Bull. Egypt. Soc. Physiol. Sci. 28 (2) 2008 Heibashy et al.

Protective and Therapeutic Effect of (Camellia sinesis) against Rat Prostate Cancer

Mohamed, I.A. Heibashy; Amal, M. El-Nahla* and Sherif, Y. A. Saleh** Biological Application Department, Nuclear Research Center, Atomic Energy Authority, Egypt Physiology* and Biochemistry** Departments, Faculty of Veterinary Medicine, Suez Canal University

ABSTRACT

This investigation was conducted to evaluate the protective and therapeutic effect of green tea to ameliorate the deleterious effects of prostate cancer in rats. The obtained data revealed a significant elevation in tumor markers (PSA, TAP and PAP levels) after induction of cancer prostate in rats in comparison with the normal control one. Also, there was a significant decrease in total , free testosterone and DHEA-S concentrations, but the serum MDA level was increased significantly in rats with cancer prostate as compared with the corresponding levels in control rats. On the other hand, administration of green tea before or/and after induction of prostate cancer in rats led to a considerable improvement in the previous parameters but, their values did not revert to normal level. Any how, the results of the present investigation showed that the green tea when taken before and after induction of cancer prostate gave the prophylactic and therapeutic effects. The underlying mechanisms through which green tea counteracted cancer prostate were discussed. Key words: Green tea, Prostate cancer, Tumor markers, Rats.

INTRODUCTION Chemoprevention involving the use of natural agents to prevent or Prostate cancer (PCa) is one of reverse the process of carcinogenesis the biggest killers of men and is often could be an effective approach to (4) referred to as the hidden cancer reduce the progression of PCa . because it can develop without any Development of effective obvious symptoms. It has become the chemopreventive and agents against second leading cause of related PCa in human, however, requires death(1,2). It is a malignant tumor conclusive evidence of their efficacy which was considered a major cause in animal models that closely emulate of morbidity and mortality in men(3). human disease and possess surrogate It is therefore necessary to forward endpoint biomarkers for rapid efforts to diagnose and manage that evaluation of chemopreventive and/or (5) disease early through developing therapeutic agents . novel approaches for its diagnosis, Tea polyphenols have been prevention and treatment. proposed as potential

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Bull. Egypt. Soc. Physiol. Sci. 28 (2) 2008 Heibashy et al. chemopreventive agents(1,6,7). Both animals were fed to appetite on a green and black tea and their standard laboratory animal diet constituents have been extensively according to the National Research studied both in vitro and in animal Council (NRC)(12). Deionized water models of carcinogenesis(7,8). Green was available all time. tea is derived from the plant Camellia Rats were divided randomly into sinensis, which is widely consumed five equal groups (ten for each). Rats allover the world(5). It is chemically of the first group (negative control) characterized by the presence of large were injected subcutaneously with amount of polyphenolic compounds 500µl of physiological saline (0.9% known as including Na Cl) daily for 8 weeks. Members of epicatechin gallate (ECG), epicatechin the second group (postive control) (EC), epigallocatechin 3-gallate received orally 50 mg cyproterone (EGCG), and epigallocatechin acetate (Sigma Chem. Co., St. Louis, (EGC)(9). Mo, USA)/kg body weight daily for The role of tea in cancer 21 consecutive days. Cyproterone prevention is supported by results acetate inhibits androgen secretion from a large number of studies in from the testis, thereby causing animal models carried out over more atrophy of prostatic epithelial cells. than a decade(9,10). Using the Starting on the day after the last transgenic adenocarcinoma mouse injection of , rats prostate model of prostate received s.c. injections of 100 mg carcinogenesis, it was demonstrated (Sigma Chem. that oral consumption of 0.1% of Co., St. Louis, Mo, USA)/kg body green tea polyphenols decreased weight daily for another 21 days. That tumor incidence by 65%(1,6,11). sequence of antiandrogen treatment Based on the standing of animal followed by androgen treatment models of carcinogenesis and the synchronizes and stimulates cell bioavailabilty of the tea polyphenol, proliferation in the prostate and the present article was planned to thereby maximizes neoplastic explain the potential relevance of development in response to a single these models to cancer protection in dose of chemical carcinogen(13). rats. Twenty four hours after the last dose of testosterone propionate, rats MATERIALS & METHODS received 50 mg N-methyl-N- nitrosurea (MNU) (Sigma Chem. Co., Fifty adult male albino rats St. Louis, Mo, USA) dissolved in (Rattus rattus) at 8 weeks of age were sterile saline (pH 5.0)/kg body weight (14) obtained from the Animal House of as a single i.v injection . After Nuclear Research Center, Inshas, induction of cancer prostate, blood Egypt. They were maintained in samples were withdrawn from tail plastic cages at 23°C, housed in a well vein of rats and PSA was assayed in ventilated animal house and kept order to determine the incidence of under the same managerial and prostate cancer. Rats of the third environmental conditions. The group received green tea as a drinking

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Bull. Egypt. Soc. Physiol. Sci. 28 (2) 2008 Heibashy et al. water for 8 weeks before induction of using commercial kit (Cayman Chem. prostate cancer by the same previous Co., USA). method. Green tea solution was All data were statistically prepared freshly every day as follow, analyzed using one way analysis of 5 g of commercial green tea (Arab Co. variance (ANOVA) followed by for Pharm. and Medicinal Plants Duncan’s multiple range test (MEPACO), Inshas, Egypt) were according to Snedecor and boiled in 100 ml boiling water for five Cochran(23) using a computer program minutes, allowed to stand at room (Costate). temperature an hour before use. In the fourth group prostate cancer was RESULTS & DISCUSSION induced firstly by previous method then green tea was administered in the The incidence of prostate tumors same dose for 8 weeks. The last group was reported to increase exponentially received green tea four weeks before with age including benign prostatic and four weeks after prostate cancer hyperplasia, which tends to occur in induction. At the end of the the transitional zone and experimental period (8 weeks), rats adenocarcinoma, which arises mainly were scarified by decapitation and the in the peripheral zone(23). Cancer is a blood samples were collected from fermentative disease caused by a each group of the rats in clean dry test compromised robust oxidative tubes and sera were separated and mechanism, giving uncontrolled stored frozen under-20˚C until cellular growth(25,26). analysis. In the current study, it is obvious Serum total acid phosphatase that rats treated with N-methyl-N- (TAP) activity was determined nitrosurea in the presence of kinetically using commercial kits (Bio cyproterone acetate an inhibitor of Merieux Co., Mary-L-Eolilie, androgen secretion and testosterone Chorbonnieres, Les- Brain, propionate as stimulator of cell (15) France) . Prostatic acid phosphatse proliferation in the prostate, showed a (PAP) activity was assessed by significant (P< 0.05) elevation in the ELISA using commercial kits (IBL- activity of TAP and PAP beside the Gesellschapt, Hamburg, Co., levels of PSA and MDA in serum as (16) (17) Germany) . Testosterone , free compared to negative control one (18) testosterone and (Table 1). PSA is a specific tumor dehydroepiandrosteron sulfate marker for prostate carcinoma, thus (19) (DHEA-S) , prostatic specific these results are anticipated and (20,21) antigen (PSA) levels were promoted to the occurrence of prostate estimated by radioimmunoassay cancer . Ruddon(27) reported that the (RIA) using solid phase system. The level of PSA in serum is liable to kits were purchased from Diagnostic detection if there is a tumor in the Product Corporation (DPC) USA. prostate. Many authors attributed the (22) Serum malondialdehyde (MDA) elevation in the tumor marker level was determined by ELISA technique due to the elevation of free radical production, lipid peroxidation, DNA

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Bull. Egypt. Soc. Physiol. Sci. 28 (2) 2008 Heibashy et al. damage, mutation in DNA, transformation and depressing the abnormalities of gene sequence and mitogenic effects of carcinogens(35), disturbance in the cytochrome also they were shown to inhibit P450(1,2,28). TAP and PAP leaks into prostate cancer induction in rats(36). In the serum from the damaged prostate the present work, rats with prostate gland and elevation in its activity cancer exhibited lower level of suggest the presence of metastatic DHEA-S corresponding to higher prostatic carcinoma or at least levels of PSA, PAP, TAP and MDA prostatic damage as the level of (Table. 1). These results may explain increased activity depends upon the the oxidative stress that, can play a size of lesion(29). These results are in major role in induction of prostate harmony with those obtained by cancer. Moreover, DHEA-S is able to Heibashy and Badie-Bakshwan(30). inhibit certain enzymes involved in It has been postulated that the formation of free radicals by carcinogen may increase tissue increment the levels of reduced oxidative stress with accelerated lipid glutathione(3) and enhancement of the peroxidation which subsequently activity of superoxide dismutase, induces DNA damage(29,31) or glutathione peroxidase and synthesis of prostaglandins and catalase(34). Also, DHEA-S reduces leukotrienes that stimulate prostate the lipid peroxidation level by cancer cell proliferation(32), that could preserving the cellular reduced explain the elevated MDA level in glutathione(3). Another study found prostate cancer group of the current that, DHEA may also be effective in study (Table. 1). As, lipolysis of enhancing the function of the immune stored fat releases glycerol and fatty system, which may play a role in acid oxidation of which are increased cancer defense(37). in cancer patients(33). Also, Ruddon(27) In relation to reproductive reported that tumor cells are found to performance, the obtained data have abnormal activities of showed a significant (P<0.05) antioxidant enzymes and this explain reduction in total testosterone and free the elevated level of MDA. As well, testosterone in rats with cancer Heibashy(28) found that tumor cells are prostate group (positive control) when low in activities of SOD and catalase. compared to negative control one. (3 beta- These results may be attributed to hydroxy-5-androstene-17 one; DHEA) either the conversion of testosterone and its conjugates are abundant to (DHT) which is circulating that originate an important factor in the largely from the adrenal cortex and to development of prostate cancer as it a lesser extent by the testes and stimulates the growth and ovaries. It is a precursor in the body proliferation of cancerous prostate for synthesis of testosterone, cells and therefore is the primary fuel and a number of other for the growth of prostate cancer(14,38), hormones(34). DHEA and DHEA-S or may be due to the negative have shown protection against tumors feedback caused by injected by blocking carcinogen-induced cell testosterone.

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The obtained data in (Table. 1) to prevent the spread of prostate showed a significant improvement in cancer by targeting molecular prostate tumor markers (PSA, TAP pathways that shut down the and PAP) levels as well as total proliferation and spread of tumor testosterone, free testosterone, DHEA- cells, as well as inhibiting the growth S and MDA concentrations, when of tumor nurturing blood vessels(40). green tea were either given before These results may be due the role of cancer induction, after cancer green tea polyphenols (GTP) in induction and/or when taken before modulating the insulin-like growth and after cancer induction when factor-1 (IGF-1), by reducing its compared to rats with cancer prostate levels or by increasing the levels of but all of these parameters did not one of the binding proteins for IGF-1. return to their normal levels. This explanation bears a significance Green tea is particularly rich in in light of studies that indicated an polyphenols, including catechins, increase in the levels of IGF-1 which theaflavins and , which associated with increased risk of are thought to contribute to the health several cancers, such as prostate, benefits of tea. These polyphenols act breast, lung and colon. Moreover, as antioxidants in vitro by scavenging GTP also caused a reduction in the reactive oxygen and nitrogen species expression of proteins known to be and chelate redox-active transition associated with the metastatic spread metal ions. They may also act of cancer cells, as it inhibited the level indirectly as antioxidants through I) of urokinase plasminogen activator as inhibition of the redox-sensitive well as matrix metalloproteinases 2 transcription factors, nuclear factor-β and 9, cellular molecules linked to the and activator protein-1; II) inhibition metastasis. GTP contributed to of "pro-oxidant" enzymes, such as minimize tumor development by inducible nitric oxide synthase, governing the amount of vascular lipoxygenases, cyclooxygenases and endothelial growth factor (VEGF) in xanthine oxidase; and III) induction the serum of the prostate cancer of phase II and antioxidant enzymes, mouse model. The reduction of VEGF such as glutathione S-transferases and may result from GTP-induced superoxide dismutases(39). suppression of IGF-1 levels. VEGF The results of the present study acts to recruit and develop new blood showed that administration of green vessels that carry nutrients to tea may have chemopreventive effect developing tumors. By reducing the on prostate cancer. The most amount of VEGF, GTP works to interesting point obsereved in the minimize nutrients flowing and current investigation is the supporting tumor growth(40). improvement in all determined Furthermore, the protective effect parameters as a result of green tea of GTP may be due to its blockage administration. These results are in effect on the production of oxygen parallel with the results of previous free radicals derived during study which mentioned that, the carcinogenesis, enhancement of the polyphenols present in green tea help levels of antioxidants defense

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Bull. Egypt. Soc. Physiol. Sci. 28 (2) 2008 Heibashy et al. enzymes system by increasing the mechanisms in cells and contribute to activities of some enzymes which cancer prevention at the early stage of convert the oxidized molecules to carcinogenesis(11,49,50,51). their reduced form(39). In vivo, some present in tea can also studies have shown that, catechins are exert a protective effect on cancer hypothesized to help protection promotion. They maintain normal against ROS by increasing total growth by blocking the activation of plasma antioxidant activity(41,42). So, an oncogene activator protein (AP), the decrement in the level of MDA maintain cell-cell communication and shown in prostate cancer rats after apoptosis of malfunctioning cells(48,52). treated with green tea (Table 1), may Prevention of cancer may be also be attributed to catechins present in studied through anti-mutagenic the tea which have a direct or indirect protective properties of green tea. antioxidant effect(41,43). Also, GTP EGCG has reactive oxygen species exhibit modifying influence on the (ROS) scavenger property and the protein phosphorylation process(44) most potent antimutagenic agent and following catalytic activities of protecting DNA scissions and many enzymes especially the oxidant nonenzymatic interception of ones(45). superoxide anions. ECG emerges as The tea polyphenols consist of the most potent enzymatic scavenger strong metal ion chelators such as iron amongst the green tea and copper which are required for polyphenol(11,53,54). generation of reacrive oxygen radicals Although, numerous health by means of Benton and Haber Weiss benfites have been proposed for the reactions(46). Moreover, oral feeding consumption of tea, the effectiveness of green tea leaves to rats resulted in of tea as a cancer preventive agent in enhanced SOD activity in serum and human remains unclear because catalase activity in liver and an animal models of carcinogensis may increased concentration of glutathione be different from the human situation. in the liver(47). Thus, antioxidants Judging from the inhibitory activities present in green tea could contribute of tea polyphenols observed in the to the preventive effect on cancer(48). present study in animal model, it is Interaction of tea with likely that there are multiple pro-carcinogens plays a prominent mechanisms by which tea constituents role of the beneficial effects of tea induce inhibitory effects against against cancer initiation. Masuda et prostate cancer either as prophylactic al.(49) examined the influence of and therapeutic agent. To this end EGCG and ECG on protein kinase information on the biotransformation, activator, EGCG blocks the bioavailability and tissue level of interaction between proteins and theaflavins, EGCG, ECG and other ligands while, both EGCG and ECG tea constituent should be a vital goal inhibit the gap functional intracellular for future mechanistic researches. communication caused by tumor Further studies are required to promoters. Thus, tea polyphenol can determine the best dosage and route interact with enzymatic defense by which tea constituents deliver to

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Bull. Egypt. Soc. Physiol. Sci. 28 (2) 2008 Heibashy et al. certain organ. More detailed researches will help to verify the molecular cellular mechanism studies effects of tea in humans by in animals and humans are needed comparison with studies in animals. because the results of the previous

Table (1): Chemo protective effects of green tea on prostate cancer in rats Treatment Group Group Group Group Group Groups I II III IV V Parameters PSA 0.152 ± 1.752 ± 1.416 ± 1.138 ± 0.639 (ng/ml) a b c d e 0.04 0.23 0.19 0.24 ±0.18

TAP activity 1.974 ± 3.056 ± 2.754 ± 2.458 ± 2.249 (U/L) a b c d e 0.09 0.17 0.19 0.19 ±0.15 PAP activity 0.642 ± 1.787 1.493 ± 1.107 ± 0.899 (U/L) a b c d e 0.05 ± 0.023 0.22 0.16 ±0.09 Testosterone 1.827 ± 0.659 ± 0.881 ± 1.128 ± 1.367 ± (ng/ml) a b c d e 0.08 0.07 0.11 0.08 0.09 Free 0.693 ± 0.181 ± 0.237 ± 0.416 ± 0.589 Testosterone a b c d e 0.01 0.02 0.03 0.05 ±0.02 (Pg/ml) DHEA-S 260.17 127.89 151.46 192.36 227.13 (µg/dl) a b c d e ±1.94 ±1.46 ±1.73 ±1.62 ±1.76 MDA 0.132 ± 0.319 ± 0.271 ± 0.218 ± 0.194 (Um/dl) a b c d e 0.02 0.09 0.09 0.08 ±0.06 a,b,c,d,e means in the same row with no common superscript are significantly different at (P<0.05).

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الدور الوقائى والعالجى للشاى االخضر ضد مرض سرطان البروستاتا فى الجرذان

محمد اسالم حبيشى - امال النحله*- شريف صالح** قسم التطبيقات البيولوجية - مركز البحوث النووية- ھيئة الطاقة الذرية - مصر قسمي *الفسيولوجيا ** الكيمياء الحيوية – كلية الطب البيطرى - جامعة قناة السويس

اجريت ھذه الدراسة إللقاء الضوء على الدور الوقائى والعالجى للفينوالت المتعدده بالشاى االخضر ضد مرض سرطان البروستاتا فى الجرذان. أظھرت النتائج المتحصل عليھا إن سرطان البروستاتا يتسبب في حدوث زيادة ذات قيمه احصائيه في مستويات كل من الفوسفاتاز الحمضي الكلي ، الفوسفاتاز الحمضي البروستاتي، انتيجين البروستاتا النوعي وثنائي الدھيدالمالون بينما يحدث انخفاضا ذات قيمه احصائيه لمستويات كل من التستوستيرون الكلي والتستوستيرون الحر و الدھيا-س وذلك بالمقارنة بنتائج المجموعة الضابطة. وأوضحت أيضا نتائج الدراسة قدرة الشاى االخضر في تحسين قيم جميع القياسات البيوكيميائية المتحصل عليھا بالرغم من إنھا لم تصل إلى نفس مستويات مثيالتھا في جرذان المجموعة الضابطة. و لوحظ ان التاثير العالجى للشاى االخضر عندما تم اعطاءه قبل وبعد احداث السرطان افضل من التاثير الوقائى وعلى أي حال فنتائج ھذا البحث أوضحت أن الشاى االخضر بما يحتويه من مضادات األكسدة يمتلك فوائد كامنة تسھم في تقليل خطر بعض قياسات الدم المصاحبة لمرض سرطان البروستاتا في الجرذان. وقد نوقشت النتائج وتم إلقاء الضوء على أسبابھا المحتملة و ال بد من استمرار عمل الدراسات لمعرفه افضل جرعه و الوقت المناسب للوصول الي افضل النتائج.

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