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NeuroPhytomedicine
FIGURE 8.5 Neurophytomedicine and biotechnology.
8.6 FUTURE PROSPECTIVE OF PHYTOMEDICINE
IN DISEASE CONTROL
The ongoing environmental issues related to climate change lead to serious health
problems in humans. The conventional allopathic medication process becomes
incapable of dealing with these ongoing challenges as it is unable to cure the
root causes of the diseases. Under this scenario, traditional medicinal practices
like Ayurveda are gaining importance. The importance of phytomedicine is
increasing day by day in order to achieve sustainability in the health care sector.
Underthese circumstances, the advancement of phytomedicine with the help of
modern technology becomes a necessary step in order to improve the health of
humans. The application of modern technologies like nanotechnology, biotechnology, and genetic engineering improves the quality and efciency of phytomedicines. The genomic, proteomic, and transcriptomic study of medicinal plants
leads to the advancement of phytomedicines. Biotechnology will increase the
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productivity and efciency of medicinal plants, resulting in advancements in both
the health and agricultural sectors. The application of nanotechnology enables
sustainableand eco-friendly growth of medicinal plants by increasing productivity through the application of nanofertilizers and nanoremediators. The in vivo
efcacy of neurophytomedicines will be increased by the application of nanocarriers that will lead to effective targeted and non-targeted drug delivery. The production of bioactive secondary metabolites will be increased in the plant body by the
application of specially engineered genes through nanocarriers. The phytokinetic
study of neurophytomedicines can be improved by using nanosensors, which will
allow for a more detailed in vivo study of neurophytomedicine mechanism. The
neuroinformatic study reveals the detailed biological mechanisms of the nervous
system, whereas the bioinformatic study of the plant extracts leads us to study
the bioactive mechanisms of phytoconstituents. It results in the development of
more effective neurophytomedicines for the sustainable treatment of neurological
diseases (Figure 8.6).
FIGURE 8.6 Future prospective of neurophytomedicine.
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The detailed study of neuroinformatics facilitates the preparation of databases
for the biological functions of the nervous system. The neuroinformatic study of all
sensory, motor, and interneurons activities must be improved in order to develop
effective phytotherapeutic techniques for the treatment of nervous system dysfunctions as well as psychological disorders.
Moreover, the phytochemicals have the potential to act as potential biomarkers by
effectively interacting with the DNA, proteins, and other biomolecules. It will help to
study the pharmacokinetic mechanism of the medicinal products within the nervous
system, leading to the development of research in the elds of neurology, pharmacology, and herbal medicine.
Modern biotechnological innovations enable the development of new herbal
plants that produce more medicinal secondary metabolites. It will facilitate the
development of the eld of herbal medicine and also improve the pharmacokinetic
efciency of the phytochemicals in the nervous system.
The development of nanophytomedicine improves the in vivo efcacy of phytomedicines by improving phytochemical bioavailability and delivery mechanisms in
the body.
The promotion of neurophytomedicine also facilitates the development of tribal
populations, as a large proportion of herbal plants belonging to tribal areas have
potential therapeutic properties. It also increases the availability of herbal drugs.
Furthermore, many tribes have unique knowledge about the use of phytomedicines
that can be incorporated into formal medical sciences for the benet of both sidesof
society. The use of nanotechnology and biotechnology increases the in vivo efcacy of neurophytomedicines by increasing the solubility and bioavailability factors of herbal products. The phytochemicals have already shown efciency in the
treatment of serious pandemics like COVID-19. The mental stress and trauma generated due to the change in social behavior resulting from the recent outbreak of
COVID-19 viruses can be effectively mitigated by the use of phytomedicines. The
health policy should focus on increasing the acceptability of neurophytomedicines
by replacing traditional allopathic medicines for the effective treatment of sensitive nervous system diseases as well as behavioral disorders. Neurophytomedicines
require additional in vitro and in vivo research before they can be used effectively.
The promotion of traditional Ayurvedic plant products in the treatment of chronic
diseases enhances the scope of rural employment and income for small and marginal
farmers associated with it.
NeuroPhytomedicine
8.7 CONCLUSION
The allopathic approaches to medicinal treatment based on the remediation of a
target disease are becoming an outdated idea in today’s scenario as the prevalence
of chronic diseases is increasing due to the changing nature of the environment.
The improvement of overall body function and the boosting of the immune system become the basis of modern medicinal treatment, just like in ancient times.
Phytomedicines are gaining importance in the effective treatment of chronic diseases due to their potential to improve the efciency of removing the root cause
of disease by keeping the balance among the physiological, mental, and emotional
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health of human beings. The nervous system is one of the most important and sensitive physiological systems, as it controls other body functions. The risk of allopathic
neurological disease dosage increases due to the risk of side effects causing major
damage to healthy neurons. On the other hand, herbal medicines focus on the repair
of the overall nervous system, reducing the risk of side effects. The advancement of
modern technologies like nanotechnology and biotechnology improves the efciency
of phytomedicines. The rapid development of the eld of bioinformatics leads to the
emergence of neuroinformatics, which enables the detailed study of the mechanisms
of the nervous system. In this way, the eld of herbal medicine is developing through
the application of advanced techniques. The adoption of ayurvedic medicine instead
of conventional allopathic medicines promotes the healthy growth of the human
population under the current challenges of global warming and climate change. The
increasing use of phytomedicines also facilitates the egalitarian economic development of society by expanding the scope of the primary sector. The improvement of
tribal populations is also another component of the promotion of Ayurveda. The
emergence of neurophytomedicine plays a signicant role in the achievement of sustainable development in the health sector. It also promotes economic growth and the
development of the economy.
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9
Phytopharmaceuticals as
Adjuncts in Treatment of
Glioblastoma Multiforme
Ameya Kothekar, Rajesh Pradhan,
and Rajeev Taliyan
9.1 INTRODUCTION
Glioma is an aggressive type of solid tumour associated with the central nervous system (CNS) which develops from the glial cells or supporting cells. According to the
latest, World Health Organization (WHO) classication gliomas are further divided
into classes/grades I, II, III, and IV. This classication is done based on pathological
examination of the malignancy degree of the tumour utilizing molecular information (Louis et al, 2016). This classication is important in the clinical scenario as
it helps in determining the type and mode of treatment. Grade I tumours are slowgrowing neoplasms that can be treated surgically. Grade II tumours are tissue invasive and have a high chance of recurrence despite their low capacity for proliferation.
Grade IV gliomas are the most treacherous and it is the nal stage where the tumour
becomes malignant with a signicant risk of death (Louis et al, 2014).
Glioblastoma/glioblastoma multiforme (GBM), with a WHO grade 4, is the most
advanced malignant brain cancer. It is the second most common brain tumour after
meningioma. Intracranial radiation, ionic radiation, and rare genetic disorders like
type 1 and 2 neurobromatosis are the major factors responsible for GBMs (Salvati
et al, 2003). However, other factors like environmental stresses, smoking, drinking, and organochlorides from pesticides have shown no conclusive proof to cause
GBM. Poor prognosis and a median patient survival time of 12–15 months after
diagnosis are the major concerns in GBM (Wen and Kesari, 2008). In total, 95% of
the tumours arise in the supratentorial region and less than 5% originate in the cerebral hemispheres and brainstem (Nakada et al, 2011). Though the occurrenceof this
cancer is lower than other cancers like colon, lung, and breast cancer, the average
years of life lost is about 20 years, thus representing a signicant problem in oncology. Moreover, the prognosis of GBM has hardly changed since the early 1970s.
Even after decades of study, glioblastoma is still one of the most dangerous and
feared cancers. Therefore, the molecular mechanisms must be well studied which
can help in better managing and designing effective therapeutic regimens with
signicant results. The rst line of treatment is still surgery by chemotherapy and
161DOI: 10.1201/9781003389781-9
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radiation. Despite its moderate effect and debatable efcacy, chemotherapy has been
a routine therapeutic option for glioblastoma. The role of chemotherapy is important in treating glioblastoma. GBM is renowned for the development of chemoresistance. This is a key impediment during the development of an effective therapeutic
regime. Temozolomide (TMZ), an oral alkylating agent, is the rst line of drug
for GBM. Methylguanine-DNA methyl transferase (MGMT), a TMZ metabolite,
induces intrinsic resistance to TMZ and is the reason for complications associated with TMZ. After, many studies aimed to explore more effective and efcient
chemotherapeutic targets, bioactive has emerged as excellent adjuncts to traditional
chemotherapy. Plants have a vast array of phytochemicals with the capacity to target
invasive brain tumours and alter oncogenic pathways to aid in causing apoptosis.
These phytopharmaceuticals also inhibit the activity of various oncogenic proteins
that are overexpressed in cancer and are responsible for invasion, metastasis, chemotherapy resistance, and angiogenesis.
In this chapter, the scope of the bioactive as anti-cancer agents against GBM has
been discussed. This chapter also includes their mechanism of action, associated
limitations, and regulatory considerations.
9.2 PATHOGENESIS OF GLIOBLASTOMA MULTIFORME
Understanding the pathophysiology is essential for creating prospective chemotherapeutic drugs as well as for discovering disease biomarkers (refer Figure 9.1). Based on
the presence or absence of lesions, GBM can be divided into two categories: Primary
and secondary. Primary GBM arises without any pre-existing tumours or neoplasia
(Agnihotri et al, 2013). Secondary tumours develop from precursor lesions like astrocytoma or from other lower-grade gliomas within 5–10 years of diagnosis (Cloughesy
FIGURE 9.1 Schematic drawing depicting characteristics of glioblastoma multiforme (GBM).
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et al, 2014). Based on the transcriptional characteristics, previously there were four
classes of glioblastoma classical, neural, pro-neural, and mesenchymal. However,
comprehensive longitudinal analysis of the GBM tumour transcriptome points
towards the existence of three distinct forms of GBM, that is, classical, pro-neural,
and mesenchymal. Tumour-specic biomarkers play an important role in the identication of therapeutic targets. MGMT, IDH (isocitrate dehydrogenase) 1, and IDH2 are
some of the most common biomarkers of glioblastoma (Marumoto and Saya, 2012). A
representative diagram for the pathogenesis of GBM has been depicted in Figure 9.1.
9.2.1 unique histoPAthology of glioBlAstomA multiforme
GBM is characterized by small cells with polymorphism, anaplasia, and signicant
anisokaryosis. These cells are polygonal or spindle-shaped containing acidophilic
cytoplasm and indistinct cellular borders. Their nuclei are oval or elongated, with
coarsely clumped hyperchromatic chromatin and numerous discrete nucleoli in
the centre or peri-centre. Conventional histologic characteristics of glioblastoma
include cellular polymorphism, nuclear atypia, a high mitotic index, and pseudopalisading cells. These pseudopalisading cells are exclusive to malignant glioma and
serve as a protective barrier. Therefore, these cells are used as prognostic markers
for advanced glioma. In glioblastoma, dense migratory zones of cells surround the
necrotic tissue and are termed pseudopalisades or “false palisades.” Necrotic foci
are among the most distinctive characteristics of GBM and have two distinct forms.
Onetype is within the tumour’s central region and is a result of insufcient blood
supply. The other form consists of tiny, irregularly shaped necrotic foci surrounded
by radially oriented pseudopalisading zones. Due to vascular collapse and necrosis,
the pseudopalisading cells co-localize to full their oxygen demand. This vicious
cycle is the primary malignant pathway in cases of glioma. The presence of hypoxia
also causes the activation of perivascular glioma cells. This leads to the generation of
pro-angiogenic molecules that drive the formation of a new vasculature that increases
and hastens the progression of GBM. Excessive vascular endothelial growth factor
(VEGF) expression also causes endothelial cell over-proliferation, resulting in leaky
and damaged blood vasculature. This inhibits the delivery of oxygen, medicines, and
immune cells in the tumour microenvironment.
9.2.2 oncogenic PAthwAys
Many critical cellular functions, such as growth, differentiation, metabolism, and
survival, are regulated by signal transduction pathways. In human cancer, many
of these signalling pathways are disrupted. The biology and clinical behaviour of
GBM have tremendously beneted from research into these signalling pathways
(Figure 9.2). A more comprehensive understanding of signal transduction will aid in
the development of innovative therapies for this deadly disease.
In patients with GBM, the expression of 12 genes were found to be strongly
associated with the characteristic mortality rate. These 12 genes are E2F2 (cell
cycle signalling pathway), CTBP2 (Notch signalling), MAFF (Nrf2 signalling),
SLC2A3 (Nrf2 signalling), ECSIT (PI3K signalling), HSP90B1 (PI3K signalling),
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FIGURE 9.2 Oncogenic signalling pathways involved in GBM.
TNFRSF1A (PI3K signalling), PAK1 (RTK signalling), ID4 (TGF- signalling),
DDB2 (p53 signalling), MDM2 (Han et al, 2022; Sanchez-Vega et al, 2018). Also,
various growth factor receptors corresponding to different oncogenic signalling
molecules like EGFR, PDGFR, and VEGFR are overexpressed in cases of GBM
(Nakada et al, 2007). Mesenchymal-epithelial transition factor (c-Met) is a type
of receptor tyrosine kinase that is needed for epithelial-to-mesenchymal transition
(EMT) during developmental stages. c-Met shows abnormal expression in malignant gliomas like GBM which can be attributed to its aggressive malignancy. These
growth factor receptors are involved in RTK type of paracrine/autocrine signalling.
Some other RTKs unique to GBM are tyrosine kinase with immunoglobulin-like and
EGF-like domains 1 (TIE1), discoidin domain receptor (DDR1), epoxide hydrolase
(EPH1), and Axl. These play an important role in glioma invasion by suppressing the
immune system. Recently, researcher identied ring-like contrasts which surround
the tumours in MRI images and concluded that these contrasts indicate angiogenic
changes during the progression of GBM. Along with VEGF and VEGFR, bronectin, tenascin-C, and vitronectin along with cathepsin B and matrix metalloproteinases (MMPs) are the key angiogenesis factors in glioblastoma. These prevent ECM
degradation via the regulation of collagenase expression. Aberrant activation and
overexpression tumour suppressor protein phosphatase and tensin homolog (PTEN),
sphingosylphosphorylcholine (SPC), Rho kinases, and GPCRs of RTK/PI3K/Akt
cascade (refer Figure 9.1) are prominent in cases of GBM (Sanchez-Vega et al, 2018).
Integrins like β1 and β5 are linked with invasion and migration. RAC of the Rho
GTPase family is involved in lamellipodial formation which is important in tumour
migration. Identifying the mechanisms that contribute to the increase of oncogenic
signalling and other pathways during glioma growth is critical. Such researches lead
to the discovery of new prospective targets, better therapeutic regimen selection, and
personalized medication.
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9.3 THERAPEUTIC APPROACHES TO GBM
Every year cancer claims millions of lives globally. Due to this, innovative and novel
cancer therapeutic approaches are underway. Diagnostic technologies play an important role in the development of therapeutic strategies for cancer treatment. Surgery,
radiation therapy, and chemotherapy are the most common treatment options whereas
hormonal therapy and immunotherapy are some of the recent options. GBM is a type
of brain cancer that is the cause of many hindrances during the development of a
therapeutic approach. Some of them are:
• Intracranial malignancy.
• The danger of irreparable damage to the brain during surgery.
• The blood-brain barrier (BBB) prevents drugs from entering the brain.
• ATP-binding cassettes efux drugs from the BBB.
• Resistance of tumour cells to chemicals.
• Mutations in isocitrate dehydrogenases inhibit complement-mediated tumour
repression.
Thus, the majority of the treatment options are focused on symptomatic relief
(palliative treatment) and improving the patient’s life expectancy. While designing
any treatment option for cancer, certain factors should be taken into consideration.
These are tumour location, potential symptoms, potential benets, and associated
limitations.
9.3.1 surgery
Surgery is one of the oldest yet the go-to options during the initial stages of cancer. Chemotherapy and radiation therapy follow surgery if only surgery is not
an option. The surgery is carried out to remove the tumour and some of the surrounding tissue to prevent metastasis. But it is hardly effective when the tumour
has undergone aggressive metastasis. There are three stages to surgery. The rst
is the diagnosis in which a biopsy is used to diagnose the type of cancer. The
second is staging where the size, metastasis rate, and other parameters are evaluated. The last step is the surgical removal of the tumour by debulking or palliative surgery. Maximal safe resection is the most effective and safe surgical
procedure in which the glioma is excised while ensuring maximum preservation
of the surrounding neurological tissues. This can also be achieved by the use of
5-aminolevulinic which denes the tumour region for safe resection. But before
this, some preoperative procedures like MRI, diffusion tensor imaging, and navigated transcranial magnetic stimulation need to be conducted to effectively map
the surgical procedure.
9.3.2 rADiAtion therAPy
Radiation therapy is typically administered following surgery. Comparative studies
have shown that combining surgery and radiation therapy is more benecial than
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