The potential role of natural molecules in the treatment and management of glioblastoma
There are not only synthetic drugs in the treatment of cancer. There is considerable interest in natural molecules to treat tumors, with the paradox that almost half of current anti-cancer drugs are derived from modified natural molecules. However, different molecular entities are under investigation, apart from those of natural antibiotics and alkaloids. Polyphenols are among the most abundant natural substances in the plant kingdom and are often the active ingredients of many medicinal herbs. Several of them have been shown to be effective in in vitro and in vivo systems against many animal and human tumor models. Their mechanisms of action in several contexts are also known and the fact that they have little biological toxicity makes them attractive molecules for an upcoming anticancer therapy of the future. Unfortunately, for polyphenols such as flavonoids their in vivo bioavailability is impaired by some factors, including poor solubility. If we take into account that the brain affects the passage of many substances from the blood through the blood-brain barrier, unless they are fat-soluble, we understand that using polyphenols directly in the treatment of brain tumors is practically unfavorable. Biotechnologies seem to be meeting this problem. The main natural molecules that have been shown to be effective against brain tumors are described below.
Resveratrol (RESV) is an effective antioxidant represented by grapes, blueberries, mulberries and peanuts. It showed that RESV therapy in T98G glioblastoma cells significantly reduces the resistance of temozolomide (TMZ), one of the central chemotherapy drugs used against this tumor. Resveratrol works by downregulating the transcription factor NF-kB and the DNA repair enzyme called MGMT. A mixture of RESV and TMZ significantly reduced the development of the transplanted malignant cells, reducing the survival proteins XIAP and Bcl-2. Another mechanism by which RESV enhances the effects of TMZ is that of activating the fasting-mimicking AMPK kinase pathway (the same one activated by metformin), which reduces the activity of the mTOR complex necessary for the protein synthesis of tumor cells.
Curcumin, a member of the ginger family, is the active component of Curcuma longa (diferuloylmethane) and its anticancer properties have been studied in various cancers such as bowel cancer, breast cancer, lung metastases and brain tumors. In in vitro and in vivo models of multiple tumors, curcumin exhibits substantial growth inhibition, inhibits angiogenesis and induces apoptosis in GBM; it has been shown to attenuate the development of U87 xenografts in intracranial cancer and improve the overall survival of mice. Although it has low human bioavailability leading to weak absorption and rapid removal from the body, its anticancer effects are diminished.
Ramachandran et al. found that cytotoxicity in the U87 cell line was enhanced by the addition of curcumin to etoposide or TMZ. The overexpression of matrix metalloproteinases (MMPs) encourages malignant brain tumor cells to migrate and invade adjacent brain tissues. In human malignant gliomas, these MMPs are upregulated. Curcumin potently disrupted glioma invasion by inhibiting all MAPK pathways and the expression of metalloproteases. Curcumin also induces autophagy in GBM cell lines and xenograft models by inhibiting the AKT / mTOR / p70S6K pathway. Inhibition of PI3K and AKT expression, which controls that of mTOR, is a viable technique for inducing autophagic death in GBM cells.
Green tea catechins
Epigallocatechin-3-gallate (EGCG) is the main catechin present in polyphenolic green tea and has multiple roles as anti-inflammatory, antidiabetic, antiobesity and antitumor. EGCG inhibits the activity of carcinogenesis, tumorigenesis, angiogenesis and triggers cell death. These results are compatible with the evolution of ROS modulation. Although it has dual antioxidant and pro-oxidant properties, its antitumor activity is believed to be due to EGCG-mediated modulation of ROS growth. In contrast to the above overview, several studies have demonstrated the pro-oxidant function of EGCG in the action of anticancer drugs. Li et al. indicated that the oxidative stress of EGCG is compatible with the DNA-induced repair response and apoptosis. Unfortunately, this compound has low bioavailability, rapid metabolism and rapid elimination, which limit its clinical management. However, as a distribution tool to increase its bioavailability, nanotechnology-based techniques are the most promising approach.
Quercetin is a natural flavonoid found in abundance in apples, honey, raspberries, tomatoes, red grapes, cherries, citrus fruits, and green leafy vegetables. The quercetin content in onions is highest among fruits and vegetables. There is growing evidence of the therapeutic value of quercetin for the prevention and treatment of multiple diseases, including cardiovascular, oncological and neurodegenerative diseases. Mechanically, quercetin has been shown to exert antioxidant, anti-inflammatory and anticancer activities in various cellular and animal models, as well as in humans, by modulating the signaling pathways and gene expression involved in these systems. Many studies have shown that quercetin interacts with many proteins, including PI3K / Akt / mTOR, HSP70, MMP-2, Bax, VEGF, IL-6, STAT3 and Bcl-2, which are involved in the formation of the transduction pathways of the signal in glioblastoma cells. Several studies have shown that quercetin mediates cell death via the Caspase-3 / -7 activation pathway, or by causing senescence-like stunting in several glioblastoma cell lines.
Cannabidiol (CBD) is a non-toxic, non-psychoactive cannabinoid that has been shown to have anticancer activity in several types of cancer. Glioblastomas possess specific receptors for cannabinoids of both CB1 and CB2 types. In GBM cell lines, ex vivo primary tumor cells from GBM patients and in tissue biopsies, the expression of these receptors was confirmed. It has been reported that several in vitro and in vivo studies have investigated and the antineoplastic effects of cannabinoids. Preclinical studies have also studied the anticancer effects of cannabinoid combinations (specifically THC:CBD) and have observed that when coupled with CBD, the antineoplastic effect of THC is greater.
A placebo-controlled phase II clinical trial, studying a blend of THC:CBD in combination with intensive dose TMZ in patients with GBM, contributed to these positive effects of THC:CBD preparations in preclinical models. GW Pharmaceuticals has announced promising results in treating GBM in its orphan drug study. Drug resistance was thought to be caused by increased expression of the Nrf-2 antioxidant response mechanism or by the SLC7A11 channel for drug expulsion. Consequently, the researchers hypothesized that combining CBD therapy with inhibition of the SLC7A11 system, using specific modulators, could reduce glioma stem cell survival and tumor invasion.
Gingerol is a phenolic compound found naturally in Zingiber officinale, also known as ginger, which can be used to treat tumors and reduce inflammation. Its functionality is due to several intrinsic active compounds, namely 6-gingerol, 8-gingerol, 10-gingerol, 6-shogaol, 6-hydroshogaol. 6-Gingerol can stimulate cellular autophagy (self-digestion) in U-118MG glioblastoma cells. Gingerol increased the levels of the DR5 death receptor with the help of the tumor suppressor p53. Furthermore, it lowers the abundance of anti-apoptotic proteins (survivin, c-FLIP, Bcl-2 and XIAP) and increases the lethal ones, such as Bax and tBid, through oxidative stress. It was also found that the sensitizing effects of gingerol in cell death induced by TRAIL were blocked by eliminating free radicals, which proves that the molecule acts through oxidative stress. Therefore, gingerol may play a role as a sensitizing agent in inducing the death of glioblastoma cells resistant to the immune molecule TRAIL.
Plumbagin is a quinoid constituent (a naphthoquinone) isolated from the roots of Plumbago zeylanica. It has antiproliferative effects against leukemia, lung cancer, breast, melanoma and prostate cancer. This molecule modulates various signaling pathways, notably Akt / mTOR, NF-kB and the stress kinase JNK. The inhibitory effect of plumbagin mediates DNA damage and apoptosis of comparable intensity and can block telomerase activity. This molecule effectively prevents cell replication, migration and invasion and by arrest in the G2 / M phase. It is interesting to note that both at the mRNA and at the protein level, plumbagin decreases the expression of the nuclear factor FOXM1 with consequent reduction of effectors such as cyclin D1, Cdc25B, survivin. On the other hand, it raises the expression of p21CIP1 and p27KIP which cause cell growth arrest. Therefore, plumbagin can be considered a possible natural inhibitor of FOXM1, leading to the production of new anticancer agents against brain tumors.
Nanotechnology at the service of the clinic
Nanotechnology has emerged as one of the most important fields in recent years, with strong socioeconomic ramifications in several fields. Furthermore, it has been proposed to minimize the amount and frequency of the dose while maintaining a similar pharmacological profile and fewer side effects and this is attributed to the ability of the nanocarrier to deliver within the confined tissue. Patients with malignant brain tumors have a very low prognostic value, despite improvements in surgical techniques and therapeutic protocols. Drug delivery across the blood-brain barrier (BBB) has been the largest barrier in chemotherapy for brain tumors, requiring a drug agent capable of infiltrating the BEE and targeting cancer cells.
Treatment for GBM is often hampered by the inability of chemotherapy drugs to penetrate target cancer cells; the presence of the BBB aggravates the problem. The tight junctions and adherence junctions between brain endothelial cells from the BBB selectively control the movement of ions and nutrients in the brain. These can prevent drugs from accessing malignant cells, causing a subset of stem cells to escape cytotoxicity and develop therapeutic resistance. The weak distribution of chemotherapeutic agents can also be explained by their large-scale hydrophobic nature and the efflux of multidrug-resistant efflux systems expressed by BBB and tumor cells. Consequently, tailored and successful treatment regimens are needed that are able to cross the BEE and reach the desired target in the brain.
Passive permeation of lipid-coupled products, production of a prodrug capable of hijacking the BEE transport system, and drug-loaded nanocarriers are just some of the suggested strategies. Like some small fat-soluble molecules, most other molecules require a particular transport mechanism to cross the BBB. Consequently, a more selective and targeted approach, such as that based on nanoparticles, can be used to create targeted therapies. The nanomedicine of synergistic drug formulations has increased in popularity in cancer therapy, due to its promise of offering superior therapeutic benefits to conventional drug combination therapy used in clinical practice. Colloidal structures, such as the nanoparticle system, enable the production of nanocarriers with surface properties that transcend biochemical / biophysical barriers and can be optimized to transport drugs through the BBB.
In addition, the surface properties of the nanocarriers can be modified to enable the targeted and controlled delivery of drugs with minimal side effects and greater efficacy. Liposomes, dendrimers, polymer micelles, and carbon nanotubes are examples of nanomaterial-based chemotherapy agents that have been shown to bypass BBB and enter the target site of action. The production of some of these materials initially encountered many difficulties, which made their clinical use almost prohibitively expensive from an economic point of view. This is why supramolecular chemistry has made great strides in the past 20 years to develop efficient, simple and inexpensive synthesis strategies, for the production of these special materials.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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