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of T. cordifolia stems increased the number of bone marrow cells (18.16 106/femur) and
esterase-positive cells (1423/4000 cells), as well as the total number of WBCs. The extract
also improved macrophage activation and the humoral immune response by boosting the
splenic plaque-forming cells. T. cordifolia extract inhibited the growth of solid tumors and
worked in concert with CP to shrink animal tumors (Shivaprasad et al., 2006).
5.2.49 TERMINALIA CHEBULA RETZ. (FAMILY: COMBRETACEAE)
The plant is also recognized as “Myrobalan,” “Haritaki,” or “Harar” and primarily
established in India’s deciduous woods and sub-Himalayan regions. Tannins are primarily
found in their fruits. The fruit is astringent, laxative, stomachic, and is used as a tonic.
“Triphala,” an ayurvedic remedy, contains Harar as one of its ingredients. The impact of
the aqueous fruit extract of Terminalia chebula on the immune system’s humoral and cell-
mediated components in mice have been studied. Mice fed with T. chebula extract showed
increased titers of HA and DTH (Bin-Hafeez et al., 2003).
5.2.50 TRIGONELLA FOENUMGRAECUM L. (FAMILY: FABACEAE)
Trigonella foenum-graecum is a common food and therapeutic herb distributed around
the world. The plant’ s hypoglycemic, anti-inflammatory, antiallergic, and other biological
potentials are well known. Bin-Hafeez et al. (2003) assessed the immunomodulatory
effect of the aqueous extract of T. foenum-graecum. The outcome showed that the extract
considerably raised the relative organ weight of the thymus and liver at 50, 100, and
250 mg/kg. At the same extract doses, cellularities of the thymus and bone marrow were
likewise noticeably elevated. At extract concentrations of 50 and 100 mg/kg, a substantial
rise in the DTH response was seen. Plaque-forming cells were used to test humoral
immunity in the extract at a dose of 100 mg/kg. Additionally, mice treated with the extract
showed a significantly higher phagocytic index, macrophage phagocytic capacity, and
lymphoproliferation assay (Akbay et al., 2003).
5.2.51 URTICA DIOICA L. (FAMILY: URTICACEAE)
In Germany , it is employed as an adjuvant for the treatment of arthritis. Extracts from plant’s
aerial parts and leaves include active ingredients that block the genetic transcription factor
to lower TNF-α and other inflammatory cytokines. The major compounds as quercetin-
3-O-rutinoside, kaempherol-3-O-rutinoside, and isorhamnetin-3-O-glucoside have been
isolated from methanol extract of its aerial parts. These compounds are known for their
immunomodulatory activities by chemotaxis (in vitro) and intracellular killing activity
(NBT reduction) tests. These bioactive compounds exhibited significant chemotactic
effects at dosages of 4, 8, and 16 g/ml. These findings suggested that extract and fraction
may be helpful in treating people with chronic granulomatous illnesses and neutrophil
function deficiencies (Mukherjee et al., 2014).
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5.2.52 WITHANIA SOMNIFERA (L.) DUNAL (CULTIVATED VAR.) (FAMILY: SOLANACEAE)
The herb Withania somnifera commonly known as Indian ginseng has played a significant role in the Ayurvedic and Indigenous medical systems for more than 3000 years.
Researchers from several fields have noted antiserotogenic, adaptogenic, anticancer, and
anabolic activity, as well as positive benefits in the management of stress, arthritis, and
geriatric issues. In animal models of immunological inflammation, W. somnifera has been
found to act as an immunostimulator and immunoregulator . Administration of W . somnifera
extract has reportedly been shown to lessen leucopenia brought on by CP. This might be
connected since this extract lessens the toxicity caused by CP and increases its efficacy as
a cancer treatment. Following the treatment using W. somnifera extract, an improvement
was observed in the antibody titer and the cell numbers that form plaques in the spleen.
Furthermore, it was discovered that the methanolic extract of W. Somnifera had a radiopro-
tective outcome on healthy BALB/c mice, increasing the cellularity of the bone marrow
and reducing chromosomal damage brought on by sublethal doses of gamma radiation.
By giving normal BALB/c mice a dose of W. somnifera root extract, it was discovered
that their levels of IL-2, IFN-γ, and granulocyte-macrophage colony-stimulating factor
increased. Withanolide, an active ingredient of W. somnifera also demonstrated to possess
antidepressant action with beneficial effects on memory and learning capability among
rats. In albino rats of Wistar strain and Swiss mice, glycowithanolides and a combination
of sitoindosides IX and X were examined for their immuno-stimulatory and CNS effects
(learning, antistress, and memory) and it was observed that it attenuated cerebral function
deficits in the geriatric population and to provide nonspecific host defense (Mukherjee
et al., 2014).
5.3 TRADITIONAL IMPORTANCE OF RESEARCH TO SOCIETY AND RESEARCHERS
The prominent Ayurvedic notion of rasayana, which describes herbs with revitalizing
properties, is used to control immunological response. The Indian Ayurvedic system of
medicines and others also recognize different plant species as rasayanas containing a
variety of immunomodulatory properties such as adaptogenic, antiaging, immunoadjuvant,
anticancer, immunostimulant, antirheumatic, neurostimulant, antistress, and so on. Thus,
such traditional medicinal plant knowledge can act as a creative and effective discovery
engine for better, safer, and inexpensive treatments because of its holistic and systemic
approach, which is supported by experimental evidence. When the host defense mechanism
needs to be activated due to impaired response of the immune system or when particular
immunosuppression is preferred in conditions such as immunomodulation, or autoimmune
disorders, traditional medicinal plants offer an alternative to chemotherapy in numerous
diseases. After learning that herbal antioxidants also have strong immunomodulatory
effects, the idea of employing rasayanas for health gains greater legitimacy. In light of
this, this review offers a view of how natural resources might be used to create therapeutic
plants that are powerful immunomodulators.
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5.4 CONCLUSION
The description of immunomodulators containing phytochemical substances and their
pertinent mechanisms of action are the major highlights. In order to develop new drugs and
to determine their efficacy using conventional resources, it might assist in recommending
prime bioactive components derived from natural resources. In this review, a number of
plants with possible immunomodulatory properties have been described. A number of
additional plants with similar activities have been investigated as potential natural immune
stimulants. Thereby, the present review aims to encourage various researchers in both
learning about natural immunostimulants as well as in utilizing a number of traditional
medications for the discovery and development of new drugs.
KEYWORDS
• natural
• immunomodulatory
• plants
• nitric oxide
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CHAPTER 6
Natural Products with Anticancerous Properties
NIDHEE CHAUDHARY*, OGIREDDY SRI APOORVA, and MANSI AGRAWAL
*Corresponding author
ABSTRACT
Cancer, a dreadful disease has a significant global impact on people. There is a continuous
need for the development of novel drugs to treat and prevent this fatal disease. Nowadays, natural products are gaining attention for their use in chemotherapy because they
are thought to have fewer hazardous side effects than existing therapies. Plant secondary
metabolites such as polyphenols, flavonoids, brassinosteroids, and alkaloids are being
tested by researchers for their potential anticancer properties, which might lead to the
creation of novel pharmaceuticals. Microorganisms are also very useful to produce natural
products such as actinomycin D, bleomycin, anthracyclines, L-asparaginase, and arginine
which have anticancer properties. There is a continuous demand for natural products
derived from medicinal plants and microorganisms as possible targets for cancer therapy.
These natural products will be helpful for researchers and scientists working on developing
natural, affordable therapeutic agents, and medications to treat various malignancies.
6.1 INTRODUCTION
Cancer stands as one of the foremost global health concerns affecting populations worldwide, affecting millions of individuals of all ages and genders and greatly impacting quality
of life. In 2020, nearly 10 million deaths were caused by cancer worldwide—a number that
is expected to reach over 16 million by 2040, making it a severe danger to human life and
health. Although significant efforts have been made to combat cancer, the current clinical
cancer treatment methods still have some drawbacks, including serious side effects, limited
efficacy in metastasis and recurrence, and excessive costs (Lin et al., 2021). Certain antitumor medications, such as liposomal paclitaxel, which is an active ingredient derived from
the bark of the pacific yew tree (Taxus brevifolia) have demonstrated positive therapeutic
benefits by enhancing their biological dispersion and buildup in specific destinations. It
is used in chemotherapy drugs in the treatment of various cancers, but it is encapsulated
110
in liposomes to improve its delivery and efficiency, therefore called liposomal paclitaxel.
This has further encouraged the development of antitumor medication-targeted delivery
systems (Chen et al., 2023).
Cancer is a condition that occurs when cells of a particular tissue grow out of control
and spread to other tissues of the body. Most multicellular organisms, including plants
and animals, can develop cancer anywhere in the body (Franks and Knowles, 1990). The
disease is characterized by uncontrollable and unstoppable cell proliferation throughout
the body (Ochwang’I et al., 2014). As a result, malignant cells form tumors that have the
potential to spread elsewhere. Cancer affects a lot of people around the world, and new
treatments to cure and to prevent this deadly disease are always in high demand. Presently ,
some of the prevailing treatment methods encompass chemotherapy , radiation therapy, and
pharmaceuticals derived from chemicals. As an illustration, chemotherapy may impose
signicant strain on patients and exacerbate their overall well-being. As a result, utilizing
alternative cancer treatments and therapies is emphasized (Thomford et al., 2018; Sung et al.,
2021).
Natural compounds are getting more attention from scientists because they have fewer
side effects than current treatments like chemotherapy (Ochwang’I et al., 2014). Secondary
metabolites that are naturally occurring in the plant kingdom are being studied for their
anticancer properties, leading to the development of new clinical drugs. These secondary
metabolites are not directly involved in growth but play an essential role in ecological
interactions. These compounds include alkaloids, avonoids, and terpenoids. The combination of secondary metabolites from plants has led to the development of crucial cancer
treatment medications. As a result, ongoing advancements in this eld are continuously
emerging to promote further progress and innovation in the area of cancer treatment.
Nanoparticles used in nanomedicines represent a cutting-edge technology aimed at regulating the controlled release of plant-derived drugs. This innovative approach also explores
novel administration techniques to improve the effectiveness of these drugs in treating
cancer. The demand for medicinal plant-derived natural compounds and the properties that
make them potential targets for anticancer treatments are the subjects to review.
T oday, the fraction of anticancer drugs derived from natural sources in one way or other
amounts to over 60% of overall cancer drugs (Cragg and Pezzuto, 2016). While in the
1990s they momentarily fell out of favor with commercial pharmaceutical research due to
the introduction of focused medicines, recently a resurgent interest in bioactive molecules
has emerged (Newman and Cragg, 2012). Between the 1940s and 2010, the FDA of the
United States conducted a study of new and approved cancer medications, nding that
out of the 175 small molecules, 74.8% were not synthetic (Valentová et al., 2023). In
developing nations, plant-based medicines have been the primary source of medical treatment for many years. Numerous plant species such as Curcuma longa L, Viscum album L.
are already being used to treat or stop cancer from growing. Plant species like Colchicum
autumnal and Tinosopra cordifoila with anticancer properties have been identied by
several researchers and are used as herbal medicine in developing nations (Espirito Santo
et al., 2020).
Over the span of four decades, whether occurring naturally or having undergone
synthetic alterations, natural products have played a crucial role as established agents in
111
cancer chemotherapy (Elrayess and El-Hak, 2019). There are some instances where anthracyclines like doxorubicin (DOX), bleomycin, dactinomycin, actinomycin, and mitomycin
C (MMC) are antitumor antibiotics derived from microbes (Tan et al., 2006).
Arthropods, higher plants, and marine invertebrates are among the biggest taxonomi-
cally identied classes of organisms that could be investigated as potential sources of novel
anticancer drugs (Cragg et al., 2012). Algae, bacteria, fungi, and even terrestrial vertebrates
are a few of the other taxonomic classes of organisms that have been studied by natural
product researchers. However, there is mounting proof that diverse types of organisms
may produce the same secondary metabolite that is important as a potential anticancer
agent (Berdy, 2005). Amino acids, organic acids, and various other compounds fall under
the category of primary metabolites, which directly participate in regular growth and
developmental processes. In contrast, secondary metabolites, such as alkaloids, phenols,
avonoids, and others, do not play a direct role in normal growth and development.
The rst step in carcinogenesis involves deregulation of the control of hypermeth-
ylation of tumor-suppressor genes, resulting in their silencing or inactivation. In recent
years, there has been the development of medications that can either inhibit or reverse
epigenetic changes (Zhong et al., 2022). Epigenetic changes in cancer can lead to the
silencing of tumor suppressor genes or activation of oncogenes, disrupting normal cellular
processes. DNA methylation, histone modications, and noncoding RNAs are key epigenetic mechanisms involved. Understanding and targeting these alterations hold promise for
personalized cancer treatments and epigenetic therapies (Kim et al., 2023). Nonetheless,
developing a chemically derived drug that exclusively targets the cytotoxicity of cancer
cells while remaining nontoxic to normal cells proves to be a challenging task. There is a
growing demand for the development of naturally derived compounds that can be used to
treat cancer, particularly those derived from plants (Katanaev et al., 2019). Various types of
cancer occurring in the human population have the same characteristics, with an inability
to respond to signals that stop cell growth and make their replication endless (Fares et al.,
2020). Cancer cells can survive within the tumor tissue because angiogenesis is maintained,
and apoptosis is never induced. Plant-derived compounds such as taxanes and campothecin
derivatives have been shown to exhibit anticancer activity, inhibiting cancer cell proliferation, thereby triggering apoptosis.
6.2 PLANT-DERIVED ANTICANCER COMPOUNDS
In developed countries, numerous plants are consumed for their health benefits, while in
Asia and Africa, medicinal plants have been used in traditional remedies for centuries. The
World Health Organization (WHO) reports that some countries still rely mostly on plantbased treatments for medical care, and developing countries are taking advantage of the
therapeutic benefits of substances derived from naturally occurring sources. Polyphenols,
brassinosteroids (BRs), and taxolare are among the substances that have been discovered
and isolated from terrestrial plants and possess anticancer characteristics (Khan et al.,
2019; El-Sayed, 2020; Sajadimajd et al., 2020).
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6.2.1 POLYPHENOLS
Flavonoids, tannins, curcumin, resveratrol, and gallocatechin are polyphenolic substances
that can be obtained from plants such as grape plant, olives, onion and turmeric that are all
regarded as anticancer substances. Foods containing resveratrol include red wine, grapes,
and peanuts. Green tea is rich in gallocatechin. Since polyphenols are natural antioxidants,
it is believed that incorporating them into a person’s diet can enhance health and lower
cancer risk.
Polyphenols are cytotoxic to a variety of cancer cells, and their antioxidant capabilities
have been shown (Montané et al., 2020). It is believed that polyphenols have useful
apoptosis-inducing characteristics that exhibit anticancer capabilities. Plant polyphenols
also can prevent the development of cancer cells by interfering with the proteins found
in cancer cells. Polyphenols, as bioactive compounds, possess the remarkable ability to
interact directly with cellular processes, like acetylation, methylation, or phosphorylation.
By modulating these mechanisms, they have the potential to alter the behavior of cancercausing agents, offering promising avenues for cancer prevention and treatment strategies.
These interactions may lead to changes in gene expression, cell signaling, and other critical
pathways, inuencing cancer cell growth, proliferation, and survival.
6.2.2 FLAVANOIDS
With 10,000 known structural variations, flavonoids, which belong to the polyphenolic
chemicals, are a vast family of secondary metabolites found in plants. These are
physiologically active plant compounds that are gaining significant scientific attention
for their potential health benefits (Kopustinskiene et al., 2020). Many plants, including
fern species and plants used in traditional Chinese treatments like litchi leaves, have been
studied for their flavonoid content and their effect on cancer cells (Sak, 2014). Seeds
are also rich in flavonoids, including anthocyanins, flavones, flavanols, chalcones, etc.
(Wen, 2014). Cao et al. (2013) isolated flavonoids from the fern Dryopteris erythrosora
and studied their anticancer effects on human lung cancer cells (A456 cell line). They
discovered that flavonoids exhibit cytotoxicity against cancer cells and have significant
free radical scavenging capacity. Pure flavonoids have also demonstrated anticancer
properties against various human malignancies, such as breast cancer, cervical carcinoma,
and hepatoma (Bailly, 2020).
It was discovered that the avonoids 4′-methoxy licoavanone [MLF] and apinumisoavone [AIF] isolated from Erythrina suberosa stem bark had cytotoxic effects on HL-60
cells (human leukemia). MLF and AIF trigger apoptosis through both internal and extrinsic
signaling pathways. This induces the activation of apoptotic proteins, leading to a signicant reduction in mitochondrial membrane potential. As a result of mitochondrial damage,
cancer cells struggle to survive within these affected cells. Researchers have examined
that avonoid extracts from fern species exhibit a signicant proportion of anticancer
action even at low doses. Antiapoptotic and transcription-activating signal transducers and