Phytonutrients in the Treatment of Gastrointestinal Cancer

Cancers of the gastrointestinal tract (GIT) are the most common human malignancies. The prevalence of esophageal Cancer, pancreatic ductal adenocarcinoma, gastric Cancer, hepatocellular carcinoma, colorectal Cancer and gallbladder Cancer are on the rise now a days. Despite advances in cancer treatment, increasing reports are focusing on finding novel therapies with lower side effects and higher potency. From the mechanistic point of view, several dysregulated factors are behind the pathophysiology of GIT cancers. Multiple studies have shown molecular targeted therapies in various GIT cancers, including epidermal growth factor receptor pathway (EGFR), vascular endothelial growth factor pathway (VEGF), Wnt/β-catenin pathway, and insulin-like growth factor receptor (IGFR).The aforementioned mediators are the critical targets of the existence of monoclonal antibodies and small molecules in treating GIT cancers. Accordingly, providing the exact dysregulated mechanisms behind GIT cancers could pave the road in the treatment of cancers. This chapter reveals dysregulated signaling pathways and potential therapeutic agents in the treatment of GIT cancer.

Phytonutrients in plants play a great role in their protection against certain bacteria, viruses, and fungi resulting from certain detoxification processes within the plant. There are many recommendations to increase the intake of high amounts of fresh colored vegetables and fruits, besides whole grains (cereals) and beans, which contain phytoconstituents to lower the risk of certain cancers, diabetes and hypertension, in addition to certain heart diseases. The effect of phytonutrients differs according to their chemical class and amount. They may act as antioxidants which prevent the effect of carcinogens on the healthy body. The sources constituents and mechanisms of the phytonutrients are summarized in this chapter. 

Cancer is considered one of the primary causes of death all over the world; Thus, there is an urgent need for its management. Anticancer drugs available in the market target rapidly growing cells while unable to distinguish between healthy and tumor cells producing significant side effects resulting in discontinuation of therapy after a few months. On the other hand, phytochemicals can induce similar potential effects on cancer cells with less or no side effects deliberately leaving non-cancer cells. However it takes a relatively more extensive period for noteworthy results. The United States Department of Health and Human Services governs Food and Drug Administration (FDA), which accounts for public healthcare, food, and drug product endorsement. Particularly a drug product approval requires ultra-precautions; therefore, multiple safety measure steps are followed right from target-based high-throughput screening process to clinical trials. In the past few decades, the FDA has approved several anticancer drugs, either phytochemicals or derived synthetic drug molecules; thus, using phytochemicals isn’t a new idea in biomedical research. Due to the very stringent criteria of the FDA for drug approval, many potential phytochemicals and molecules fail to pass clinical trial phases. In this book chapter, we have discussed the stepwise drug approval process followed by enlisting approved or potential phytochemicals in the drug discovery pipeline and their limitation in approval.

Globally, cancer is a leading cause of death next to cardiovascular disease. Gastrointestinal malignancies (GI) are extremely widespread malignancies, but their prevalence varies significantly amongst nations and communities. Existing cancer treatments are primarily concerned with low tissue availability, adverse drug reactions related to the demand for larger dose levels and non-specificity of the medicine. Phytochemicals have been important resources of preventive and curative entities for a variety of diseases, such as cancer. To a certain extent, enough investigation has been made over the last few decades to investigate natural compounds that possess anticancer properties. Phytochemicals used in the management of malignancies appear to be obligatory, serving as the cornerstone for the latest medicine as well as a rich reserve of novel medicines. Flavonoids are plant-derived secondary metabolites, which are readily available and considered safe, depicting perfect agents for cancer therapy or as adjunctive options in clinical practice. Flavonoids have already received increasing attention as anti-cancer entities, with promising findings as cytotoxic anti-cancer entities that induce apoptotic cell death in malignant cells. Flavonoids, such as kaempferol, Quercetin, Curcumin, myricetin, apigenin, luteolin and silymarin, are among the phytochemicals that have been revealed to be potential agents for the prevention and treatment of malignancies. Flavonoids like Kaempferol and luteolin are reported as potential therapeutic agents for the management of ovarian and GI malignancies. Flavonoid metabolism in major areas of the hepatic and colon cells, unveils reasonably considerable variations in the anti-cancer potential, presumably as a result of exposure to multiple metabolites with multiple functions. Luteolin and apigenin have a real insight into cervical cancer. Flavonoids are now explored to have an inhibitory action on cell cycle development at the G1/S or G2/M stages of the cell cycle via modifying several regulatory proteins of the cell cycle. This chapter is designed to provide comprehensive knowledge about flavonoids, their targeted mechanism of action in the management of GI cancer, clinical findings of flavonoids, synergistic effect with other anti-cancer medicines and future prospects of flavonoids in treating GI carcinoma.

Gastrointestinal (GI) carcinomas are tumors that impact the digestive system and its supporting organs. Esophageal, gastric and colorectal cancers are among the common cancers in the gastrointestinal tract. GI cancers are responsible for about 2.7 million deaths of the 8.2 million mortalities that occur from cancers every year around the globe. Chemoprevention is the method of intervening in this mechanism by essential dietary control or the addition of nutraceuticals to the daily nutritional intake. The initial stages of cancer growth, known as oncogenesis, have sparked a lot of emphasis on the function of dietary food. The intensity of the epidemiological studies attracted research scholars' interest in the mechanisms underlying the anti-proliferative activities; however, investigation has indeed discovered lots of new phytochemicals in vegetables and fruits which might prevent the development of carcinogenesis. In cancer treatment, drugs obtained from plant sources have a significant role in cancer treatment. The plant alkaloids isolated from Catharanthus roseus, such as vincristine and vinblastine, are clinically used to treat testicular carcinomas, leukemia, and breast cancer. Paclitaxel is isolated from Taxus brevifolia and is used in the management of lung cancer, breast cancer and ovarian cancer. In the 1960s, there has been initial proof of the in vitro cytotoxic impact of glycosides on human cancer cell lines and their in vivo anti-tumor activities. Cardiac glycosides are Na+/K+ATPase inhibitors and elevate the Ca+2 concentrations, which in turn leads to a positive inotropic effect and is thus used as cardio-tonic in the management of congestive heart failure. Cardiac glycosides have recently been documented to play roles in initiating, developing and metastasizing the tumor by controlling cell viability and mortality pathways. It has been reported that Na+/K+ATPase inhibitor causes cell death by inducing autophagy, apoptosis and synthesis of free radical species. Notwithstanding the advances in cancer treatments, the need for new medicinal products and treatments to enhance their effectiveness and to decrease the toxicity of existing regimes is strong and unequaled, although a broad objective is to improve the therapeutic results of GI cancers. This chapter briefly describes the glycosides, gastrointestinal malignancies and the diverse types of glycosi- des involved in the management of GI malignancies and the clinical trials under progress for the clinical efficacy.

Gastrointestinal cancers are the most common cancer group, accounting for approximately one-fourth of the total cancer incidence and one-third of cancer-related deaths in developing countries. Treatments for the disease include surgery, radiation, and administration of chemotherapy components, such as docetaxel, mitomycin, and cisplatin injection. However, due to the side effects seen in these treatments and for the purpose of supporting the treatment, the trend towards medicinal herbs and phytonutrients, which have certain biological activities and potential benefits to human health, including the prevention of diseases, has increased. Natural products and their derivatives are consistently the most successful source of phytonutrients and pharmaceutical leaders. Terpenoids are one of the most important families of natural compounds known for their medicinal value. Terpenoids are found in higher plants, algae, mosses, liverworts, and lichens, as well as insects, microbes or marine organisms; and have been shown to exhibit anti-infective, anti-inflammatory, and antitumoral properties. Recently, research activities on the preclinical and/or clinical potential of this class of components in cancer have continuously risen. In this review, the molecular basis of the antitumoral effect of terpenoids is presented, with special emphasis on the latest developments in this field, comprising recently enlightened findings of the potential of monoterpenoids, diterpenoids, triterpenoids and tetraterpenoids as antitumoral agents. Furthermore, this review will summarize promising terpenoid compounds in combination therapy with conventional chemotherapeutic agents. 

The natural glycosides with triterpenoid or spirostaneaglycones are the saponins, which are associated with a wide range of therapeutic activities, inclusive of gastrointestinal anticancer activities. To promote research and development of novel cytotoxic agents against GIT cancer, this chapter focused on the anticancer potentia l of the naturally occurring triterpenoid and steroidal saponins. The in vitro assays and in vivo studies authenticated the anticancer potential of these compounds through antiangiogenic, anti-proliferative, anti-metastatic and anti-multidrug resistance activities. The protein targets and signaling cascades behind the anticancer effect of these compounds in GIT cancer are also discussed in this chapter.

Alkaloids, nitrogen-containing compounds, are found in living organisms ranging from microbes to seed-producing plants all over the world. About more than 20,000 alkaloids have been discovered, mostly occurring in higher plants of the families Ranunculaceae, Papaveraceae, Leguminosae, Loganiaceae and Menispermaceae. These compounds are able to inhibit cancer proliferation, especially gastrointestinal cancer, which constitutes the highest incidence rate all over the world. The most diversified group of phytochemicals, alkaloids offer a mighty series of chemical scaffolds and moieties which can be harnessed to ameliorate the devastating consequences underlying cancer. Gastrointestinal (GIT) cancers constitute the malignancies of esophageal, gastric, pancreatic, colorectal and anal tumors, which possess aberrant metabolic signals giving rise to uncontrolled cell proliferation. These cancers are the most frequent of all cancers and account for the high mortality rates worldwide. Conventional therapeutic options carry the risks like being non-economical as well as they possess severe side effects. Natural products offer a wide spectrum of pharmacological properties which can overcome these risk factors by providing cheaper products and are reliable regarding their bio-safety profiles. Alkaloids can be investigated in detail to investigate their pharmacological potential against GIT cancers. Several alkaloids are known to modulate the cell signaling pathways by inducing cell cycle arrest at G0/G1, S and G2/M phases in addition to being the apoptosis inducers. In addition to that, they are also known to target various metabolic pathways, such as p53, β-catenin, MAPK and PIM3. The chapter intends to investigate the biological as well as pharmacological profiles of various alkaloids with special reference to GIT cancers in order to update scientists and researchers about the pharmaceutical potential of these compounds.

Gastrointestinal malignancies are well-known terms in the pathogenesis of the alimentary canal. They have been prevalent in different organs of the gastrointestinal tract system. Gastric tumor is the second most common cause of death due to cancer in the world. The epidemiology of cancer has changed within the last few decades. A significant deal with such carcinomas is done using essential plant constituents like alkaloids, volatile oils, and glycosides. They involve various mechanisms for eliminating these carcinomas. Many plant essential oils, such as thymol, lemon oil, limonene, carvacrol, and lavender oils, have been investigated for their anti-inflammatory, anti-oxidant, and anti-carcinogenic properties been shown to modulate numerous immunological and cellular functions. Many types of research have proven that a large number of volatile oils and aromatic compounds present in various plants have important anti-cancer activities. They showed the anti-cancer effect on cell lines and cancer cells in animals. The use of various plant volatile oils may alter or affect the pathogenesis of several types of gastrointestinal cancer like liver cancer, esophageal cancer, gastric cancer, pancreatic cancer, etc. In this chapter, the anti-cancer activity of plant essential oil components against GIT cancers has been discussed, with a focus on their possible mechanism of action. 

Phytosterols and related derivatives phytostanols are naturally occurring bioactive compounds present mainly in plant cell membranes. These lipophilic steroid alcohols contain a tetracyclic cyclopenta [a] phenanthrene structure which is substituted with a hydroxyl group at position C3 and have a side chain at position C17, usually containing one or more double bonds in the steroid skeleton. Phytosterols derived from isopentenyl pyrophosphate belong to the terpene family and are generally synthesized by the mevalonate pathway. They have similar structural and biological functions to cholesterol. It is not possible to synthesize by a human; as a result of their intake in diet, they are present in the human body as cereals, legumes, vegetables, fruits, nuts, vegetable oils, oilseeds, cereal grains, cereal-based products and related products which contain phytosterols in relatively high amount, consumed daily by the whole world population. Phytosterols are known as part of the normal human diet. Increasing interest has been given to phytosterols in recent years as epidemiological and experimental studies suggest that they have an important role in the protection from cancer besides their several beneficial effects, such as anti-inflammatory, antioxidative, anticarcinogenic, antifungal, antibacterial, antipyretic, antineoplastic, anti-ulcerative activity and cholesterol-lowering capacity. Inhibition tumor cell growth, multiplication, invasion and metastasis; reducing cell proliferation and increasing apoptosis; decreasing tumor size; inhibition of carcinogen production; reduction of angiogenesis and adhesion of cancer cells; inhibition of reactive oxygen species production and oxidative stress and increased antioxidant enzymes have been suggested as responsible mechanisms for anticancer activity of phytosterols. The current review aims to summarize the occurrence, safety, toxicity and chemistry of phytosterols to explain their potential activities in cancer with suggested mechanisms in detail. Furthermore, epidemiological and experimental studies related to treating the activity of phytosterols in gastrointestinal system cancers have been described. 

Cancer becomes uncontrolled with conventional therapeutic medications and is, therefore, able to tolerate drug activity, which contributes to increasing the adverse effects during medication therapy. The usage of anti-cancer peptides is a recent clinical technique against cancer cells. The physicochemical characteristics, amino acid composition and the addition to the anti-cancer peptides sequence of chemical groups impact their conformation, net load and secondary structure orientation, which affect the targeted specimen and peptide cell interaction, stability and effectiveness of penetrating peptides. Anti-cancer peptides are formed by replacing cationic amino acid residues with neutral or anionic amino acid residues or by introducing a chemical group, both naturally occurring and modified peptides. Updated peptides improve the potency of cancer treatment. This efficacy has recently allowed anti-cancer peptides to shape medicines and vaccines that were sequentially tested in many phases of clinical testing.

The creation of anti-cancer peptides continues to concentrate on the production of clinically adjusted anti-cancer peptides with a view to decreasing the occurrence of new cancer cases and the mortality rate. The current analysis could help promote the creation of anti-cancer peptides and, in the immediate future, improve successful anticancer peptide therapy. Anti-cancer plant peptides are part of several species of plant inborn immune response systems and are attractive candidates for the care of animals and humans against infections. Anti-cancer plant peptides also display anti-cancer activities and can inactivate a wide variety of cancer cells. Cancer appears to be a worldwide source of elevated morbidity and mortality. There is a dire need to produce novel methods to treat gastric cancer. Anti-cancer plant peptides like cyclotides, thionines, and defensins which have anti-cancer activities, are appealing alternatives. We have summarized the anti-cancer effect of anti-cancer plant peptides with a focus on their mode of activity, efficacy, and selectivity.