflammatory transcription factor NF-kappaB. FEBS Lett 1999;442:89-94.
Safarinejad MR. Urtica dioica
for treatment of benign prostatic hyperplasia: A prospective, randomized, double-blind, placebo-controlled, crossover study. J Herb Pharmacother 2005;5:1-11.
Lopatkin N, Sivkov A, Walther C, Schläfke S, Medvedev A, Avdeichuk J, et al.
Long-term efficacy and safety of a combination of sabal and Urtica
extract for lower urinary tract symptoms – A placebo-controlled, double-blind, multicenter trial. World J Urol 2005;23:139-46.
Durak I, Biri H, Devrim E, Sözen S, Avci A. Aqueous extract of Urtica dioica
makes significant inhibition on adenosine deaminase activity in prostate tissue from patients with prostate cancer. Cancer Biol Ther 2004;3:855-7.
Kennedy AR. The evidence for soybean products as cancer preventive agents. J Nutr 1995;125 3 Suppl: 733S-43S.
Durak İ, Biri H, Ergüder İ, B Devrim, E, Şenocak, Ç, Avcı, A. Effects of garlic and black grape extracts on the activity of adenosine deaminase from cancerous and noncancerous human urinary bladder tissues. Med Chem Res 2007;16:259-65.
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951;193:265-75.
Guisti G. Enzyme Activities. Methods of Enzymatic Analysis. Weinheim Bergest: Verlag Chemia; 1974. p. 1087-91.
Chang CJ, Ashendel CL, Geahlen RL, McLaughlin JL, Waters DJ. Oncogene signal transduction inhibitors from medicinal plants. In Vivo
(Athens, Greece) 1996;10:185-90.
Desai AG, Qazi GN, Ganju RK, El-Tamer M, Singh J, Saxena AK, et al.
Medicinal plants and cancer chemoprevention. Curr Drug Metab 2008;9:581-91.
Lee HZ, Hsu SL, Liu MC, Wu CH. Effects and mechanisms of aloe-emodin on cell death in human lung squamous cell carcinoma. Eur J Pharmacol 2001;431:287-95.
González-Vallinas M, Molina S, Vicente G, Sánchez-Martínez R, Vargas T, García-Risco MR, et al.
Modulation of estrogen and epidermal growth factor receptors by rosemary extract in breast cancer cells. Electrophoresis 2014;35:1719-27.
Petiwala SM, Berhe S, Li G, Puthenveetil AG, Rahman O, Nonn L, et al.
Rosemary (Rosmarinus officinalis
) extract modulates CHOP/GADD153 to promote androgen receptor degradation and decreases xenograft tumor growth. PLoS One 2014;9:e89772.
Park KW, Kundu J, Chae IG, Kim DH, Yu MH, Kundu JK, et al.
Carnosol induces apoptosis through generation of ROS and inactivation of STAT3 signaling in human colon cancer HCT116 cells. Int J Oncol 2014;44:1309-15.
Fattahi S, Ardekani AM, Zabihi E, Abedian Z, Mostafazadeh A, Pourbagher R, et al.
Antioxidant and apoptotic effects of an aqueous extract of Urtica dioica
on the MCF-7 human breast cancer cell line. Asian Pac J Cancer Prev 2013;14:5317-23.
Özkol H, Musa D, Tuluce Y, Koyuncu I. Ameliorative influence of Urtica dioica
L against cisplatin-induced toxicity in mice bearing Ehrlich ascites carcinoma. Drug Chem Toxicol 2012;35:251-7.
Trock BJ, Hilakivi-Clarke L, Clarke R. Meta-analysis of soy intake and breast cancer risk. J Natl Cancer Inst 2006;98:459-71.
Douglas CC, Johnson SA, Arjmandi BH. Soy and its isoflavones: The truth behind the science in breast cancer. Anticancer Agents Med Chem 2013;13:1178-87.
Dong JY, Qin LQ. Soy isoflavones consumption and risk of breast cancer incidence or recurrence: A meta-analysis of prospective studies. Breast Cancer Res Treat 2011;125:315-23.
Kampman E, Vrieling A, van Duijnhoven FJ, Winkels RM. Impact of diet, body mass index, and physical activity on cancer survival. Curr Nutr Rep 2012;1:30-6. eCollection 2012.