1Physiology Division, Zoology Department, Faculty of Science, Mansoura University, Mansoura 35516, Egypt.
2Ministry of Health, Makkah Region, Makkah 21514, Saudi Arabia.
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Hepatocellular carcinoma (HCC) is a growing health problem in humans. HCC is considered the most common of internal malignancy which cause the death of human, but in the developed Western world, HCC is less common accompanied by increasing essentially in incidence, due to it occurs specially in chronic liver disease. HCC associated with various risk factors including hepatitis B virus infection; hepatitis C virus infection; prolonged aflatoxin exposure; and alcoholic cirrhosis. Overall, one-third of cirrhosis patients will develop HCC during their life time. Also, chemical carcinogens cause tumor promotions through free radical metabolites result in many biochemical and molecular changes that induces oxidative stress. The identify of HCC stage and underlying liver status then choosing the most appropriate line of therapy (surgical, loco regional, radiological and medical) can be improve the survival and/or the quality of life of the patient. Taken into the account of the nutritional value of some natural antioxidant agents that support the function of the body resulting an improvement of the health and protection from different diseases, our review will provide an up-dated status of the different aspects of HCC management through covering the efficacy and the beneficial effects of different natural agents and their mechanism of action against HCC for the future therapy modalities.
Hepatocellular carcinoma, risk factors, natural antioxidants
Hepatocellular carcinoma (HCC) incidence is the most common tumor in worldwide. HCC involves major changes in multiple molecular pathways, genetic and epigenetic factors, which consequently leads to the malignant transformation and HCC progression. Chronic liver disease and cirrhosis of patients cause HCC. HCC has major risk factors for developing cirrhosis such as, alcoholic consumbtion, hepatitis B virus (HBV) and hepatitis C virus (HCV) and nonalcoholic steatohepatitis. Additionally, the contamination of water by chemicals, diabetes, obesity and genetic factors including hemochromatosis, and some physiological disorders act as risk factors for developing HCC. Cirrhosis is the most dangerous factors for HCC, especially cirrhosis which caused by hepatitis virus infections. Therefore, increasing HCC risks occur in the acquired HBV during the childbirth and early childhood. The patients with HCC present with one or more of several clinical features as weight loss, right upper. HCC causes acute disaster of abdominal by bleeding intra-abdominal or extra hepatic appearance. Also, patients have HCC with cirrhosis cause palmarerythema, obstractive jaundice, gynecomastia and portal hypertension.[7,8] HCC is associated with hypoglycemia, erythrocytosis, hypercalcemia, hypercholesterolemia and diarrhea.
The distributions of HCC are largely result from various risk factors particularly the majority of hepatitis B and C viral infection and alcoholic liver disease. Chronic HBV infection cause of HCC in different area, where the virus is largely endemic and vertical transmission common.[11,12] High alcohol consumption; smoking of cigarette; obesity; and diabetes have also been associated with an increased risk of developing HCC.[13-15] Previous studies have reported a close correlation with obesity and diabetes and an increased risk of HCC progression. Also, there are common environmental factor associated with HCC development such as aflatoxin, a product of the Aspergillus fungus. Several physiological disorders of the liver have been implicated in the HCC development, including α-1 antitrypsin deficiency; certain porphyrias; Olchi's disease; and hereditary hemachromatosis, each typically in the setting of cirrhosis. Additionally, an automimmune disorders have been implicated in HCC pathogenesis, including primary biliary cirrhosis and autoimmune hepatitis.
HCC majority occurs in the setting of liver cirrhosis. The accumulations of genetic and epigenetic changes related to hepatocarcinogenesis disease are well known. However, the regulating cell cycle and suppressing apoptosis used for maintenance the survival of cancerous cells. Retinoblastoma and p53 genes responsible for the oncogenes activation and tumor suppressor genes are the good markers that understand the molecular, physiological mechanisms and disorders in the cellular signaling pathways of HCC incidence growing. When the liver gets injured, necrosis will appear in the liver accompanied by the subsequent hepatocyte proliferation, after continuous cycles of destructive-regenerative process. The hyperplastic nodules will turn into dysplastic nodules inducing a high risk of developing HCC.
Furthermore HCC well associated with various metabolic changes including biochemical alterations. Alfa-fetoprotein (AFP) is a glycoprotein in serum that was first recognized as a major marker for HCC. AFP elevation indicating to malignant after pathological diagnosis and endodermal lining tumor of the stomach, pancreas, and biliary tree. Moreover, HCC development has also been associated with plasma lipid and lipoprotein alterations. This alterations result in cellular dysfunction, reduction in the membrane integrity, fluidity and regulation of cellular processes related to growth and cell survival causing cancer development.[24,25] The cirrhosis and HCC characterized by a decrease of total protein and impair hepatic function indicating by increasing hepatic enzymes (aspartate aminotransferase, alanine transaminase, alkaline phosphatase, and gamma glutamyl transferase) activity through the loss of functional integrity of the cell membrane in liver resulting liver damage.[26-28] Furthermore, the development and progression of HCC are well associated with the oxidative stress status that produced by increasing level of reactive oxygen species (ROS) resulting distortion and decrease the antioxidant activity in the tissues.[29,30] Lipid peroxidation (LPO) is responsible for formation of many toxic products, such as 4-hydroxynonenal and malondialdehyde MDA which attack cellular targets, thereby inducing carcinogenicity.[31-33] Many biochemical and molecular changes leads to free radical metabolites causing the chemical carcinogens induce oxidative stress leading to tumor promotion.[34,35] The failure of antioxidant defense mechanism and tissue damage were enhanced by increasing LPO. Glutathione (GSH) is present in high concentration of liver and widely distributed in cells. It has many properties as, protects the cell against free radical, peroxides and other toxins, so after decreased of GSH level in tissue causing DNA damage, protein oxidation and LPO of the cell membrane biomolecules lead to hepatocyte damage. However, the decrease of the antioxidant enzymes activity (superoxide dismutase and catalase) caused the increase of hepatocytes in the cirrhotic livers. The production of cytokines, ROS, and inflammation-mediated events leads to tumor formation. The inflammatory diseases of cell, is produced by many pro-inflammatory cytokine as TNF-α and structural cells especially the pathogenesis of asthma. Liver cirrhosis causes elevated in the pro-inflammatory cytokine TNF-α as a major marker for inflammatory state in the cirrhotic liver. HCC has an anti-apoptotic genes expression and rapid cell proliferation, due to apoptosis resistance under conventional therapies and incomplete cell cycle arrest. HCC increased apoptosis by the down-regulation of the Bcl2 level, the activation of caspase cascade, and the up-regulation of Bax and the p53 level.[43-45] Additionally, HCC contains various histological changes such as: (1) pseudoglandular pattern including gland-like dilatation of the canaliculi in tumor cells; and (2) trabecular pattern of growth. Cytologically; polygonal and displaying of tumoral hepatocytes; smaller tumor cell; granular eosinophilic cytoplasm; vesicular nuclei; giant tumor cells; and conspicuous nucleoli are associated with HCC.[46-48]
There is a wide heterogeneity in HCC pattern, patient variations as candidates for recommended treatments, and increasingly complex available therapeutic options with diverse responses to these therapies in clinical practice. Also HCC is highly associated with variable biologic behavior and the frequent coexistence of chronic liver disease and cirrhosis. So, it is important to manage HCC patients by multidisciplinary HCC teams including hepatologists; medical and surgical oncologists; transplantation surgeons; diagnostic and interventional radiologists; pathologists; nurses and nurse practitioners. The most commonly used treatment by the enhancement of latent antitumor immune response through chemotherapy. Chemotherapy has varying effects, and work is underway in the search for active chemotherapy and appropriate for chemo-embolization, an intensive localized chemotherapy method by using improvement prognosis. However, chemotherapy still has severe side effects and low survival rates. As a recent reports, a large number of natural antioxidant extracts have been suggested to induce beneficial effects on human health and disease control. The beneficial effects of many medicinal plants may be due to the presence of antioxidative, antibacterial and antimicrobial components. Antioxidants such as flavonoids, phenolic acids and diterpenes can be used to treat the undesirable and harmful action of the free radicals related to various diseases.
Natural agents are alternative therapeutic agents to control different diseases including cancer progression through their antioxidant activity. They stimulate the normal metabolic function in cancer cells and regulate the tumor suppressor genes and immunity. These natural products control the over expression of metabolic enzymes and tumor growth factors in cancer cell. Also they have the ability to control DNA damaging factors in cancer cells and regulate DNA transcription in tumors. Moreover, they possess numerous therapeutic benefits such as anti-obesity effects; anti-diabetic effects; immune enhancement; and anti-inflammatory effects. Previous studies recorded that natural extracts, herbs and spices have been used for controlling diseases, including cancer through different mechanisms such as prevention of tumor initiation; delay or arrest of the development of tumors; extension of cancer latency periods; reduction in cancer metastasis and mortality and prevention of recurrence of secondary tumors.[58,59] Vegetables and fruits rich with polyphenol plays a crucial role in the protection of liver against hepatitis due to its potential activity in the reduction of early pro-inflammatory cytokines, activation of anti-inflammatory IL-10, and inhibition of lipo-polysaccharide induced activation of nuclear factor kappa B (NF-κB) in hepatocytes.[60-62] Furthermore, flavonoids are a group of polyphenolic compounds, different in chemical structure and characteristics, naturally founded in plants. They showed versatile health benefits such as anti-inflammatory; antioxidant; anti-proliferative and anticancer activity; free radical scavenging activity; and antihypertensive effects.[63,64]
Chicory (Cichorium intybus L.) has been reported in medicine from North Africa to South Asia for several 100 years. It contains many useful compound such as anthocyanins, vitamins A and C , potassium, calcium, and phosphorus and rich chioric acid. It act as anti-inflamatory, anti-bacterial agent as well as it has immune-modulatory effects. Many types of edible plants and vegetables contain high level of chicoric acid. Chicoric acid have essential properties as antioxidant, antivirus and immunoregulation. Chicory has a many properties as antioxidant, hepatoprotective, hypoglycemic, diuretic, and anti-testicular toxicity.[70-73] Also, chicory is a good source for inulin.[74,75] Inulin is a hepatoprotective compound that prevent of the tissue from demolition by inhibited oxidative degradation of DNA in liver mice. In addition, inulin has hypolipidemic effect where it is not affected by digestive enzymes due to it is expected to behave like a soluble fiber. Moreover it has prebiotic effect by decreasing the activity of growth pathogens and harmful microorganisms as well as increase the activity of growth colonic of beneficial bacteria to the host.[77,78]
Milk (Silybum marianum) is one of the most famous herbal agents that act as hepato-reno protective agent from 16th century due to it contains approximately 4-6% silymarin and 20-35% fatty acids, particularly linoleic acid.[79,80] Silymarin composed of both polyphenolic molecules, including flavonolignans (silybin A, silybin B, isosilybin A, isosilybin B, silychristin, isosilychristin, and silydianin) and one flavonoid (taxifolin), silibinin, a semipurified. These components have the beneficial effects, including liver protection and antioxidant, anti-viral, and anti-inflammatory properties. Silybum is effective in the treatment of liver diseases (cirrhosis, jaundice and hepatitis). Various studies including in vitro and animal research suggest that silybum may have hepatoprotective and antihepatotoxic properties that protect liver cells against toxins through its ability in the reduction of ROS and LPO production, as well as the rebalancing of cellular REDOX status.[81,83] Moreover its role in inhibition of pro-inflammatory signals, cellular proliferation and expression of survival proteins, resulting a significant protecting the liver.
Glycyrrhizin is the active constituent obtained from aqueous extraction of root liquorice (Glycyrrhiza glabra). It has been used in traditional medicine to reduce bronchitis, jaundice as well as gastritis. Its major constituents are glycyrrhetic acid; flavonoids; hydroxycoumarins; and beta-sitosterol. Licorice and their products have been reported to be useful in the treatment of human hepatitis; animal inducible hepatocarcinogenesis; and attenuating titanium dioxide nanoparticles-induced hepatotoxicity. Glycyrrhizin has pharmacologic roles such as anti-inflammatory; antiviral; antioxidant; immunomodulatory; hepatoprotective and cardioprotective activities through the inhibition of beta-hydroxysteroid dehydrogenase enzyme. Also it blinded to high mobility group box 1 (HMGB1) directly to suppress HMGB1-induced injury, inhibit toll-like receptor-4 pathway, lower uclear factor-κB (NF-κB) concentration and inhibit the production of inflammatory cytokines.[87,88]
Ginseng (Panax ginseng), a valued Chinese and Korean traditional medicinal herb, has been clinically used in China, Europe, United States and North America for thousands of years.[89-91] Ginseng is one of the well-known medicines in alleviating the development of HCC in chronic hepatitis patients.[92,93] Ginseng extract has an antioxidant activity due to its ability to scavenge free radicals and suppression of lipid peroxidation. It has been shown to improve general conditions and non-specific complaints due to the exhaustive and feverish illness through enhancement of natural healing power. Also, it has been shown to prevent cancer development and inhibit carcinogenesis in several organs.[95,96] Recent studies suggested the efficacy of ginseng extract to induce apoptosis so it has antitumor activity.[97-99]
Dandelion (Taraxacum officinale) has been used in traditional medicine in the treatment of inflammation and several diseases including cancer. It has anti-rheumatic and anti-inflamatory.[101-104] Moreover it has antioxidant properties as well as hepatoprotective activity and success in promotion of liver detoxification and support kidney function. All of these beneficial effects may be attributed to their several flavonoids including caffeic acid; chlorogenic acid; luteolin; and luteolin-7-glucoside. Additionally it is a rich source of vitamins A, B complex, C, and D, as well as minerals such as iron, potassium, and zinc.[106-109] Dandelion extract showed a protective effect against membrane fragility consequently, and minimizing the leakage of liver enzymes into the blood circulation and suppressed the production of tumor necrosis factor (TNF)-α by inhibiting interleukin-1production.[107,110] Also it has been shown to have stronger free radicals scavenging activity due to its high polyphenol content.
Garlic (Allium sativum) has been widely used as a food stuff and a traditional medicine throughout the world. Garlic is available in different forms such as powder or garlic oil. Garlic has a beneficial value such as anti-atherosclerotic, antihypertensive, antimicrobial, anticancer, immunomodulatory, antioxidant, and radioprotector effects. These beneficial effects may be attributed to its components including organo-sulfur compounds such as diallyl sulfide; diallyl disulfide; diallyl trisulfide; S-allylcysteine (SAC) and S-allylmercaptocysteine. Several studies evidences have proved that SAC is an anti-tumor agent against different human cancers such as prostate, breast, oral, neuroblastoma and non-small-cell lung carcinoma. On the other hand, allicin (diallyl thiosulfonate), which is the main biologically active component of freshly crushed garlic cloves, has anti-hepatocarcinogenic effect through the p53 gene modulating apoptosis. Garlic oils have capable for promotion apoptotic signaling as evidenced by the upregulation of Bax and Caspase-3. Also, garlic oil exhibited potent antioxidant capacity were it reduced the generation of ROS, suggesting that the different mechanisms of hepatocarcinoma prevention. Additionally, the major role of garlic extract rich in SAC against hepatocarcinogenesis as well as organs tumors may be due to its effect on inhibition of proliferation, induction of apoptosis and suppression of invasion and adhesion.[115,121]
Curcumin (Curcuma longa) is turmeric spice derived from the rhizome of the East Indian plant Curcuma longa. It is a polyphenol contains a class of compounds such as curcuminoids, demethoxycurcumin and bisdemethoxycurcumin. Turmeric has also been widely used in medicine for cardioprotective, hepatoprotective, carcinoprotective, and neuroprotective in addition it acts as anti-oxidant, antiseptic, analgesic, antimalarial and anti-inflammatory. Curcumin rich in curcuminoids are known to inhibit oxidation owing to their methoxy group, 1, 3 B-diketone moiety and phenolic hydroxyl group so it can decrease the free radicals generation, which it was an important step in tumor formation. Curcumin was found to inhibit NF-κB, which activates inflammatory cytokines and chemokines, leading to several inflammatory conditions. NF-kB activation promotes cellular proliferation, angiogenesis, and invasion and inhibits apoptosis. In addition, curcumin also inhibits IL1, IL1B, IL6, IL8, tumor necrosis alpha, and cyclooxygenase pathways. Several studies have supported curcumin’s antioxidant and anti-inflammatory, particularly in HCC in addition to its ability to control the cellular signal transduction pathways pertinent to growth, differentiation, and malignant transformation.[129,130]
Thyme (Thymus vulgaris) is widely used in folk medicine for the treatment of a variety of diseases including gastroenteric and bronchopulmonary disorders specially in almost everywhere in the world. It is effective as anthelmintic, antispasmodic, carminative, sedative, diaphoretic, antimicrobial, antioxidant, and antifungal agents because its contents of essential oils and anti-oxidative phenolic compounds [geraniol (G), α-terpineol (A), thuyanol-4 (U), linalool (L), carvacrol (C), and thymol (T)].[131,132] The volatile oils of thyme has been shown to exhibit anti-microbial, anti-mutagenic, anti-platelet, analgesic, anti-inflammatory, anti-angiogenic, anti-oxidant, anti-elastase, insecticidal, anti-parasitic, cell-protective, and anti-tumor activity.[133,134] Recently, the various studies showed that the beneficial effects of thyme was based on the activation of the apoptosis response, including reduction in mitochondrial membrane capacity and Bcl-2/Bax ratio as well as elevation in cytochrome release from mitochondria and caspase activity. Furthermore, it increases the cleavage of PARP and fragmentation of DNA, which belong to the mitochondrial pathway of the apoptosis pathway.
In conclusion, HCC is the common malignancy of the liver that considered one of death reasons in the worldwide. Chronic infection of HBV and HCV and subsequent liver injury regeneration cycle are considered a major etiology of HCC. HCC is well accepting for multi-drug resistance and not response to current chemotherapeutic agents. Nowadays, no single or combined chemotherapy regimen has been found yet to be effective in HCC. Traditional medicine, especially the herbal medicine plays a vital role in the management of various liver disorders. In this era of science and technology the demand for therapeutic drugs from natural products is increasing day by day, due to their effective therapeutic action and lack of side effects. Recent studies have shown that medicinal herbs and natural agents rich in antioxidants and other safety micronutrients protect against hepatic dysfunction, carcinogenesis, mutagenesis, DNA-damage and LPO. The greatly positive effect of natural antioxidants on membrane stabilizing by mechanisms that include up-regulation of the key apoptotic regulators, modulate cell cycle arrest and improvement of DNA content by the free radical scavenging, the antimutagenic and antioxidant properties. Thus, it was recommended that the supplementation with edible natural agents may help in safe application of cancer technology in medicine as well as in many other aspects of nowadays life.
There are no conflicts of interest.
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