A Potential Anticancer and Immune enhancing Agent for Cancer Patients.

Nigella Sativa and its Extract (Thymoquinone): A Potential Anticancer and Immunoenhancing Agent for Cancer Patients
Many Investigations revealed the broad spectrum of pharmacological properties in the n.sativa seeds and its constituents. Thymoquinone (TQ) has shown potential medicinal properties in traditional medicine and most of these properties have been attributed to the quinone constituents of the seed. Thymoquinone has been known to act as immunopotentiation, anti- diabetic, anti- hypertensive, anti-inflammatory, antimicrobial activities, chemopreventative potential and may reduce the toxicity of standard antineoplastic drugs. Many of these activities have been attributed to the quinone constituents of the seed (Mbarek, 2007). Furthermore, many studies have shown that thymoquinone (TQ, 2-methyl, 5-isopropyl 1,4-benzoquinone) isolated from the seeds of nigella sativa has different immunomodulatory and immunotherapeutic potentials. Many published findings also provide clear evidence that both the oil and its active ingredients, in particular, TQ, contain a potent anti oxidant effects by stimulating and improving the oxidant scavenger system. The oil and TQ have also shown powerful anti-inflammatory effects on several inflammation-based models including experimental encephalomyelitis, colitis, peritonitis, edama, and arthritis through suppression of the inflammatory mediators prostaglandins and leukotrienes (Salem, 2005). Most importantly, the oil and certain active ingredients in nigella sative seeds demonstrate beneficial immunomodulatory properties by improving the T cell and natural killer cell-mediated immune responses. Furthermore both the oil and its active ingredients expressed antimicrobial and anti-tumor properties toward different microbes and cancers (Salem, 2005). Coupling these beneficial effects from the use of nigella sativa with anticancer drugs and cancer therapy would pose potential therapeutic model for most types of diseases.
Impairment of the Immune Recovery after Cancer Treatment
Conventional anticancer therapy including chemotherapy has been historically thought to act through direct killing of tumor cells. This concept stems from the fact that cytotoxic drugs interfere with DNA synthesis and replication. Accumulating evidence, however, indicates that the antitumor activities of chemotherapy also rely on several off-target effects, especially directed to the host immune system, which cooperates for successful tumor eradication (Bracci, 2014). Several studies have shown that treatment of cancer patients with intensive chemotherapy results in profound depletion of the immune system and most likely weakens the immune system especially the lymphocytic populations, especially of B cells. Chemotherapy medicines target rapidly dividing cells, which cancer cells are, but so are many of the healthy cells in the human body. As chemotherapy drugs damage the bone marrow, the marrow is less able to produce enough red blood cells, white blood cells, and platelets. Typically, the greatest impact is on white blood cells. During chemotherapy, patients are considered to be immunocompromised. After finishing chemotherapy treatment, it can take anywhere from 21 to 28 days for your immune system to recover. In a study of the Impairment in Immune Recovery Following Cancer Therapy, Kang (2009) found that the immune recovery following cancer therapy is delayed significantly for an extended time period in numerous immune parameters. The type of cancer treatment and cancer adjuvant therapy has selective influence on immune recovery. The ability to restore the immune system without the need for continuous treatment is the target goal of therapies for cancer disease.
Complementary and Alternative Medicine to Treat Cancer
Although the effectiveness and safety of certain CAM modalities are questionable, studies have reported widespread CAM usage amongst cancer patients to increase the body’s ability to fight cancer, improve quality of life, strengthen the immune system, and cope with disease symptoms. Others use CAM as a last resort and as a way of finding hope. Essentially, CAM meets the demands that mainstream medicine cannot principally satisfy, and provides complementary solutions to conventional medicine. A recent European survey reported that the overall prevalence of CAM used by cancer patients was 35.9%. As cancer incidence increases and survival time lengthens, patients using CAM are likely toincrease. Oncologists gradually recognize this trend, although not many patients discuss these therapies with them (Dhanoa, 2014). Several scientific researches studies have been done on herbal medicine and plants to treat cancer, and some plant products have been marketed as anticancer drugs, based on the traditional uses and scientific reports. These plants may promote host resistance against infection by re-stabilizing body equilibrium and conditioning the body tissues. Many scientists describe that the anticancer activity of medicinal plants is due to the presence of antioxidants in them. The medicinal plants are easily available, cheaper and possess no toxicity as compared to the modern (allopathic) drugs. It has been also reported that more than 50% of all modern drugs in clinical use are of natural products, many of which have been recognized to have the ability to include apoptosis in various cancer cells of human origin (Umadevi, 2013).
It is essential to discover the benefits of herbal medicine and tries to understand the association between the alternative herbal medicine and its therapeutic potentials since almost 80% of the population in the world depends on traditional medicine in order to treat diseases (Paarakh, 2010).
Use of Herbal Supplements as Adjuvants in Conventional Anticancer Therapies
Several herbal medicines have been found to have potentially beneficial effects on cancer progression and may ameliorate chemotherapy or radiotherapy induced complications and side effects (Qi, 2010). Herbal medication in general was applied as a combination therapy with the conventional chemotherapy to increase therapeutic benefits and quality of life (QoL) as well as to decrease the side effects or complications. This practice is highly detracted from by many western physicians and health care providers. Understanding the use of specific herbal medicines as adjuvants to conventional therapy needs to be increased in consultation and in coordination with physicians and other health care providers (Yin, 2013).
Safety and Adverse Reactions: Tauseef (2009) indicated that fixed oil 4.0% and essential oil 0.30% are safe as serological indices, like liver and kidney functioning tests, serum protein profile, level of cardiac enzymes and electrolytes balance were remained in the normal ranges even after 56 days of study. Similarly, El-Shabrawy and Nada (1996) reported no toxic symptoms in mice or rats after oral administration of NS extract doses up to 25 g/kg. Bh et al. (2003) reported that administration of either the seed extract or its oil has been shown not to induce significant adverse effects on liver or kidney functions. It would appear that the beneficial effects of the use of the seeds and thymoquinone might be related to their cytoprotective and antioxidant actions, and to their effect on some mediators of inflammation. In further support of the safety of nigella sativa adminstration, another study to determine the toxic effect of Nigella sativa powder on the liver function and was evaluated by measuring liver enzymes and through histopathological examination of liver tissue in rats showed that supplementation of Nigella sativa up to the dose of 1 g/kg supplemented for a period of 28 days resulted no changes in liver enzymes level and did not cause any toxicity effect on the liver function (Dollah, 2013).
In contrast, there are some data indicated negative effects. The use of nigella sativa oil in high doses and prolonged duration might be unsafe due to the presence of some toxic components such as glucoside in its oil. In animals, the fixed oil of N. sativa orally administered to rats for up to 12 weeks did not produce any significant changes in hepatic enzymes and did not cause mortality. However, high doses may cause liver damage (Khader, 2009).
Furthermore, nigella sativa extract should be used with precaution in pregnant women and children due to its hypoglycemic properties. In children, it was recommended that NS should be administered in weight-adapted doses. All these studies conclude that nigella sativa seeds and their extracts appear to have a low level of toxicity and could be considered safe at normal concentrations in cells (Darakhshan, 2015). However, in spite of the large number of experimental studies, there have been few studies on humans. Additional human research studies are necessary to further evaluate the effect Nigella sativa may have on the kidneys or liver and metabolism.
Anticancer Effect of Nigella Sativa and Cancer Chemopreventive Potential researchers provided evidence for the anti-cancer activity and activity of thymoqunone, the most bioactive compound of the Nigella sativa seed oil, and its anti-oxidant, anti-inflammatory and anti-neoplastic actions with selective cytotoxicity for human cancer cells compared to normal cells. In addition, thymoquinone has a potential role in preventing cancer via modulation of genetic cascades. TQ shows a critical role in controlling cancer via the activation of tumor suppressor gene, phase II gene/enzymes, and peroxisome proliferator activated receptors (PPARs), inactivation of angiogenesis and anti-inflammatory gene, and induction of apoptosis (Rahmani, 2014).
In vitro studies thymoqunone also induced cancerous cells apoptosis in melanoma, squamous cell carcinoma, certain forms of lymphoma, cervical cancer, osteosarcoma, and lymphoblastic leukemia (Rajput et. al., 2013). Thymoquinone analogs (TQ), isolated from the seeds of Nigella sativa, show moderate efficacy against pancreatic cancer, the disease that show a five year survival rate of less than 3% amongst afflicted patients. Thymoquinone analogs have been shown to inhibit pancreatic cancer cell proliferation in vitro and enhance cancer cell sensitivity to chemotherapy alone or in combination with Gemcitabine (a drug used to treat pancreatic cancer) against pancreatic cancer cells (Yusufi, 2013). This study was backed up by a research at the Kimmel Cancer Center at Jefferson in Philadelphia. They found that thymoquinone, inhibit the development of pancreatic cancer as a result of its anti-inflammatory properties. The researchers used pancreatic ductal adenocarcinoma (PDA) cells, some of which were pretreated with the cytokine TNF-a to induce inflammation. Moreover, findings of a recent in vitro study showed that Nigella sativa seed extract and seed oil decreased human lung cancer cell growth significantly (Al-Sheddi et. al., 2014). Additional study found that oral administration of thymoquinone (1,2 and 4 mg/kg/day) for five days increased the activity of quinone reductase and glutathione transferase in liver and protect against chemical carcinogenesis in hepatic cancer (Paarakh, 2010). Shafi et al. (2009) found in his study that that the methanol, n-Hexane and chloroform extract of nigella sativa dramatically killed human epithelial cervical cancer cells by promoting apoptosis. Despite that, since these studies are all in vitro, additional studies are needed to conclude the anticancer effects of Nigella sativa seed and its extracts.
In Vivo studies It was shown that Nigella sativa administration produced a potent inhibitory effect on rat tumor development and on cellular proliferation in multiple organ sites like colon, lung, esophageal and fore stomach tumors in the post initiation phase with no evidence of clinical side effects (Ahmed, 2013). Paarakh. (2010) reported in his review that administrating thymoquinone in drinking water with Ifosfamide (IFO), an antineoplastic drug solution, significantly enhance the antitumor effect of IFO in rats and mice with Ehrlich ascites carcinoma. These results indicate that TQ improved the effect of IFO by reducing its nephrotoxicity reaction and enhancing its antitumor properties. Furthermore, Mabrouk et al. (2002) showed that honey and N. sativa supplementation along with cancer drugs has a protective effect against methylnitrosourea-induced oxidative stress, inflammatory response and reduced carcinogenesis by 80% in lung, skin and colon in vivo.
In a study of two stages performed by EL-Sayed et al. (2010) the chemopreventive potential of crude oils in N. sativa on tumor formation was demonstrated in vivo. 76 rats with five different multi-organ carcinogens were fed 1000 or 4000 ppm N. sativa volatile oil for 30 weeks. The researchers found that after post initiation phase of administrating 1000 or 4000 N. sativa volatile oil mixed with powdered diet, the dosage significantly reduced malignant and benign colon tumor sizes, incidences and multiplicities. The treatment also significantly decreased the incidences and multiplicities of tumors in the lungs and in different parts of the alimentary canal, particularly the esophagus and stomach. The study also found that, N. sativa administration exerts potent inhibitory effects on rat tumor development and on cellular proliferation in multiple organ sites specifically, the ability to significantly inhibit murine colon, lung, and esophageal and forestomach tumors was demonstrated in the post-initiation phase, with no evidence of clinical side effects. Badary and Gamal. (2001) also treated mice having fibrosarcoma induced by 20-methylcholanthrene (MC) with Administration of TQ (0.01% in drinking water) significantly inhibited the tumor incidence (fibrosarcoma) and tumor burden by 43% and 34.additionally, TQ delayed the onset of MC-induced fibrosarcoma tumors that appeared at 12 weeks and produced less MC-induced mortality. The authors explained that the possible modes of action of TQ might be through its antioxidant activity and interference with the DNA synthesis coupled with enhancement of detoxification processes. These findings suggest that TQ can be a potential powerful chemopreventive agent against MC-induced fibrosarcoma tumors. Regarding Breast Cancer, an animal model study conducted by El-Aziz et al., (2005) they discovered that the supplementation of N. sativa, in combination with melatonin and retinoic acid reduced the carcinogenic effects of DMBA (7, 12-di methylbenz (a) anthracene) in mammary carcinoma of rats. The anti-cancer activities of N. sativa components have become a major topic for experimental and scientific research. Nigella sativa is a safe and promising anticancer agent particularly when given orally to experimental animals (Al-Ali et al., 2008) that demonstrate anti-neoplastic potential and encouraging chemopreventive as well as chemotherapeutic properties. This can provoke more research works and Specific experimental animal models and human clinical trials to understand the mechanism of action and the efficacy of this herb both on animal models and humans.
The Impact of Nigella Sativa on the Immune System
There has been particular interest in the strong link between various immune activities tumor tissues and the progression of tumor growth. Enhancement of the immune system and tumor surveillance by the host immune system has been considered to be a key strategy to facilitate anticancer effect. In this section, we address the specific effects of nigella sativa extracts especially its major active ingredient, thymoquinone on the enhancement of the immunity and analyzing in vitro and in vivo experimental studies regarding nigella sativa and TQ properties to modulate immune responses and improve antioxidant status.
Muhtasib et al. (2006) reviewed the Effects of thymoquinone on the immune system, TQ has also been shown to inhibit inflammation and oxidative stress in cells and produce an increase in the ratio of helper to suppressor T cells and enhance natural killer cell activity in healthy volunteers. Most recently, Sultan et al. (2015) demonstrated the role of Nigella sativa fixed and essential oils (NSFO & NSEO) in improving the antioxidant status along with its modulation effect of antioxidant enzymes and immunity on rats. Rats were fed Nigella sativa fixed and essential oils and immunity parameters along with antioxidants enzymes were evaluated at 4 weeks interval. They concluded that, Nigella sativa fixed and essential oils have a potential positive effect in improving the antioxidant status significantly and immune boosting potential.
Several researches has identified the enhancement of the cytotoxic activity of NK cells as a mechanism underlying the anti-cancer effects exhibited by N. sativa. Elkadi and Kandil. (1987) performed an in vivo study on healthy volunteers to evaluate the immunomodulatory effects of N. sativa seeds oil with regard to the ratio of helper to suppressor T cells and the cytotoxic activity of NK cells. The authors concluded that the ratio of helper to suppressor T cells and NK cytotoxic activity were significantly increased experimental group who consumed nigella sativa oil for 4 weeks. Sativa plant extract is more effective than standard chemotherapeutic anti-cancer drugs. N. Sativa extract stimulates bone marrow cells, protects the normal cells from cytopathic effects of virus, destroys tumor cells and increases antibody producing B cells. Further, it protects the bone marrow against chemotherapy and can act as an anti-cancer agent. nigella sativa plant extract also has been found to help restore immune competent cells in immunosuppressed cancer patients and to over stimulate bone marrow formation in normal individuals (Liu,1987). Moreover, nigella sativa extract can enhance macrophages of the innate immune functions that could control infectious diseases and regulate adaptive immunity.it is also indicated that daietry supplementation with Nigella sativa oil improved the immune response of healthy old subjects, which is mediated by a change in the factors closely associated with T cell activation (Darakhshan, 2015). Salem et al. (2005) explained that one of the precious properties of N. sativa is the immunomodulatory effect of its constituents including thymoquinone. The immunotherapeutic efficacy of TQ is linked to its antitoxic, anti-histaminic and anti-inflammatory properties. He concluded his study by stating that More than 150 studies conducted since 1959 confirmed the pharmacological effectiveness of N. sativa seed constituents. Therefore, further studies are required to explore the specific cellular and molecular targets of N. sativa constituents, in particular TQ, and its immune effect.
Discussion : Despite the move toward synthetic medicine, traditional remedies still have an important role. There is an increasing demand for researches to identify plant-derived natural substances and understand the mechanisms of their pharmacological actions in the management of chronic diseases, instead of conventional treatments. Nigella sativa have been used for centuries by diverse human cultures around the world. The experimental evidence explaining the anticancer and immunomodulatory activity of N. sativa and its major active ingredient, TQ are expanding both in vitro and in vivo. Based on the current studies reviewed, Clinical and animal studies have demonstrated many therapeutic effects of nigella sativa. N. sativa extract increases the activity of antioxidant enzymes and acts as an anti-cancer agent. Its immunomodulation effects and the enhancement of T cell and natural killer cell mediated immune responses have been also demonstrated. Moreover, most of the studies suggest the effectiveness of the combination of thymoquinone and chemotherapeutic agents and how it can result in potential cytotoxic effect. These results suggest the possibility that thymoquinone can be used to complement conventional medicine to achieve greater therapeutic effect in clinical treatment. Most of the studies indicated a single limitation, which is the need and the lack of human trials to investigate the effect of nigella sativa seeds and its constituent on humans before Nigella sativa can be recommended. Further investigations on the mechanisms of action are also required. Overall, findings suggested that Nigella sativa seed oil and its active ingredients possess a multiple therapeutic potentials and deserve consideration as a potential multi-purpose product for pharmaceutical anti cancer and immunoenhancing purpose.
Conclusion and Future Development
Nigella sativa seeds has been used without any reported side effects in traditional medicine and in recent years. Nigella sativa seed and thymoquinone (TQ), the most bioactive compound of the nigella sativa seed oil, has demonstrated many therapeutic effects as an anti cancer and immunomodulatory agent. The combination of TQ with clinically used anti-cancer drugs, such as isofosfamide, cisplatin and doxorubicin, has led to improvements in their therapeutic index and to the protection of non-tumor tissues against chemotherapyinduced damage (Muhtasib et al, 2006). Experimental evidence suggests that n. sativa extracts and TQ can potentially be employed in the development of effective therapeutic agents towards the regulation of immune reactions implicated in various infectious and non-infectious conditions including different types of allergy, autoimmunity, and cancer (Majdalawieh, 2015).
No attempts have been made to test the chemotherapeutic potential of TQ at the clinical level despite its promising anti-cancer effects. At this moment, there are much experimental data that could stimulate the development of clinical studies to evaluate the potential therapeutic effects and the specific cellular and molecular mechanisms of nigella sativa seeds, alone or in combination with other drugs.

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