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Evaluation of anticancer activity of sida cordifolia L. against Aflatoxin B1 induced hepatocellular carcinoma
Abstract
Hepatocellular carcinoma is the fourth common cancer globally occurring by many factors such as mycotoxins, chemicals, genetical, viral factors etc. AFB1 is a potent mycotoxin classified in group I carcinogens by IARC found in contaminated food stuffs. The present study was aimed at evaluating the ethanolic extract of whole plant of sida cordifolia L against AFB1 induced HCC. Hepatocellular carcinoma (hepatoma) was induced in wistar rats by intra peritoneal administration of AFB1 (250μg/kg/dose) for 7 days. The effect of concurrent administration of ethanolic extract of sida cordifolia L. at doses of 250mg/kg and 500mg/kg were given orally was observed by estimating the serum levels of SGOT, SGPT, ALP, LDH, GGT and TP. DNA, RNA and TP were estimated from liver. Antioxidant and pro-oxidant studies were also measured. The results showed a significant decrease in serum SGOT, SGPT, ALP, LDH and GGT and increase in total proteins of groups treated with EESC. Elevated DNA and RNA found decreased with a prominent increase in total proteins in liver of EESC groups. Significant increase in antioxidants and a decrease in lipid peroxidation were also observed. The extracts at both doses (250mg/kg and 500 mg/kg b.w) shows a significant (p<0.001) reversal of altered biochemical, molecular and antioxidant parameters showing that sida cordifolia L. possess antioxidant and antitumor activity.
... In many parts of the African countries, it is used against several health problems, especially for treating respiratory diseases (Galal et al. 2015;Dinda et al. 2015). The plant possesses antiinflammatory (Kanth and Diwan 1999), hypoglycemic, analgesic (Dinda et al. 2015;Siddiqui et al. 2016), anti-protozoan (Khare 2004), antiulcer (Philip et al. 2008;Akilandeswari et al. 2013), antimicrobial (Masih et al. 2014;Halilu et al. 2016), antihelminthic (Pawa et al. 2011;Nathaniel et al. 2014), and anticancer (Dassonneville et al. 2000;Mallikarjuna et al. 2013;Srinithya et al. 2016) properties. The presence of the constituent, ephedrine, imparts psychostimulative properties to the plant and affects the heart and central nervous system. ...
... Also, they observed that cells treated with S. cordifolia extract have arrested the cells by apoptosis. Likewise, the ethanolic extract (70%) of S. cordifolia at 250 and 500 mg/kg bw dose had significantly restored necrotic cells, by exhibiting antioxidant and anticancer activities (Mallikarjuna et al. 2013). In another study, it has been reported that cryptolepine, an alkaloid compound of S. cordifolia, hinders the growth of mutated osteosarcoma (MG63) cells at ≥0.5 μM within 72 h of incubation. ...
... In many parts of the African countries, it is used against several health problems, especially for treating respiratory diseases (Galal et al. 2015;Dinda et al. 2015). The plant possesses antiinflammatory (Kanth and Diwan 1999), hypoglycemic, analgesic (Dinda et al. 2015;Siddiqui et al. 2016), anti-protozoan (Khare 2004), antiulcer (Philip et al. 2008;Akilandeswari et al. 2013), antimicrobial (Masih et al. 2014;Halilu et al. 2016), antihelminthic (Pawa et al. 2011;Nathaniel et al. 2014), and anticancer (Dassonneville et al. 2000;Mallikarjuna et al. 2013;Srinithya et al. 2016) properties. The presence of the constituent, ephedrine, imparts psychostimulative properties to the plant and affects the heart and central nervous system. ...
... Also, they observed that cells treated with S. cordifolia extract have arrested the cells by apoptosis. Likewise, the ethanolic extract (70%) of S. cordifolia at 250 and 500 mg/kg bw dose had significantly restored necrotic cells, by exhibiting antioxidant and anticancer activities (Mallikarjuna et al. 2013). In another study, it has been reported that cryptolepine, an alkaloid compound of S. cordifolia, hinders the growth of mutated osteosarcoma (MG63) cells at ≥0.5 μM within 72 h of incubation. ...
Sida cordifolia Linn. belonging to the family, Malvaceae has been widely employed in traditional medications in many parts of the world including India, Brazil, and other Asian and African countries. The plant is extensively used in the Ayurvedic medicine preparation. There are more than 200 plant species within the genus Sida, which are distributed predominantly in the tropical regions. The correct taxonomic identification is a major concern due to the fact that S. cordifolia looks morphologically similar with its related species. It possesses activity against various human ailments, including cancer, asthma, cough, diarrhea, malaria, gonorrhea, tuberculosis, obesity, ulcer, Parkinson’s disease, urinary infections, and many others. The medical importance of this plant is mainly correlated to the occurrence of diverse biologically active phytochemical compounds such as alkaloids, flavonoids, and steroids. The major compounds include β-phenylamines, 2-carboxylated tryptamines, quinazoline, quinoline, indole, ephedrine, vasicinone, 5-3-isoprenyl flavone, 5,7-dihydroxy-3-isoprenyl flavone, and 6-(isoprenyl)- 3-methoxy- 8-C-β-D-glucosyl-kaempferol 3-O-β-D-glucosyl[1–4]-α-D-glucoside. The literature survey reveals that most of the pharmacological investigations on S. cordifolia are limited to crude plant extracts and few isolated pure compounds. Therefore, there is a need to evaluate many other unexplored bioactive phytoconstituents with evidences so as to justify the traditional usages of S. cordifolia. Furthermore, detailed studies on the action of mechanisms of these isolated compounds supported by clinical research are necessary for validating their application in contemporary medicines. The aim of the present chapter is to provide a detailed information on the ethnobotanical, phytochemical, and pharmacological aspects of S. cordifolia.
... Antitumor activity of S. cordifolia was tested on hepatocellular carcinoma and HeLa cell lines and extract was found to be effective [14][15]. Taka-Aki Matsui et. ...
Background: Sida cordifolia of family Malvaceae is traditionally, used in treating the various ailments of respiratory and urinary system. It possesses astringent and emollient properties. Aim and objectives: Present study was aimed to assess in vitro antioxidant and antiproliferative potential of aerial parts of Sida cordifolia. Material and Methods: Serial extraction of aerial parts of Sida cordifolia was done by using Soxhlet apparatus. In vitro antioxidant potential was evaluated by DPPH, H 2 O 2 and NO radical scavenging ability. Antiproliferative activity was assessed by MTT assay on human breast cancer (MCF7), ovarian cancer (PA1), colon cancer (HT29), melanoma (A375), liver cancer (HepG2) and normal mouse embryonic fibroblast (NIH-3T3) cell lines by treating them with increasing concentration of the extract for 24 hours. Results: Ethanolic extract of S. cordifolia showed good DPPH, H 2 O 2 and NO radical scavenging activity (IC50 value 20.93µg/mL, 85.14μg/mL and 320.99µg/mL respectively). Extract also showed dose dependent cytotoxicity against all cancer cell lines used in the study. Among cancer cell lines, A375 and HT29 were more sensitive (IC50 16.51 and 49.86μg/mL respectively) than the other cancer cell lines. Conclusion: Further work to study mechanism of its action on these cell lines can be helpful in drug discovery program.
... This plant is shown for its antioxidant activity [143], anti-inlammatory activity [144], antiulcer activity [145], antidiabetic activity [146], nephroprotective activity [147], cytotoxicity [148], anti-hypercholestrolemic activity [149], hepatoprotectivity [150], cardiovascular activity [151], and anticancer activity [152]. ...
https://www.intechopen.com/books/drug-discovery-concepts-to-market/medicinal-plants-of-west-godavari
... These researchers report that cells treated with the extract of this plant arrest the cell activity via apoptosis. Its 70% ethanolic extract at a dose of 250 and 500 mg/kg bw has significantly restored necrotic cells, which can be attributed to its antioxidant and anticancer activities (Ahmed et al., 2018;Mallikarjuna, Reddy, & Prabhakaran, 2013). ...
Cancer is second leading disease after heart related disease which causes death and is marked by uncontrolled growth and proliferation of cells. There are round about 100 types of cancers, each classified by type of cells they initially affect. Vast number of the plants from valley are claimed to possess the anticancer, anti-inflammatory and analgesic properties and are used extensively by the people not only for inflammation but as analgesic, antispasmodics and antimicrobials etc. Medicinal plants are playing a major role to cure many diseases related with the inflammation. As we know prolonged inflammation can also be a cause for development of cancer. When vascular tissues show systematic response it is known as inflammation. Therefore, the researchers today are emphasizing on various plant constituents their evaluation and characterisation that have a role to play against many diseases. In this current review, an endeavour has been created to give a list of some important medicinal plants that are found in Kashmir valley having anticancer as well as anti-inflammatory properties.
... Earlier reports [12] stated that Mallikarjuna G et al., 2013 evaluated the ethanolic extract of Sida cordifolia against AFB1 (Aflotoxin B1) induced HCC (hepatocellular carcinoma) in winstar rats (250μg/kg/dose). The results showed a significant restoration of abnormal serum and tissues indicating the protective effect [13]. ...
Objective: The present study aims to evaluate the anti-tumor potential of EEED (ethanolic extract of Ervatamia divaricata. L. Burkill) on EAC (Ehrlich ascites carcinoma). Methods: The ethanolic extract of Ervatamia divaricata. L. Burkill was subjected to preliminary phytochemical screening and the antitumor effect of EEED was assessed by employing in-vitro methods. Compounds present in the ethanol extract of the plant were identified using GC-MS (Gas chromatography-mass spectrometry) and attempts were made to understand the mechanism of action using insilico methods. Results: The results of the in vitro cytotoxicity assay and MTT assay revealed the anticancer potential of the ethanol extract of Ervatamia divaricata. When different concentrations of EEED were assayed, the dead cells were found to increase with increase in concentration of the extract. This proved that there was considerable damage of the cell membrane that leads to the blocking of the cell signaling in cancer cells. Conclusion: The present study revealed that EEED possessed significant antitumor activity against EAC. © 2015, International Journal of Pharmacy and Pharmaceutical Science. All right resurved.
Search for new therapeutic agents and alternative strategies for chemoprevention of colorectal cancer is needed to reduce morbidity and mortality resulting from this disease. This study aimed to compare the effect of aqueous extract of Sida cordifolia L. and 5- fluorouracil (5-FU) on colon carcinogenesis induced by 1,2- dimethylhydrazine (1,2-DMH). The extract reduced the frequency of aberrant crypts to regarding the positive control, but there was no significant difference among the positive control animals, those who received the extract and those receiving standard anticancer drug. Thus, the aqueous extract of Sida cordifolia L. 800 mg/kg showed no statistical impact on carcinogenesis in animal models, but showed a significant anti-inflammatory effect on the colon mucosa.
The Himalayan region harbors a rich diversity of medicinal plants and fruits which are used as traditional medicines for a variety of diseases and complications. The Himalayas has rich biodiversity of plants and the majority of these plants have medicinal properties, especially anticancer potential, that have been used in traditional health care systems for thousands of years. These have been used since the ancient past in traditional health care systems and diverse cultures around the world still depend on medicinal plants for their primary health care. With the recent advancements and technological developments in plant sciences, the people of the Himalayan region have learned and practiced the medicinal use of plants for centuries. Through the ages, this ancient prized wisdom has been transmitted from generation to generation as part of oral traditions. So the current study throws light on medicinal plant diversity and the plant parts used, and an emphasis was laid preferably on the anticancer potential of different medicinal plants, fruits, and vegetables that are found in the Himalayan regions.
Cancer is a serious health problem and the second leading cause of death around the globe. Present review is an attempt to provide utmost information based on ethno-pharmacological and toxicological aspects of anti-cancer plants of the world. A total of 276 articles published in English journals and containing maximum ethnomedicinal information were reviewed using several data sources such as; Google scholar, Web of Science, Scopus, PubMed and floras of different countries. A total of 199 anti-cancer plants were recorded in present review and results indicated that traditional medicines are mostly being use in developing countries for cancer treatment. Traditionally and scientifically skin and breast cancer types gained more focus. Seventy plants were reportedly analyzed for in-vitro activities while 32 plants were having in-vivo reports. Twenty nine pure compounds (mostly phenolic) were reportedly isolated from anti-cancer plants and tested against different cancer cell lines. Inspite having better efficiency of ethnomedicines as compared to synthetic drugs, several plants have also shown toxic effects on living system. Therefore, we invite researchers attention to carry out detailed ethno-pharmacological and toxicological studies on un-explored anti-cancer plants in order to provide reliable knowledge to the patients and develop novel anti-cancer drugs.
Plants have been used since ancient times to heal and cure diseases and to improve health and well being. Sida cordifolia Linn belonging to family Malvaceae is widely distributed throughout the plains of India. The various parts of Sida cordifolia possess different biological perspectives such as antidiabetic, anti stress, anti-inflammatory, analgesic, hepatoprotective and anticancer activity. This plant has great potential for development of ayurvedic and modern medicines. The present study is focused on pharmacological review of Sida cordifolia L. © 2014, International Journal of Pharmacy and Pharmaceutical Sciences. All right reserved.
Hepatocellular carcinoma is one of the primary liver malignancies and is prevalent in developing countries. The present study was designed on evaluating the hydro-ethanolic extract of Chathurmuka Chooranam (CMC) herbal formulation against Aflatoxin-B1 (AFB1) induced hepatic carcinoma in Wistar strain. Hepatic carcinoma was induced in male Wistar rats by AFB1 (250 μg/kg/i.p) for 7 days. The administration of the polyherbal extract at a dose of 250 mg/kg and 500mg/kg were given orally for a period of 14 days. Estimation of enzymic antioxidants and non-enzymic antioxidants, Total proteins, DNA, RNA and LPO were measured. Elevated levels of DNA and RNA were observed in AFB1 induced rats when compared to the control rats. The administration of the polyherbal extract to the AFB1 treated group restored the normal levels of DNA, RNA and protein content. Lipid peroxidation was found to be decreased whereas increased levels of antioxidant enzymes were seen in polyherbal extract treated group when compared to the AFB1 group. From the present study, it might be concluded that the antioxidant potential of the polyherbal extract was responsible for its anti-hepatocarcinogenic potential.
Aflatoxin B1-induced liver lesion development is readily modified by dietary protein intake. Earlier work had shown that low-protein diets enhanced the acutely toxic lesion but depressed the carcinogenic lesion. This study examined the emergence of these lesions as a function of dietary protein intake, particularly with respect to whether the protein modification occurred during or after the aflatoxin B12 dosing period. High (20%) and low (5%) casein diets were fed to growing Fischer 344 rats during the dosing and postdosing periods of aflatoxin B2-induced hepatic preneoplastic lesion development. Focal areas of hepatocellular alteration were identified and quantitated by staining sections of liver for gamma-glutamyl transferase (GGT). Animals fed low casein diets during the dosing period displayed a characteristic spectrum of lesions including hepatomegaly, severe bile duct proliferation, cholangiofibrosis, and a tendency for developing large remodeling GGT-positive foci. These lesions were regarded as symptomatic of acute hepatoxicity. Animals fed high-protein diets during the dosing period had small, densely stained, GGT-positive foci, with only mild bile duct proliferation and no cholangiofibrosis, hepatomegaly, or large, remodeling GGT-positive foci. During the postdosing period, protein modulation markedly influenced the total number of foci. Animals fed high casein diets during this period exhibited an approximate 6-fold increase in the number of foci, regardless of the level of protein fed during the earlier dosing period. The marked increase in foci number (as well as area of liver occupied) in high casein diet animals during the postdosing period is regarded as an increased tendency for tumor development.
The health-related effects of interactions between reactive oxygen species (ROS) and dietary antioxidants and the consequences of dietary antioxidant supplementation on human health are by no means clear. Although ROS, normal byproducts of aerobic metabolism, are essential for various defense mechanisms in most cells, they can also cause oxidative damage to DNA, proteins, and lipids, resulting in enhanced disease risk. Dietary antioxidants (e.g., vitamin E, vitamin C, beta-carotene, and selenium), as well as endogenous antioxidant mechanisms, can help maintain an appropriate balance between the desirable and undesirable cellular effects of ROS. However, any health-related effects of interactions between dietary antioxidants and ROS likely depend on the health status of an individual and may also be influenced by genetic susceptibilities. Clinical studies of antioxidant supplementation and changes in either oxidative status, disease risk, or disease outcome have been carried out in healthy individuals, populations at risk for certain diseases, and patients undergoing disease therapy. The use of antioxidants during cancer therapy is currently a topic of heated debate because of an overall lack of clear research findings. Some data suggest antioxidants can ameliorate toxic side effects of therapy without affecting treatment efficacy, whereas other data suggest antioxidants interfere with radiotherapy or chemotherapy. Overall, examination of the evidence related to potential interactions between ROS and dietary antioxidants and effects on human health indicates that consuming dietary antioxidant supplements has pros and cons for any population and raises numerous questions, issues, and challenges that make this topic a fertile field for future research. Overall, current knowledge makes it premature to generalize and make specific recommendations about antioxidant usage for those at high risk for cancer or undergoing treatment.
Primary malignant neoplasms of the liver arise from hepatocytes, intrahepatic bile ducts, blood vessels and endothelial cells (Box 1). Hepatocellular carcinoma (HCC) is a malignant neoplasm of hepatocytes and constitutes more than 80% of primary malignant liver neoplasms. HCC is the preferred terminology and terms like "hepatoma" and "liver cancer" should be avoided because they are not precise. Hepatocellular carcinoma (HCC) is second only to carcinoma of the pancreas in being the most lethal form of human cancer1. Almost all patients die within 6-7 months after the diagnosis. This is especially true in areas of high endemicity. This dismal prognosis is due to lack of reliable biomarkers that permit early diagnosis, resistance of the tumour to chemotherapy and the underlying diffuse liver disease that limits the use of chemotherapeutic agents in medical management. Other than primary prevention, one hope of changing the prognosis is early diagnosis (See below). HCC is the fifth most common internal malignancy world wide and the commonest internal malignancy in men below the age of 45 years in Sub-Saharan Africa. There is significant geographical variation. The tumour is common in China, Southeast-Asia and Sub-Saharan Africa where the prevalence is estimated to be 100/100,000 population as compared to 3/100,000 in Europe and U.S.A.
Aim: The present study was aimed to investigate the cellular and molecular mechanisms of protective effects of allylmercaptocaptopril (AMC) against liver carcinoma induced by Aflatoxin B1, a potent inducer of liver cancer. Method: In this study we determined the protective effect of AMC on liver tissue, as well as on enzymatic liver functions by estimating glycolytic enzymes like hexokinase, phosphoisomerase and aldolase, gluconeogenic enzymes like glucose-6-phosphatase and fructose 1,6 biphosphatase. Determination of total protein, DNA and RNA content also made to elucidate its action. Result: Aflatoxin B1 treatment to rats resulted in significantly elevated levels of glycolytic enzymes like hexokinase, phosphoglucoisomerase and aldolase and along with significant decrease in serum total protein, gluconeogenic enzymes and DNA and RNA content when compared to the control rats. The administration of AMC to the hepatocellular carcinoma bearing rats resulted in restoration of most of enzymatic liver functions and also total protein content, DNA and RNA content. Conclusion: Allylmercaptocaptopril has an ability to modulate the function of glycolytic and gluconeogenic enzymes, DNA and RNA synthesis in hepatocellular carcinoma which proved its anticarcinogenic activity.
gamma-Glutamyl transpeptidase (gamma-GT) activity in various organs of mice during ontogenesis has been determined. The activity profile in foetus, neonates and the adult animal were compared to ascertain the functional significance of the enzyme. In addition, the effect of cortisol on gamma-GT activity in adult kidney is presented.
Isolated rat liver microsomes were subjected to enzymatic or non-enzymatic lipid peroxidation . NADPH-dependent cytochrome reductase activity was released from the microsomes into the media during peroxidation. This activity could be recovered from the media by DEAE-cellulose chromatography. The recovered enzyme retained high activity for the reduction of cytochrome and a lower level of activity for the reduction of cytochrome P-450. The active fractions were capable of enzymatically supporting the peroxidation of isolated mitochondria in the presence of organically complexed Fe+3 and NADPH, and in this respect the specific activity was found to be about ten times higher than in microsomes.
In rats carrying s.c. or i.p. neoplasms, there were striking (3- to 20-fold) rises in the gamma-glutamyl transpeptidase and alkaline phosphatase activity of several tissues. These included liver, lung, spleen, bone marrow, and circulating granulocytes but not lymphocytes. In response to mammary carcinoma 5A, for example, the gamma-glutamyl transpeptidase activity changed from 0.27 to 1.18 units/g lung and from 0.3 to 4.0 milliunits/million granulocytes; from 2.3 to 17 units and from 2.4 to 46 milliunits were the accompanying increases in alkaline phosphatase. These abnormalities in each host tissue were reversible in that 3 to 7 days after tumor resection the enzymes returned to control levels. Among the secondary factors which might have been responsible for the host tissue changes, it was possible to exclude stimulated adrenocortical secretion, tissue necrosis, and transplantation trauma. Comparisons of the effects of two mammary carcinomas, a fibrosarcoma, and two hepatomas on the gamma-glutamyl transpeptidase and alkaline phosphatase of various "noninvolved" tissues indicate that the faster the growth rate of the tumors, the more striking is this host syndrome.
Sialyltransferase and 5'-nucleotidase were measured in the sera of 135 women with breast cancer: 53 undergoing mastectomy for primary cancer and 83 receiving different modalities of palliative therapy for metastatic disease. The objective of this study was to determine whether these enzyme levels were associated with the extent of the disease and whether changes in these enzyme levels could be correlated with success or failure of treatment. Mastectomy caused a rapid fall of elevated enzyme levels to within the normal range in all patients with stage I breast cancer but not in those with stage II or III disease. In women with metastatic disease, elevated enzyme levels fell only in patients responding to treatment. Thus serum sialyltransferase and 5'-nucleotidase activities are reliable biomarkers of breast cancer activity, and serial measurement of these enzyme activities provides a useful tool for the monitoring of disease activity and success or failure of the treatment.
Enzymology has acquired a prominent place in human pathology, and serum enzyme investigations have become a prerequisite for various diseases, including cancer. Serum phosphohexose isomerase (PHI), aldolase (ALD) and alkaline phosphatase (ALP) levels were evaluated in 90 untreated patients with cervical carcinoma and 84 healthy age-matched females (controls). The concentrations of the three enzymes were significantly raised (p < 0.001) in patients compared to the controls. Receiver operating characteristic curve analysis revealed higher sensitivities of PHI and ALP, as compared to ALD at different specificity levels between 60 and 95%. Combined use of PHI and ALP revealed increased sensitivity and specificity. Combined use of PHI, ALD and ALP revealed a greater number of responders with enzyme values within the normal range than nonresponders. The results suggest that combined evaluation of the enzymes might be helpful to establish a useful aid to strengthen the armamentarium currently employed in the diagnosis and treatment monitoring of patients with cervical carcinoma.
A single dose of aflatoxin B1 (AFB1) caused a rapid and transient induction in c-myc mRNA levels in livers derived from adult male Fischer 344 rats. The inducibility of c-myc expression by AFB1 increased with age as c-myc mRNA levels from untreated livers declined from 18-fold in 29-day-old animals to 1-fold in 39-day-old animals, relative to untreated 43-day-old control animals. A dose-dependent increase in c-myc mRNA was found when 53- and 76-day-old rats were administered various AFB1 doses whereas 29-day-old animals exhibited essentially no change in c-myc mRNA levels for the doses examined. Rats were treated with multiple doses of AFB1 to induce hepatocellular carcinomas. C-myc mRNA levels were measured in rat liver samples taken during and subsequent to chronic AFB1 exposure. Characterization of the c-myc induction response at the time of AFB1 exposure revealed that a transient elevation of c-myc mRNA occurred during each (5-day) dosing period for the first 3 weeks, consistent with the acute exposure studies. RNA prepared from hepatocellular carcinomas exhibited elevated levels of c-myc mRNA compared to vehicle-treated control animals. Examination of tumors isolated from the 28-day-old animals showed that the increased c-myc mRNA observed was not the result of gene amplification or gene rearrangement. A comparison of tumor data showed that the 28-day-old animals had a 100% liver tumor incidence while the 38-day-old rats had a 20% liver tumor incidence.(ABSTRACT TRUNCATED AT 250 WORDS)
The high incidence of hepatocellular carcinoma (HCC) in cirrhosis, where previous studies have indicated a severe reduction in several antioxidant vitamin factors, prompted us to compare plasma liposoluble vitamins with tocopherol content in healthy and neoplastic liver tissue in humans. This, with a view to a more positive preventive dietary approach, given the conflicting results obtained by liposoluble vitamin dietary supplementation in different malignancies. Eleven patients with cirrhosis, 18 patients affected by cirrhosis with HCC, and 10 patients with liver metastases (LM) from digestive tract adenocarcinomas were compared with controls who had undergone perlaparoscopic cholecistectomy. Plasma alpha- and beta-carotene, retinol and tocopherol, together with liver tocopherol, from both nonmalignant portions and malignant nodules of the same organ, were determined by high-performance liquid chromatography following a well-assessed technique. The results confirm a trend towards a reduction in circulating carotenoids and tocopherol in cirrhosis and in patients affected by cirrhosis with HCC. Tocopherol content in liver tissue is significantly decreased in cirrhosis (0.26 + 0.03 micromol/g prot., mean + SEM, P < .001) and in cirrhotic areas of the HCC group (0.31 + 0.02, P < .002), with respect to its content in liver specimens of healthy controls (0.46 + 0.03) and in healthy areas of the same organ in patients with LM (0.41 + 0.03). Tocopherol concentration is further reduced by 50% in malignant liver nodules of HCC, with respect to surrounding cirrhotic tissue, whereas in metastatic liver nodules from digestive neoplasms the tocopherol content is almost twice that of healthy surrounding areas. This unpredictable tocopherol behavior in liver specimens, of secondary as opposed to primary malignancies of the liver, affords further insight into the conflicting effects of liposoluble vitamins employed in the chemopreventive treatment of different malignant diseases, where hepatic tocopherol concentration show opposite trends: halved in primary HCC and doubled in LM of digestive adenocarcinomas, with respect to healthy controls.
Genomic instability has been associated with cancer development. Oxidative DNA damage seems to contribute to genetic instability observed in cancer. We have used human lung cancer cell lines carrying a plasmid vector containing a (CA)(13) microsatellite sequence to study frameshift mutations mediated by ROS-generating chemicals paraquat and hydrogen peroxide. Exposure of the cells to both paraquat and hydrogen peroxide resulted in significantly higher mutation frequencies compared with untreated control cells. Mutation frequencies up to 27-fold higher than the spontaneous mutation frequencies were obtained. The majority of the reversion mutants contained frameshift mutations within the target sequence. However, the pattern of deletions and additions was significantly different in the two cell lines. These results indicate that oxidative damage may play a role in instability of microsatellite sequences in vivo.
Ayurveda, the Indian system of traditional medicine, uses a concoction of several spices, herbs and minerals for the treatment of diseases. In a clinical prospective study we have evaluated the efficacy of Ayurveda treatment (a concoction in cow's milk of powdered Mucuna pruriens and Hyoscyamus reticulatus seeds and Withania somnifera and Sida cordifolia roots) in 18 clinically diagnosed (with a mean Hoen and Yahr value of 2.22) parkinsonian patients. As per Ayurveda principles, 13 patients underwent both cleansing (for 28 days) and palliative therapy (56 days), 5 patients underwent palliative therapy alone (84 days). Only the former group showed significant improvement in activities of daily living (ADL) and on motor examination as per UPDRS rating. Symptomatically, they exhibited better response in tremor, bradykinesia, stiffness and cramps as compared to the latter group. Excessive salivation worsened in both the groups. Analyses of powdered samples in milk, as administered in patients, revealed about 200 mg of L-DOPA per dose. The study establishes the necessity of cleansing therapy in Ayurveda medication prior to palliative therapy. It also reveals contribution of L-DOPA in the recovery as observed in Parkinson' disease following Ayurveda medication.
Sida cordifolia L. (Malvaceae) is used in folk medicine for the treatment of inflammation of the oral mucosa, blenorrhea, asthmatic bronchitis and nasal congestion. The anti-inflammatory, analgesic effects and acute toxicity of an aqueous extract of S. cordifolia were evaluated in animal models. The extract was prepared using leaves collected before the flowering period. The aqueous extract (AE) showed a significant inhibition of carrageenin-induced rat paw edema at a dose of 400 mg/kg administered orally, but did not block the edema induced by arachidonic acid. The AE also increased the latency period for mice in the hot plate test, and inhibited the number of writhes produced by acetic acid at the oral dose of 400 mg/kg. The aqueous extract of S. cordifolia showed low acute toxicity in mice.
With the aim of establishing bio-indices for the development of multistep hepatotumorigenesis, rats were fed water containing 0.01% diethylnitrosamine (DEN) ad libitum for 13 weeks. This treatment with DEN only made it possible to induce hepatic tumors in 100%. After the DEN administration, several clinical symptoms were observed including minor behavioral changes, brittleness of hair and a decrease in water and food intake. The concentration of total serum protein and albumin in all treated groups was significantly lower than in non-treated controls (P<0.05). Increase of specific enzyme (AST, ALT and GGT) activity (P<0.05), variable tumor size and hepatomegaly of the liver was observed in all rats treated with DEN for 10 weeks. Both hepatocellular carcinoma and cholangiocarcinoma were found in the same livers at the same time, and were prominently developed after 12 weeks. In case of carcinoma, some of the livers showed more or less advanced states over the 12-15 weeks period. In the present study, hepatocellular carcinoma was developed by treating DEN in only the drinking water, without any other carcinogens or without partial hepatectomy. These results indicate that DEN is a new carcinogen that acts directly on it the liver, moreover, it might be very useful for investigating hepatotumorigenesis.
Adducts arise from the chemical modification of bases in DNA or amino acids in proteins by toxic chemicals. Many chemicals known to be carcinogenic in humans have been shown to form adducts or to cause oxidative damage to genomic DNA in model systems. Biomarkers of carcinogenesis reflect biological events that take place between exposure to external or endogenous carcinogens and the subsequent development of cancer. Therapeutic intervention for the purpose of cancer chemoprevention may modify these biomarkers. In this article, the potential efficacy of DNA adducts as biomarkers of carcinogenesis and chemoprevention is discussed using criteria defined for phases of biomarker development. The sensitivity of adduct detection in histologically normal tissue offers opportunities for the early detection of carcinogenesis. Extensive evidence for aflatoxin B1 adducts as biomarkers of risk and progression of hepatic carcinogenesis and for oxidative DNA adducts as biomarkers of the development of prostate carcinogenesis is reviewed together with the clinical trials measuring these adducts as biomarkers of the efficacy of chemoprevention. Favorable modification of oxidative DNA adducts by dietary intervention and chemoprevention has been demonstrated in preclinical and clinical studies. Protein adducts and DNA adducts in blood constituents or urine may act as useful surrogates for the target organ. Additional information regarding reliability, reproducibility, specificity, and confounding variables are required at the clinical level to validate adducts as suitable biomarkers of chemoprevention.
“We do not administer antihypertensive drugs to patients in clinical trials without checking their blood pressure, so why should we give antioxidants without checking that they have decreased oxidant status (B. Halliwell, Lancet 2000:355:1179–80)?”
Aflatoxin B1 (AFB1) is a potent hepatocarcinogen. We have recently detected [via electron spin resonance (ESR) spectroscopy] free radicals in vivo in rat bile following AFB1 metabolism using the spin trapping [alpha-(4-pyridyl-1-oxide)-N-tert-butyl nitrone (4-POBN)] technique. The aim of the present study was to identify the trapped free radical intermediates from the in vivo hepatic metabolism of AFB1. Rats were treated simultaneously with AFB1 (3 mg/kg i.p.) and the spin trapping agent 4-POBN (1 g/kg i.p.), and bile was collected over a period of 1 h at 20 min intervals. On-line high performance liquid chromatography (HPLC) coupled to ESR was used to identify an arachidonic acid-derived radical adduct of 4-POBN in rat bile, and a methyl adduct of 4-POBN from the reaction of hydroxyl radicals with carbon-13-labeled dimethyl sulfoxide ((13)C-DMSO). The effect of metabolic inhibitors, such as desferoxamine mesylate (DFO), an iron chelator, 2-dimethylaminoethyl-2,2-diphenylvalerate hydrochloride (SKF) 525A, a cytochrome P-450 inhibitor, and gadolinium chloride (GdCl(3)), a Kupffer cell inactivator, on in vivo aflatoxin-induced free radical formation were also studied. It was found that there was a significant decrease in radical formation as a result of DFO, SKF525A and GdCl(3) inhibition. Trapped 4-POBN radical adducts were also detected in rat bile following the in vivo metabolism of aflatoxin-M1, one of the hydroxylated metabolites of AFB1.