Abstract
Glioblastoma multiforme (GBM) is classified as a grade IV brain tumors. It is a very aggressive, malignant, and lethal brain tumor having 10–15 months of median survival rate. Currently, chemotherapeutics used for treatment have limitations of low efficacy and toxicity which gets further compounded by development of chemoresistance. There is a need to explore alternative treatments for GBM to augment the existing chemotherapeutics presently in use. The plant-derived compounds through their alternate mechanism of action may have an emerging strategy to prevent brain tumor. It can be used as single compound or combined with standard chemotherapeutic. Phytochemical can help to augment the efficacy, reduce toxicity, and improve the prognosis. All across the world, a range of different types of medicinal plants exist; out of these numbers of medicinal plants have anticancer properties. It has been shown that some phytochemicals have anti-invasive, anti-angiogenic, antiproliferative, and pro-apoptotic effects under in vitro conditions, while there are far less clinical trials on phytotherapeutics to prove its efficacy. Thus, the aim of this chapter is to focus on plant-derived compounds which have anticancer properties (like curcumin, resveratrol, lycopene, gingerol, etc.) toward their effect on brain tumor and their future prospects. The development of novel therapeutics that can improve survival in patients with GBM is need of the hour.
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9.1 Introduction
Brain tumors lead to mortality and can often result in CNS debilities. There are different types of brain tumor, but the glioblastoma multiforme (GBM) is the most common type and very aggressive in nature. GBM is a high-grade form of brain tumor (IV) with poor outcomes. The median survival rate of patients with GBM is only 14.2 months (Johnson and O’Neill 2012). The current standard treatment for GBM, a chemotherapeutic agent Temozolomide (TMZ), usage is restricted due to reversal of methylation by functional protein MGMT (O6-methylguanine DNA methyltransferase) in cells (Hottinger et al. 2014). The chemotherapeutic treatment may be given as single agent or in combination with other drugs. The efficacy of chemotherapy is commonly restricted: the diffusion of chemotherapeutic into the brain is naturally incomplete because most of the anticancer drugs do not have blood-brain barrier permeability (Oberoi et al. 2016; Sarkaria et al. 2018). Moreover the heterogeneity of GBM cells complicates the efficiency of treatment. Chemotherapy is accompanied by various side effects including drug resistance, hair loss, cardiac toxicity, and immune suppression. Thus there is a requirement for alternative therapeutics which are tumor-specific agents and have cytotoxicity against cancer cells. There are a number of plant-derived compounds which have anticancer properties (Tuorkey 2015). Certain plant-derived alkaloids, vincristine and vinblastine, and podophyllotoxin have been used for the treatment of cancer. Phytochemicals due to varied structures and mechanism of action can be novel therapeutics for the treatment of cancer. Some of the phytochemicals can potentiate the activity of drugs and help in enhanced action and counter the resistance. Some phytotherapeutics like curcumin, resveratrol, lycopene, gingerol, allicin, etc. have shown antiproliferative activity in glioblastoma and have been discussed in detail.
9.2 Types of Glioblastoma Multiforme
The World Health Organization updated its earlier 2007 CNS classification by incorporating the molecular parameters along with histological diagnosis. This classification being more precise gives an edge to neuro-oncologists toward accurate diagnosis, prognosis, and planning for treatment. GBM, grade IV brain tumor, arises from astroglial cell in CNS. These star-shaped astrocytes support the nerve cells. GBM mainly develops in the cerebral hemispheres but has also been reported in the brain stem or spinal cord. WHO classified GBM on the basis of change in isocitrate dehydrogenase (IDH) gene sequence. According to WHO 2016 classification, there are two types of GBM.
9.2.1 Glioblastoma, IDH Wild Type
This type of GBM arises de novo and is mostly found in patients ~55 years of age. Primary GBM has wild-type IDH enzyme and is estimated to be present in about 90% of cases. A new type of GBM has been added to the classification which is epithelioid glioblastoma. It consists of giant cell glioblastoma and gliosarcoma under IDH wild-type GBM. They consist of large epithelioid cells and mostly have valine to glutamic acid mutation in serine threonine protein kinase BRAF responsible for activating MAP kinase pathway (Louis et al. 2016).
9.2.2 Glioblastoma, IDH Mutant
This is secondary type, estimated in about 10% of cases, which arises from the lower grade of tumor and is mostly detected in younger patients. Mutation in IDH produces 2-hydroxyglutarate which is oncogenic in nature. Mutant forms of IDH can be recognized by immunohistochemistry, and they have been linked to improved prognosis (Chen et al. 2016).
9.3 Blood-Brain Barrier (BBB)
The BBB is a tight junction between the blood vessels and glial cells or transcellular pathways which allow restricted number of molecules to the brain. It has a key role in protecting the brain from pathogens and harmful substances. The endothelial cells of blood vessels are the main constituents of BBB apart from astrocytes, pericytes, and extracellular matrix. Most of the protein-based molecules enter through transport system across the BBB (Dréan et al. 2016). The data has supported that BBB is more irregular and leaky in glioblastoma patients as evident by the presence of otherwise impermeable radiographic contrast. At the same time there are certain tumor regions which have intact BBB, and drugs need to permeate through this barrier to be effective (Sarkaria et al. 2018). Most of the clinical trials for GBM chemotherapy have failed due to poor permeation of therapeutics through the BBB. In silico model has been developed to forecast the ability of the drug to cross the BBB, but the method has its limitations, and the accurate prediction is still a challenge. The model combined with in vitro and in vivo data yields better results. Thus, there is a need to identify the novel agents or integrate them with existing therapeutics for improved brain delivery and effective treatment. Thus, a critical part of solving the BBB challenge is effective drug delivery to improve the bioavailability of the drugs in GBM cells.
9.4 Plant Extracts/Phytochemicals and Their Therapeutic Approaches
Various plant extracts and their derived compounds found to be effective against GBM have been discussed in detailed below.
9.4.1 Curcumin
Curcumin is a natural hydrophobic phenolic compound, which is extracted from turmeric rhizomes. There are numerous in vitro and in vivo studies which have analyzed the efficacy of curcumin against GBM (Rodriguez et al. 2016). Curcumin antiproliferative effects on GBM cells have been attributed to increase in apoptosis and also via suppression of pathways linked to cell division. Certain apoptotic promoting proteins like p21 and p53 and executioner caspases have been upregulated by curcumin (Rodriguez et al. 2016). Curcumin induced apoptosis in human U87-MG and U373-MG glioma cells by downregulating protein kinase B (AKT) pathway (Sordillo et al. 2015). The antitumor application of curcumin is very limited, because it has poor water solubility and low bioavailability as reported in in vivo studies for GBM therapy. A recent research has shown that targeted drug delivery by RDP-modified nanoliposomes of curcumin in brain tumor improved the water solubility as well as biocompatibility. RDP is a derivative of rabies virus glycoprotein which is capable of crossing BBB. The results of this study suggest that the nanoliposome of curcumin can significantly inhibit the glioblastoma growth as a therapeutic approach to cure the GBM in vivo (Zhao et al. 2018). One of the major causes of GBM resistance is the presence of stem cell population in tumor cells. Gersey et al. showed that curcumin significantly inhibited the growth of GBM-like cancer stem cell (GSC) lines, by inducing reactive oxygen species (ROS), activating the MAPK pathway, and downregulating the expression of STAT3 and IAPs (inhibitors of apoptosis) (Gersey et al. 2017).
Curcumin has been shown to potentiate the effect of temozolomide in inducing apoptosis in GBM cells. Curcumin also showed significant antiproliferative effects against GBM in combination with nimustine hydrochloride (ACNU). The apoptosis was caused by the arrest of cell cycle in G2/M phase as confirmed by the reduced levels of key regulators of the M phase proteins, cyclin B1, CDK1, and CDK 2. Moreover the combination of curcumin with ACNU markedly inhibited the pro-survival pathways like AKT and NFĸB and significantly lowered the levels of matrix metalloproteinases, N-cadherin, and vimentin, the markers of migration and invasion. The treatment with combination of ACNU and curcumin might be quite effective to cure GBM (Zhao et al. 2017).
9.4.2 Resveratrol
Resveratrol is a polyphenol found in nature (in red wine, berries, peanuts, soybeans, etc.). Resveratrol is beneficial for health because it has anti-inflammatory, antioxidant, and neuroprotective properties. It also has anticancer properties and can inhibit all stages of cancer (initiation, promotion, and progression) (Jiao et al. 2015). Resveratrol significantly showed antiproliferative and anti-invasive properties in GBM stem like cells which are responsible for increased resistance to drugs in tumor. Resveratrol could modify the gene expression of Wnt signaling and also downregulated epithelial-mesenchymal transition (EMT) markers as evident by decreased levels of Twist 1 and Snail1, transcription factors, crucial for differentiation and migration in cancer. Resveratrol might be a novel therapeutic approach for GBM treatment, due to its ability to cross BBB, and can cause apoptosis and invasion in GBM-like stem cells. Still further research is needed to understand the response of GSC to the plant compound (Cilibrasi et al. 2017). Resveratrol also inhibited GSC growth in GBM, by targeting p53 via AKT pathway, and inhibited the growth of GBM in vivo. It did not show any toxicity even after intracranial injection but exhibited low bioavailability, when given orally as well as intravenously. Thus resveratrol if delivered specifically or via novel delivery routes could be a useful compound (Clark et al. 2016). Resveratrol in combination with TMZ could reduce the TMZ resistance in GBM by inhibiting NF-κB-MGMT molecular pathway. The data proposed it as novel combination with TMZ; at the same time, it should be additionally investigated in preclinical studies or in vivo models (Huang et al. 2012). To overcome the poor bioavailability, resveratrol was PEGylated in liposomes having transferrin on its surface. Transferrin was used for specific delivery as transferrin receptor is overexpressed in GBM cells. Resveratrol liposomes thus generated were more cytotoxic to GBM cells both by in vitro and in vivo model (Jhaveri et al. 2018).
9.4.3 Allium sativum
Allium sativum is one of the plant therapeutics which is known to have sulfur-containing organic compounds. Garlic main constituents include allicin, S-allyl cysteine, diallyl disulfide (DADS), diallyl trisulfide (DATS), alliinase, and methylallyl trisulfide. Epidemiological studies also suggest that improved diet of garlic may decrease the chances of cancer and also have anti-atherosclerosis, antifungal, and antimicrobial properties (Mathan et al. 2017). It has been reported that DATS and DADS increase the calcium levels in human glioblastoma cells (Das et al. 2007). DADS and DATS could activate the endonucleases, which play a role in calcium-dependent apoptosis in cells (Rizzuto and Pozzan 2003).
A study found that allicin (garlic compound) inhibited the cancer cell growth on U87MG cell line and also induced apoptosis via Bcl-2/Bax mitochondrial pathway (Cha et al. 2012). Another research also suggested that Z-ajoene (garlic derived compound) targeted CSCs (cancer stem cell) in glioma and may reduce the activity of AKT and TGF and increased the activity of ERK/p38 (Jung et al. 2014).
9.4.4 Evodiamine
Evodiamine, an alkaloid extract from Evodia fructus, is commonly used in China. Research has reported that evodiamine showed anti-inflammatory and antitumor effects in cancerous cell lines. Evodiamine inhibited the cell proliferation in glioma cells (U87 and C6) by inducing apoptosis and cell cycle arrest at G2/M stage. Evodiamine upregulated p53 protein and simultaneously p38 and c-Jun N-terminal kinase (JNK) pathway-mediated autophagy, disrupting the mitochondrial membrane potential (Wang et al. 2018; Wu et al. 2017). P38 and JNK are the types of MAP kinase cascades along with extracellular kinase 1 and 2 (ERK 1/2) and ERK5. Moreover the data also supported increased ROS levels. It has been reported that evodiamine sensitized U87MG GBM cell line to TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) and enhanced the cytotoxicity of the cells. TRAIL caused apoptosis by inducing expression of death receptors and executioner caspase-3. Thus, the combinatorial therapy of evodiamine and TRAIL might be a hopeful chemotherapeutic for GBM treatment (Khan et al. 2015).
9.4.5 Perillyl Alcohol
Perillyl alcohol (POH) is a monoterpene which is a naturally occurring compound, having anticancer properties. In a clinical trial, the patients were treated with POH by nasal route. The regular POH inhalation chemotherapy is a nontoxic approach effective for recurrent GBM, and its efficacy could be improved by incorporating ketogenic diet (Da Fonseca et al. 2013; Santos et al. 2018). In another clinical trial, intranasal POH treatment caused reduction in tumor size and also improved the overall survival (Da Fonseca et al. 2013). POH mediated its action via inhibiting Src protein kinase and activation of JNK-induced apoptosis by caspase-3 upregulation. Furthermore, POH arrested cell cycle in G2/M and prompted enhanced Fas-mediated cell death which is the extrinsic pathway of apoptosis. It has also been reported that POH acts by preventing the GTPase Ras protein isoprenylation by hindering their binding to the cytoplasmic membrane and leads to the inhibition of Ras signaling. The POH also inhibited the growth of GBM cells by blocking Na/K-ATPase, which is overexpressed in GBM cells (Garcia et al. 2015).
9.4.6 Rhazya stricta
Rhazya stricta belongs to the family Apocynaceae, which includes a number of flowering plants like trees, herbs, shrubs, and stem succulents. It is a perennial species that grows in moist and arid regions and carries out C3 cycle of photosynthesis under extreme heat, intense light, and less moisture in air. It has been reported that the species is a good source of antioxidants. More than 100 types of alkaloids have been isolated from different parts of this plant (Gilani et al. 2007). These alkaloids are the most important components in this natural herb, and they have been reported to show antiproliferative and anti-metastasis properties on different cancers under both in vitro and in vivo conditions (Lu et al. 2012).
Elkady et al. (2014) demonstrated that R. stricta extract had dose- and time-dependent cytotoxic effect on U251 GBM cell line. The extract induced apoptosis in the GBM cells as phosphatidylserine, otherwise, present in the inner membrane, gets exposed to outer region of membrane and is bound via fluorescent dye annexin V. Intrinsic pathway of apoptosis through the release of cytochrome C from mitochondria triggered the apoptosome formation by activating initiator caspase 9. The whole process was supported by pro-apoptotic proteins like bax and bak and accompanied by the downregulation of anti-apoptotic Bcl2 family of proteins (Wong 2011). Apoptosome activated caspase 3 which in turn cleaved PARP-1 (Poly [ADP-ribose] polymerase 1) enzyme, which is overexpressed in glioblastoma (Elkady et al. 2014).
9.4.7 Zerumbone
Zerumbone is a sesquiterpene compound which is isolated from the rhizome of a subtropical species of ginger called Zingiber zerumbet. This particular compound is known to exhibit antitumor and ant-inflammatory activities. It has been reported that zerumbone actuates apoptosis in GBM (GBM8401) cells (Weng et al. 2012). The mechanism by which zerumbone activates apoptosis in GBM8401 cells is through IKKα-Akt-FOXO1 cascade. It has been observed that in case of glioblastoma, NF-kB is overexpressed as there is excess of the kinase IKK in GBM cells. IKK prevents inactivation by inhibitor IkB and resulted in phosphorylation and degradation of FOXO-1 transcription factor. Zerumbone decreased the levels of phosphorylated IKKα and also suppressed the Akt pathway. It has also been reported that zerumbone could sensitize the GBM cells to radiations (Chiang et al. 2015).
9.4.8 Other Phytochemicals
9.4.8.1 Lycopene
This is a phytochemical which belongs to carotenoids pigment group and is lipophilic in nature. It is derived from tomato. Several studies have shown that it has anticancer effects both in vivo and in vitro (Holzaplfel et al. 2013). The anticancer and pro-apoptotic molecular mechanism of lycopene is mediated via cell cycle regulatory proteins such as cyclin D1, which arrests the cell cycle in G0/G1 to S phase. In a clinical trial, treatment with lycopene showed significant improvement in median survival as compared to control group (Puri et al. 2010).
9.4.8.2 Gingerol
Gingerol is an active component derived from fresh ginger (Zingiber officinale). Gingerol is normally extracted as pungent yellow oil but can also be converted into crystalline solid with low melting temperature. Gingerol induces TNF-ligand-mediated extrinsic apoptosis in GBM cells by upregulating expression of death receptors on the surface of GBM cells (Aggarwal 2003). The mechanism behind TRAIL is that the ligand upon binding to its receptor induces its trimerization, which causes recruitment of downstream signaling molecules such as Fas-associated proteins with the inner cytosolic death domain (FADD), and this finally leads to activation of caspase cascade (caspases 8, 9, 10, and 3) to transmit signals further into the nucleus of tumor cells (Aggarwal, 2003; Bellail et al. 2010). The sensitizing effects of Gingerol on death receptor were studied on the following glioblastoma cell lines: U87, U343, and T98G. Gingerol helped to elevate the level of expression of death receptor so that the receptor can transmit death signals which are stronger and persistent, such as caspase cascade. Gingerol decreased the expression of anti-apoptotic proteins like Bcl-2 and survivin by downregulating the associated genes whereas induced or increased the expression of pro-apoptotic protein like Bax. It has been reported that Gingerol can be combined with TRAIL for the treatment of TRAIL-resistant glioblastoma patients (Lee et al. 2014).
9.4.8.3 Gossypol
Gossypol is a naturally occurring phenolic compound that has been extracted from cotton plant or Gossypium. It is a yellow pigment which is able to penetrate cell membrane and inhibit several dehydrogenase enzymes. Gossypol binds to the BH-3 motif of anti-apoptotic proteins like Bcl-2 and inhibits the growth and proliferation of glioblastoma cells (Voss et al. 2010). The studies also suggest direct involvement of gossypol in suppression of angiogenesis and metastatic behavior of glioma cells (Jiang et al. 2011). The in vivo effects of gossypol were studied on a subcutaneous GBM (U87MG-luc2) model developed on mouse. The researchers showed the antiproliferative effect of gossypol on GBM cells (Jarzabek et al. 2014). It was also shown that gossypol when given along with TMZ as a combination therapy could inhibit the invasive nature of GBM cells. This property was attributed to the inhibition of matrix metalloproteinase-2 (MMP-2), a marker for invasion (Bruna et al. 2007).
Another study explored the effectiveness of gossypol along with phenformin for combination therapy in treatment of tumor cells by targeting the bioenergetics of glioma cells. Gossypol along with phenformin exhibited a dual inhibition mechanism of aldehyde dehydrogenase (ALDH) and oxidative phosphorylation in glioma cells (Park et al. 2017). It was observed that the combination therapy was significantly able to reduce ATP levels, stemness, invasiveness, and cell viability. These experiments were carried on a preclinical orthotopic mouse xenograft model for confirmation of above stated results. It has been seen that in case of glioblastoma, several different isoforms of ALDH are upregulated, which in turn undergoes catalytic reaction to produce carboxylic acid and NADH as by-product. Hence we can assume that the metabolism of glioma cells is ALDH dependent. Gossypol prevents formation of ALDH in cancer cells by inhibiting the ALDH1L1 gene, but this effect alone is not able to create an imbalance in the bioenergetics of glioma cells. Therefore in order to enhance the metabolic disruption, another drug phenformin was used which blocked the activity of mitochondrial complex 1, the rate limiting step of electron transport chain, thereby inhibiting oxidative phosphorylation in glioma cells (Park et al. 2017).
9.4.8.4 Osthole
Osthole is a chemically derived compound from coumarin. Coumarin is a natural organic substance found in a variety of plants like Cnidium monnieri. This compound has been shown to suppress tumor movements and tissue invasion in case of glioblastoma cells. A group of proteins called focal adhesion kinase (FAK) play a vital role in metastasis of tumor cells. Osthole prevented the growth and proliferation of glioblastoma cells not only by inducing cell death but also by preventing phosphorylation of FAK. Effects of osthole were studied on HS983 and U125 cell lines which had high mobility. Osthole was also reported to prevent expression of MMP-13 in case of glioblastoma cells. MMP-13 is involved in a number of biological reactions that occur in tumor cells like metastasis, tissue invasion, and cleavage of different proteins; all these events collectively led to progression of cancer (Tsai et al. 2014).
Another study showed that osthole prevented migration in case of GBM8401 cells, thereby preventing the glioma cells to infiltrate other healthy brain cells. EMT leads to metastasis, and this morphological change in cancer cells is induced by a number of growth factors like IGF-1 (Kahlert et al. 2012). IGF-1 induced GBM8401 cells, exhibiting EMT markers, upon treatment with osthole reversed morphological effects. Real-time PCR studies also demonstrated that osthole could prevent growth and proliferation of GBM8401 cells by inhibiting IGF-1-induced EMT by blocking the PI3 kinase pathway (Lin et al. 2014).
9.4.8.5 Gallic Acid
It is one of the major bio-actives and polyhydroxylphenolic compounds, which is widely distributed in various foods and plants, having various pharmacological effects. Gallic acid could cross the BBB, increase the intracellular calcium levels, and result in intrinsic apoptosis through mitochondria and more of ROS production (Hsu et al. 2016). Gallic acid could have both pro- and antioxidant effects on glial cells, and the optimal concentration needs to be used to carry out the desired cytotoxic effects (Paolini et al. 2015).
9.4.8.6 Deoxypodophyllotoxin (DPT)
It is an active and semisynthetic compound derived from Dysosma versipellis. It has multiple biological functions like antiviral, anti-inflammation, and anti-allergic and also turned out to be a potent inhibitor of several cancer cell lines (Khaled et al., 2016). DPT arrested the U-87 and SF126 GBM cells in G2/M phase and showed antiproliferative effect (Guerram et al. 2015).
9.4.8.7 Saponins
They are a class of chemical compounds and glycosides present in various plants. A triterpenoid saponin 1 from Anemone taipaiensis decreased the levels of NF-ĸB and increased the levels of inhibitors of apoptosis (IAP) in U251MG and U87MG glioma cells (Li et al. 2013). Dioscin, another saponin, increased ROS levels and induced apoptosis. Dioscin had marked antitumor effect in rats and improved their survival (Lv et al. 2013). Saikosaponin D, saponin derivative, obtained from Bupleurum falcatum, also had anti-apoptotic effects on U87 glioblastoma cells by activating JNK pathway (Li et al. 2017).
9.5 Conclusions and Future Prospects
GBM is the most common malignant brain tumor which is most difficult to treat. The current standard therapy for GBM has not shown any improvement in the overall survival of GBM. There is dire need to explore and identify novel therapeutics which can be useful to improve the survival chances and prognosis of GBM patients. Furthermore, the standard chemotherapeutics have shown limitations due to drug resistance in GBM. Here we have deliberated some studies that have shown the role of some plant-derived and dietary compounds on GBM cells in both in vitro and in vivo animal models. Certain compounds like curcumin and resveratrol have been researched alone and in combination with other chemotherapeutic drugs toward GBM. Most of the phytochemicals mechanism of killing elicited by inducing apoptosis and cell cycle arrest in G2/M phase. Most of the compounds showed increase in JNK pathway of MAP kinase cascade and mediated the killing of the cell. The data seems to be very promising especially in combination with other drugs where they can not only improve the efficacy of the drug but also reduce the chances of resistance exhibited by the chemotherapy drugs. The phytochemicals when combined with the drug also reduced the toxicity of the compound. The challenge for GBM treatment is the insufficiency of drug delivery due to the BBB, and only small or hydrophobic compounds can cross the BBB. The nanocarriers and nanomedicine of promising plant-derived compounds might help to overcome the challenge of BBB and may improve the bioavailability and GBM therapeutic approaches. The data so far is very limiting in this field and needs to be explored. The research suggests the anticancer role of naturally occurring compounds and indicates that they can be an alternative approach for more effective and relatively nontoxic GBM treatment. A lot of research is required to fully understand their potential and to be used effectively for the treatment of GBM.
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Gautam, M., Srivastav, S., Tiwary, N., Dang, S., Gabrani, R. (2019). Phytotherapeutics: The Substitutes for Glioblastoma Multiforme. In: Swamy, M., Akhtar, M. (eds) Natural Bio-active Compounds. Springer, Singapore. https://doi.org/10.1007/978-981-13-7205-6_9
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