Brain Tumor - Glioblastoma
In humans, the natural hormone melatonin is involved in the sleep-wake cycle and in endocrine function. Melatonin can stimulate the immune system and help fight inflammation (Zheng 2017; Zisapel 2018). For some patients with insomnia, melatonin can help improve their quality of sleep (Kurdi 2016; Wade 2007; Wade 2010).
Recent laboratory evidence has shown that melatonin may inhibit the viability and self-renewal of glioblastoma stem-like cells (Zheng 2017). In a study on glioblastoma stem-like cells isolated from patient surgical samples, melatonin affected cellular signaling pathways involved in cell survival and division (Chen 2016). Melatonin may block glioblastoma cells from invading new areas by inhibiting genes involved in tissue invasion and new blood vessel formation (Zhang 2013). In laboratory studies, melatonin boosted the effects of chemotherapy drugs, including temozolomide, indicating it may be especially helpful for patients undergoing conventional treatment (Martin 2013).
In one early clinical trial, 30 patients with glioblastoma were randomized to either radiation therapy plus oral melatonin (20 mg per day) or radiation therapy alone. After one year, six of 14 patients taking melatonin and only one of 16 patients in the control group were still alive. The authors also noted that side effects of radiation were less frequent in the melatonin group (Lissoni 1996).
Vitamin D and some of its metabolites can stop glioblastoma cells from dividing in a laboratory setting (Garcion 2002; Magrassi 1998; Magrassi 1995). Intriguingly, one study found that levels of the vitamin D receptor are increased in glioblastoma tissue samples compared with non-cancerous brain tissue. Patients with the vitamin D receptor present in their tumors had a better outcome in one retrospective analysis (Salomon 2014). A laboratory study showed that vitamin D enhanced the toxicity of temozolomide against glioblastoma cells. Also, combined treatment with temozolomide and vitamin D prolonged survival and reduced tumor progression in a rat model of glioblastoma (Bak 2016).
Selenium is an essential trace element (Tinggi 2008). The first clinical evidence of a link between selenium and brain cancers came when it was found that selenium levels in the blood were significantly lower in patients with brain malignancies than in healthy individuals (Philipov 1988). Clinical studies have not yet confirmed the benefit of selenium supplementation for glioblastoma patients, but laboratory studies suggest selenium may reduce some of the negative effects of chemotherapies while making cancer cells more sensitive to chemotherapies (Yakubov 2014). For instance, sodium selenite decreased cell proliferation and caused cell death in several types of human glioblastoma cells (Hazane-Puch 2016). In another laboratory study, sodium selenite inhibited the proliferation of human glioblastoma cells and rat glioma cells (Zhu 1995). A mixture of nutrients that contained several ingredients, including selenium, lysine, proline, ascorbic acid, and green tea extract, significantly decreased the ability of glioma cells to invade through a gelatinous material used in the laboratory to study tumor dissemination (Roomi 2007). A study that chemically linked selenium to temozolomide reported that the new compound was effective against temozolomide-resistant glioma cells; also, in human glioblastoma cells, the new compound caused DNA breaks and killed the cells more effectively than temozolomide alone (Cheng 2012).
Carotenoids, which are precursors of vitamin A, and retinoids, which are derivatives structurally similar to vitamin A, have shown anti-oxidative properties and protective effects against certain cancer types (Niles 2000; Uray 2016; Milani 2017; Shapiro 2013). The anticancer effects of one retinoid, called all-trans retinoic acid (ATRA), have been examined in several studies (Haque 2007; Yang 2018; Yin 2017). ATRA, either alone or in combination with a drug called rapamycin, stimulated glioblastoma cancer stem cells to change into specialized cells and slowed their movement (Friedman 2013). Another study found that ATRA disrupted the movement of stem-like glioma cells and decreased production of chemicals that stimulate blood vessel formation (Campos 2010). A recent study found that ATRA enhanced the effects of temozolomide on human glioblastoma cells (Shi 2017). The treatment of human glioblastoma cells with ATRA or another retinoid, called 13-cis retinoic acid or isotretinoin, made the cells more likely to die when exposed to the chemotherapy drug paclitaxel (Taxol) (Das 2008). Bexarotene (Targretin), a retinoid used to treat lymphoma (Zhang 2006), inhibited the migration of glioblastoma cells and changd the expression of several cancer-related genes towards a more beneficial profile. The compound also killed tumor cells in a mouse model of glioblastoma multiforme (Heo 2016).
The beneficial effects of retinoids have been explored in clinical trials that enrolled patients with glioblastoma (Yung 1996; See 2004; Levin 2006). Isotretinoin has been explored in several studies as maintenance therapy, intended to help delay tumor recurrence. One retrospective analysis found that patients taking isotretinoin lived for an average of approximately 25 months without disease progression, as compared to an average of approximately 8 months in those not taking isotretinoin (Chen 2014). The most common side effects were skin-related (Yung 1996).
There are naturally-occurring plant compounds under investigation for their anti-tumor properties, such as boswellic acids, which are gum resin extracts of Boswellia plants (Schneider 2016; Strowd 2015). Boswellic acids have shown promise in cell culture experiments and animal studies against several cancer types, including colorectal cancer, glioma, prostate cancer, pancreatic cancer, and leukemia (Roy 2016). In particular, these potent compounds can induce cell death, suppress inflammation, decrease tissue invasion and blood vessel formation, and inhibit signaling pathways that stimulate cancer development (Roy 2016; Winking 2000).
A recent study described experiments designed to determine whether boswellic acids could enhance the anticancer effects of standard therapies, such as temozolomide or radiation. The treatment of human glioblastoma cells with boswellic acids led to cell death. When boswellic acids were used in combination with temozolomide or radiation, a combined effect greater than the sum of their separate effects was observed, indicating that boswellic acids could be a promising complementary medicine for patients with glioblastoma (Schneider 2016). Boswellic acids are also helpful in reducing brain swelling, which may develop as a result of brain tumors or their treatment with radiation therapy (Lin 2013; Brandes 2008; Streffer 2001). One study tested the effects of H15, a boswellic acid-containing extract from the gum resin of the Boswellia serrata plant, on brain swelling in 12 patients with brain tumors. Swelling was reduced in two of seven glioblastoma patients (Streffer 2001). In a second study, 44 patients with brain tumors took either 4,200 mg daily of a Boswellia extract or a placebo while undergoing radiation therapy. The Boswellia extract group had a significant decrease in brain swelling compared with the placebo group. An over 75% reduction of swelling was seen in 60% of patients receiving the extract versus 26% of patients receiving placebo (Kirste 2011).
Curcumin (diferuloylmethane), derived from the Curcuma longa plant, is a component of the spice turmeric (Sordillo 2015). Several laboratory studies have examined the cellular effects of curcumin on glioblastoma cells. Curcumin affects several cancer pathways necessary for cell division, survival, invasion, and metastasis (Klinger 2016; Rodriguez 2016). Curcumin may reduce or even eliminate glioblastoma stem cells, which are notoriously unaffected by chemotherapy, by reducing their number, killing them, or changing them into a less dangerous cell type (Sordillo 2015; Fong 2010; Zhuang 2012).
One study used a form of curcumin bound to an antibody to help target curcumin to the glioblastoma cells and nearby microglia, a type of support cell in the central nervous system. The combination was used to treat mice with glioblastoma. Remission of the glioblastoma was noticed in half of the animals. Laboratory analyses indicated curcumin killed the glioblastoma cells and improved the ability of the microglial cells to kill nearby cancer cells (Mukherjee 2016). In another study in mice, animals were transplanted with human glioblastoma cells and treated with curcumin. Curcumin crossed into the brain, inhibited the formation of new blood vessels, and decreased the hemoglobin concentration in the tumors (Perry 2010).
There is also evidence that curcumin may enhance the efficacy of chemotherapy drugs (Klinger 2016). In a laboratory study on glioblastoma cells, curcumin increased the anti-proliferation, anti-migration, and cell death activities of nimustine hydrochloride, a chemotherapy drug widely used for treating glioblastoma. This combined treatment might be a promising therapeutic approach (Zhao 2017). Curcumin may also have an effect on cancer cells through its ability to increase the production of ceramide, a type of fat molecule (lipid) found within the membranes of cells, where it has important roles in signaling (Moussavi 2006; Burgert 2017; Stancevic 2010). This finding is important because increased ceramide has been found to sensitize glioma cells to chemotherapy (Grammatikos 2007).
Resveratrol is found in certain plants (Valentovic 2018). Blueberries and grapes are excellent sources (Zeng 2017). Resveratrol is being explored as a potential anticancer treatment that may affect each of the three major stages of cancer development: initiation, promotion, and progression (Jang 1999).
In one study, resveratrol inhibited the growth of human glioblastoma cells and caused cell death in a dose-dependent manner (Mirzazadeh 2017). It also inhibited the growth of glioblastoma stem-like cells and suppressed the growth of glioblastoma in a mouse model (Clark 2017). A research study examined glioblastoma-initiating cells, which are tumor cells with increased invasive potential (Mughal 2015) that have been linked to resistance to treatment (Rivera 2013). Resveratrol inhibited a signaling pathway in these cells and suppressed the production of a protein involved in cellular invasion (Jiao 2015). In a laboratory study that used several glioblastoma cell types, resveratrol inhibited cellular movement and invasiveness by activating a major signaling pathway (Xiong 2016).
Resveratrol may also increase the sensitivity of the cancer cells to temozolomide and radiation. In one study, glioblastoma-initiating cells were isolated from two patients with glioblastoma. Resveratrol sensitized these cells to temozolomide (Li, Liu 2016). In in vitro studies and mouse models, temozolomide more effectively induced cell death and inhibited cell migration when used together with resveratrol (Li, Liu 2016; Yuan 2012). Resveratrol may overcome temozolomide resistance by reducing the amount of MGMT in the resistant cells (Huang 2012). In a glioma stem cell line resistant to radiation, resveratrol increased the sensitivity of the cells to radiation (Wang 2015).
Quercetin is a naturally occurring plant flavonoid with many potential anticancer properties (Vidak 2015; Natural Medicines Database 2017). Multiple laboratory experiments have demonstrated that quercetin can kill human glioblastoma cells. Quercetin may also inhibit the ability of glioblastoma cells to metastasize (Liu, Tang, Yang 2017; Liu, Tang, Lin 2017; Kim 2013), reduce their viability (Pan 2015; Kim 2013), decrease their ability to proliferate and migrate (Michaud-Levesque 2012), and inhibit blood vessel formation (Liu, Tang, Yang 2017). Other research found that quercetin may increase the sensitivity of glioblastoma cells to temozolomide and radiation (Sang 2014; Pozsgai 2013).
Green Tea and EGCG
Epigallocatechin-3-gallate (EGCG) is a green tea flavonoid with known anticancer, antioxidant, and anti-inflammatory activities (Siegelin 2008; Chu 2017). In laboratory studies that used human glioblastoma cell lines, exposure to EGCG contributed to cell death (Siegelin 2008; Yokoyama 2001). EGCG targets several cellular events mediated by matrix metalloproteinases, including some pathways that control cellular migration (Annabi 2002). EGCG can also inhibit a protein that makes glioblastoma cells more resistant to chemotherapy and blocks their death (Bhattacharjee 2015). In human glioblastoma stem-like cells, EGCG synergized the effects of temozolomide (Zhang 2015). EGCG and other catechins from green tea may fight cancer partly through their ability to inhibit the activity of an important cellular signaling pathway (Sachinidis 2000). In two different human glioblastoma cell types, EGCG activated cell death pathways. Interestingly, EGCG did not have this effect on healthy human brain cell (Das 2010). Research in mice with glioblastoma is also encouraging. EGCG significantly improved the therapeutic effects of temozolomide, and the combination extended survival of the mice compared with temozolomide alone (Chen 2011).
Chrysin, a naturally occurring flavonoid found in honey, propolis, and many plants, may fight inflammation and cancer (Mani 2018). Chrysin promoted cell death in studies of several glioblastoma cell lines (Han 2017; Noureddine 2017). Another study found that chrysin reduced the mitochondrial function of glioblastoma cells and decreased the production of a protein involved in tumor invasion (Santos 2015). An extract of propolis killed human glioblastoma cells and enhanced the effects of temozolomide (Markiewicz-Zukowska 2013).
Another plant-derived compound called apigenin inhibited cellular pathways involved in glioblastoma cell proliferation and survival. Apigenin treatment caused the cells to stop at a certain point in their cell division process (Stump 2017). Apigenin also powerfully suppressed the invasiveness of glioblastoma stem-like cells (Kim 2016). This is a significant finding, because stem-like cells can self-renew and are resistant to radiotherapy and chemotherapy (Yi 2016; Gursel 2011). In human glioma cells, apigenin reduced the production of TGF-beta 1, a signaling molecule involved in migration, invasion, and the formation of blood vessels (Freitas 2011). Importantly, apigenin may not have the same effects on normal cells. One study found that apigenin activated cell death pathways in two different human glioblastoma cell lines, but not in normal human astrocytes (Das 2010).
Phytoestrogens are compounds from plants that are similar in structure to the hormone estrogen (Khani 2011). Soy beans, flaxseed, and nuts are all good sources (Carmichael 2011; Cotterchio 2006). In a mouse model of human glioblastoma, a phytoestrogen called genistein inhibited tumor growth after 10 days of treatment. Cellular and molecular analyses suggested genistein slowed tumor growth by decreasing the formation of new blood vessels in the tumor (Liu, Liu 2015). Another study found that genistein may decrease the proliferation of glioblastoma cells by stopping their division and lowering the activity of telomerase, an enzyme that cancer cells need to protect the ends of their chromosomes and survive (Khaw 2012; Jafri 2016).
Daidzein is another phytoestrogen. One study found that daidzein can help activate cellular pathways involved in cell death in glioblastoma cells. Healthy brain cells were not affected by this treatment (Siegelin 2009).
Honokiol is a natural bioactive polyphenol extracted from the bark of the tree Magnolia officinalis. Honokiol had anti-inflammatory, anti-microbial, and anticancer effects in laboratory studies (Cheng 2016; Lin, Chang 2016). Researchers have reported that honokiol can inhibit the division of glioblastoma cells and cancer stem-like cells (Lai 2015) and kill glioblastoma cells by several mechanisms (Zhang, Ren 2014; Liang 2014). The ability of honokiol to cause glioblastoma cell death may result, at least in part, from its ability to stimulate a protein that causes cell death and inhibit a protein that prevents cell death (Jeong 2012). Another study found that honokiol inhibited the interaction between human glioblastoma cells and cells that line the blood vessels, suggesting that it may inhibit the spread of tumor cells via the bloodstream (Joo 2014). In glioblastoma cell culture experiments, honokiol and a similar compound called magnolol were more effective at killing cancer cells when used together (Cheng 2016).
Honokiol is of particular interest for treatment of glioblastoma because studies in mice suggest the compound can cross from the blood into the brain (Lin 2012). In a mouse model of human glioblastoma, honokiol caused cell death and significantly prolonged survival of the mice (Lin, Chang 2016). A number of genes involved in regulating the cell cycle were activated in the treated mice. In a similar study, the combination of honokiol and magnolol inhibited tumor progression and killed cancer cells more efficiently than the chemotherapy drug temozolomide (Cheng 2016).
Polyunsaturated Fatty Acids
Several types of polyunsaturated fatty acids (PUFAs) have been studied for the treatment of glioblastoma. Treating glioblastoma cells with docosahexaenoic acid (DHA), an omega-3 PUFA, led to several cellular and molecular changes that indicate cell death. The authors followed up with an additional experiment in mice with glioblastomas. The mice were altered to express an enzyme that converts omega-6 PUFAs to omega-3 PUFAs. The increase in omega-3 PUFAs was associated with a decrease in tumor volume (Kim 2018). When various types of glioma cells were exposed to different PUFAs, including arachidonic acid, gamma linolenic acid (GLA), and DHA, the expression of certain genes involved in cell death increased (Farago 2011). Open-label clinical studies have suggested GLA may be effective against malignant gliomas (Das 2007; Das 2004). In patients with glioma, delivering GLA directly into the tumor was found to be safe, and in some cases, it led to tumor regression. Several participants survived without new symptoms for up to two years (Das 1995).
Silibinin (silybin) is a biologically active compound in extracts from the seeds of the herb milk thistle (Silybum marianum) (Zou 2017; Ham 2018). In a laboratory study, silibinin inhibited the invasive features of highly invasive glioblastoma cells (Momeny 2010). Another strategy tested silibinin in combination with luteolin, another plant-derived compound. The combination inhibited the growth of glioblastoma cells more effectively than temozolomide, slowed cell migration, and caused glioblastoma cells and glioblastoma stem cells to die (Chakrabarti 2016; Chakrabarti 2015).
Silibinin also works well in combination with arsenic trioxide, a drug approved for treatment of a form of leukemia (Khairul 2017; Lengfelder 2012). In glioblastoma cells, the combination of silibinin and arsenic trioxide slowed tumor cell metabolism and increased cell death (Dizaji 2012). A recent study found that silibinin increased the accumulation of arsenic inside glioblastoma cells treated with arsenic trioxide (Gulden 2017).
Alpha-, beta-, gamma-, and delta-tocotrienol are compounds belonging to the vitamin E group and may help fight cancer and inflammation (Comitato 2017; Abubakar 2015). In a laboratory study, alpha-, gamma-, and delta-tocotrienols inhibited the growth of human glioblastoma cells and caused DNA breaks. Delta-tocotrienol killed the cells more effectively than alpha- and gamma-tocotrienol (Lim 2014). Delta-tocotrienol also worked well in combination with extracts from the Tabernaemontana corymbosa plant, a traditional cancer treatment in Bangladesh (Abubakar 2016), and extracts from plants in the genus Ficus (Abubakar 2015).
Ellagic acid, a natural compound found in many fruits and plants, may also have health benefits for glioblastoma patients. In human glioblastoma cells, ellagic acid inhibited the viability and proliferation of the cells and damaged their DNA. The authors then confirmed these results in mice with glioblastoma and found that ellagic acid inhibited signaling pathways involved in cancer cell proliferation and invasion (Wang 2017). Another study reported that ellagic acid dramatically reduced levels of proteins that protect tumor cells from death (Wang 2016). A root extract of Leonurus sibiricus L, a traditional medicinal plant found in China, Japan, Korea, Vietnam, and southern Siberia, contains ellagic acid and several other polyphenolic compounds. The extract effectively killed human glioblastoma cells by regulating genes involved in cell death (Sitarek 2016).
Chlorogenic acid is a phenolic compound found in coffee, green tea, apples, and pears. The compound inhibited the growth of glioblastoma cells and reduced the growth of glioblastomas in mice. Some of the immune cells in the tumors of these treated mice were changed to a form that can more readily destroy tumor cells (Xue 2017). Another study found that chlorogenic acid inhibited cell migration and the secretion of a protein implicated in tumor invasion (Belkaid 2006).
Folate and Folic Acid
Folate (vitamin B9) is an essential nutrient belonging to the group of B vitamins. Its synthetic analogue is folic acid. Folate is found in a variety of dark green vegetables such as spinach, as well as avocados, strawberries, and orange juice (Bannink 2015; Donnelly 2001; Milman 2012). Folate is required for the synthesis of DNA and RNA and provides the methyl groups that can affect the expression of genes such as MGMT (Greenberg 2011; Blom 2011). A laboratory study showed that exposing glioma cells to folate leads to certain beneficial DNA methylation changes, including methylation of MGMT. The methylation changes were associated with reduced proliferation and increased sensitivity to temozolomide (Hervouet 2009). In glioma cells, exposure to folate also affected the methylation status of the growth factor gene PDGF-B, and significantly decreased cellular proliferation (Zhou 2014).
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