Natural Compounds and Cancer: Current Evidences

Abstract

ABSTRACT

Natural compounds are constantly gaining ground in the treatment of various chronic diseases and in cancer research. Recent efforts have been focusing on them due to their special features consisting of low toxicity and high bioavailability. These compounds have already demonstrated important antitumor activity against several cancers in vitro through several mechanisms, including cell viability reduction, suppression of cell proliferation, cell death induction and cell cycle arrest.

Herewith, we reviewed natural compounds that can be potentially used for head and neck cancer, glioblastoma and gastrointestinal cancers.

Keywords: natural compounds, glioblastoma, head and neck cancer, gastrointestinal cancer.

Introduction

Natural compounds represent chemical substances that are found in plants, animals and other natural sources. These substances are not artificially synthesized and their molecular structures are produced by living organisms or natural processes. It is reported that are essential to life and have a significant impact on a number of biological processes including metabolism, growth and development. It is already widely known that many natural products have their origins in Chinese herbal therapy. They have been used to treat a variety of diseases for several decades due to their well-known antibacterial and anti-inflammatory characteristics.

However, recently they became widely known for their anti-cancer properties, because they are rich in anti-cancer substances that directly cause cancer cells to undergo apoptosis through cytotoxic actions. They indirectly regulate the tumor microenvironment and cancer immunity, thereby improving chemotherapy regimen. Thus, many studies have focused their attention to these low toxicity natural compounds, as novel potential therapeutic medications for the management of various cancer subtypes (1, 2).

Cancer constitutes a dramatic healthcare problem worldwide, with a considerable impact on patients, families, healthcare systems, and societies. The World Health Organization (WHO) (3) estimated that it was one of the world's main causes of mortality in 2020, leading to approximately 10 million deaths. It is a complex disease that arises from the aberrant cells in the body growing and spreading out of control. Up to date, there are over 200 various cancer types, each with unique causes, risk factors and treatments. Cancer diagnosis and treatment often require extensive healthcare resources, such as diagnostic imaging, surgery, chemotherapy, radiation therapy and supportive care (4). Considerable advancements have been achieved in the diagnosis, treatment and prevention of cancer in the last few decades. The international scientific community has made great effort in finding natural compounds that are efficacious in inhibiting cancer cells growth (5).

In this review we made an extensive literature search, using several key words (natural compounds, head and neck cancer, glioblastoma, gastrointestinal cancer, alkaloids, curcuminoides, flavonoids, treatment), in order to determine which natural compounds could be potentially used for head and neck cancer, glioblastoma and gastrointestinal cancers offering also, in our opinion, a significant view towards the future.

Natural compounds

It is widely known that natural substances have been utilized for many ages in traditional healthcare. Additionally, they have demonstrated a range of therapeutic actions, such as analgesic, antioxidant, anticancer and anti-inflammatory effects. They can be classified into different groups based on their molecular structures and activities. Common groups of natural compounds include alkaloids, curcuminoids, flavonoids and coumarins.

Alkaloids are compounds that contain nitrogen which are frequently present in plants and have been associated with antibacterial, analgesic and therapeutic effects. Spice turmeric contains a group of naturally occurring chemicals called curcuminoids. Their anti-inflammatory and antioxidant properties are well established.

Natural flavonoids are polyphenolic chemicals that come from a variety of plant sources, including Phyllanthus emblica, Apium graveolens, Flemingia vestita and Petroselinum crispum, which are used as therapeutic plants. Flavonoids are considered to contain anti-inflammatory, anti-oxidant and anti-cancer properties via a number of different mechanisms (6). Coumarins are substances that belong to a class of colorless, crystalline, oxygenated heterocyclic compounds that were initially identified by Vogel, in 1820, from the plant Dipteryx odorata Willd (Fabaceae), commonly known as "coumaroun" (7). Natural compounds have shown up to date encouraging results in preclinical and clinical studies. However, further targeted studies are required to comprehend and 'establish' their potential anticancer activity (Figure 1) (8).

Head and neck, glioblastoma and gastrointestinal cancer

Cancer represents today a major health issue (4). With a predicted 12 million fatalities in 2022, is the second most common cause of death worldwide, according to WHO. Additionally, the prevalence of cancer is rising (3).

Glioblastoma (GBM) is the most prevalent malignant tumor of the central nervous system (CNS) with a bad prognosis, which is also thought to be the deadliest malignancy in humans (9). Currently, surgery, radiotherapy and chemotherapy represent the therapeutic choices; nevertheless, the median survival time with GBM is still rather low, with five-year survival rates up to 5%. Glioblastoma can cause death in less than six months if not treated promptly (10). For GBM, the Food and Drug Administration (FDA) has approved a number of medications, of which temozolomide (TMZ) is the most common treatment. However, the median lifespan is only prolonged by 2.5 months with TMZ, and greater dosages of TMZ can result in systemic adverse effects (11). In addition, most medications are unable to cross the blood-brain barrier (BBB), which prevents many chemotherapeutic medicines from activating and permits some low molecular weight compounds to pass through selectively (12). The use of less harmful substances has been the focus of research efforts due to the failure of targeted medications and standard chemotherapies (13).

Head and neck cancers are the sixth most frequent malignancy globally, accounting for over 830,000 new cases and over 430,000 deaths annually (14). Referring to head and neck malignancies, oral squamous cell carcinoma (OSCC), which mostly affects the lips and oral cavity, has the greatest rate of incidence and death (>40%). Surgery or a mixture of surgical procedure, radiation treatment, and chemotherapy are used to treat OSCC. Unfortunately, a number of side effects, including toxicity, drug resistance, malfunction, malformations of the face and medication resistance, may arise from these treatments and significantly lower quality of life (15).

What is more, gastrointestinal cancer refers to any cancer that affects the digestive system, including the esophagus, stomach, pancreas, liver, colon and rectum. With a high frequency and death rate, it is a major global health issue. Estimates for colorectal cancer in 2018 were 1.8 million cases and 881,000 deaths, leading it to be the third most frequent cancer globally. Gastric cancer is another common type of gastrointestinal cancer. With a predicted 1.1 million diagnoses and 783,000 deaths in 2018, it is the fifth most frequent cancer globally. Additionally, liver cancer ranks sixth globally in terms of incidence, with an anticipated 841,000 cases and 782,000 fatalities in 2018. With a predicted number of 42,230 new cases and 31,780 deaths in 2021, it is the ninth most prevalent cancer in women and the fifth most common cancer in males in the United States. Overall, gastrointestinal cancers represent significant health problem worldwide. Early detection, proper diagnosis and appropriate treatment are crucial to improving outcomes and survival rates (16).

Natural compounds have been gaining attention from scientists because of their ability to modify metastasis, apoptosis evasion, angiogenesis, and cell cycle regulation. They have demonstrated their effectiveness when used alone or in combination with other chemopreventive drugs (17).

NATURAL COMPOUNDS

Alkaloids

Alkaloids represent a family of simple, organic compounds that exist naturally with at least a nitrogen atom in their structure. Originating from amino acids, they can be synthesized by plants and animals as secondary metabolites. Alkaloids have a variety of important effects on human beings, including anti-inflammatory, anticancer, analgesic, neuropharmacological, anti-bacterial, antifungal and regional anesthetic and pain relieving properties (18).

Alkaloids and glioblastoma

Concerning GBM, there are alkaloids which have investigated for their anti-cancer effect. Moschamine is an indole alkaloid with serotoninergic and cycloxygenase inhibitory properties. In glioma cell lines which have been studied, moschamine treatment drastically decreased cell viability, while confirming the induction of cell death and cell cycle arrest. Furthermore, the expression of CD24 and CD44 decreased in a dose-dependent way (19).

N-(p-coumaroyl) serotonin (CS) is another indole alkaloid with antioxidant and antitumor properties. In glioma cell lines, CS treatment reduces cell viability, cell death and cell cycle arrest in G2/M and S-phase. Additionally, there was a boost in caspase-8 activity as well as a dose-dependent rise in the expression of CD15 and CD71 (20).

Alkaloids and head and neck cancer

Concerning malignancies of the head and neck, which are tumors that frequently spread and become invasive, using plant-based therapeutic agents as an adjuvant treatment in conjunction with surgery and/or radiation therapy can be a viable therapeutic alternative. Vinblastine and vincristine, alkaloids derived from the Madagascar periwinkle (Catharanthus roseus), are two examples of anticancer drugs derived from higher plants, sometimes referred to as vascular plants (21). An alkaloid called paclitaxel has been demonstrated to be useful in the in vitro and in vivo treatment of HNC. It works by interfering with the normal functioning of microtubules, which are important for cell division (22).

Sophoridine, a natural alkaloid, exhibits anticancer effects for tumors in the head and neck by preventing cancer cells from proliferating and by triggering cell cycle arrest and death through the manipulation of cell cycle regulatory protein expression (23). There is also evidence to suggest that some alkaloids may be effective in preventing HNC. For example, studies have found that nicotine, an alkaloid found in tobacco, increases the possibility of developing HNC. However, it has been demonstrated that several tea alkaloids, including epigallocatechin gallate (EGCG), have chemopreventive actions against HNC (24).

In conclusion, alkaloids have shown potential in the management and avoidance of cancers of the head and neck. To completely comprehend their methods of action and create potentially beneficial treatments, additional study is necessary.

Alkaloids and gastrointestinal cancer

A naturally occurring alkaloid called sophoridine is obtained from Sophorae flavescentis Radix. Numerous pharmacological effects, such as antiviral, anticancer, and anti-inflammatory properties, have been described. The prospect of using sophoridine to treat pancreatic cancer has drawn more interest in recent years. Research has indicated that sophoridine can cause cell death in carcinomas of the pancreas by triggering the G2/M cell cycle arrest and the c-Jun N-terminal kinase/extracellular regulated protein kinases (JNK/ERK) signaling mechanism (25).

In addition, three years ago an important study investigated the combination of sophoridine with gemcitabine, a common chemotherapy medication used to treat tumors in the pancreas. The results demonstrated that sophoridine and gemcitabine worked in harmony to prevent pancreatic cancer cell proliferation and trigger apoptosis, suggesting that sophoridine could enhance the efficacy of gemcitabine. Furthermore, it blocks the expression of matrix metalloproteinases (MMPs), which are important enzymes in tumor metastasis, hence preventing the spread and invasion of pancreatic cancer cells (26).

Magnoflorine, an alkaloid that comes from the plant Coptis coptidis, has the ability to cause autophagy-dependent cell death in gastric cancer cells by blocking AKT/mTOR and stimulating the production of reactive oxygen species (ROS) (27). Cepharanthine (CEP) is a cationic and amphipathic alkaloid that is found naturally in Chinese herbs including Stephania cepharantha Hayata and Stephania japonica. It has been shown to have a thinning effect on cellular membrane fluidity. Cepharanthine primarily inhibits tumor growth by triggering apoptosis. Furthermore, p53-mutated colorectal cancer cells, which are frequently resistant to widely used chemotherapeutic drugs, are effectively inhibited from growing by CEP (28).

Curcuminoids

Turmeric naturally contains polyphenol chemicals called curcuminoids. Curcuma longa, or turmeric, is a member of the family of ginger plants. Although it initially originated in tropical Southeast Asia, it now grows all over the world, including China and Latin America (29). One of the primary ingredients, curcumin, has a long history of use in South Asian traditional medicine as a spice and food supplement for a variety of disorders, including autoimmune conditions, cardiovascular diseases and neurological conditions like multiple sclerosis, Parkinson disease and Alzheimer disease (29, 30).

Curcumin and other curcuminoids have been shown in numerous preclinical studies to have anticancer properties against a variety of tumor types, including glioblastoma, melanomas, and malignancies of the breast, head and neck, prostate and ovary (30, 31). Numerous deadly effects, including apoptosis, autophagy, cell cycle arrest, alterations in gene expression, and molecular signaling, were elicited in tumor cells by curcumin (32).

Curcuminoids and glioblastoma

It has been demonstrated that curcumin can selectively trigger apoptosis in cancer cells and enhance the effects of contemporary chemotherapy and radiation therapy while sparing healthy tissue, minimizing the aggressive properties of glioblastoma stem cells (33).

Curcuminoids and head and neck cancer

Through the induction of apoptosis and the inhibition of certain signaling mechanisms involved in cancer development and metastasis, curcuminoids (CUR) may be able to suppress the growth of head and neck cancer cells (34). Furthermore, curcuminoids have been shown in a recent study to increase the susceptibility of cancer cells to radiation, which may improve the effects of radiation therapy in head and neck cancer (35).

Since systemic medication absorption is not necessary, local formulations including CUR are a viable choice for superficial skin and head and neck malignancies. However, due to its poor bioavailability for oral administration and weak water solubility, it has limited healing potential and is unstable at normal pH values. To overcome these problems, studies suggest new formulations such as liposomes, nanoparticles, micelles, phospholipid complexes, polymers and adjuvants. In addition, other curcuminoids, such as bisdemethoxycurcumin (BDMC), are used (37).

Curcuminoids and gastrointestinal cancer

The anticancer efficacy of curcumin has been linked to a number of processes, some of which include modulating the gut microbiota, enhancing the function of the intestinal barrier and reducing inflammation in the colon (36). Furthermore, it is thought to be a strong autophagy regulator that can stop the normal colonic epithelium from altering. Numerous investigations have demonstrated that curcumin's ability to inhibit malignancy in colorectal cancer (CRC) is dependent upon the control of histone modification, DNA methylation, or miRNA. According to findings from many clinical trials, curcumin may prevent CRC by decreasing the size and quantity of polyps. Furthermore, curcumin has demonstrated amazing synergistic effects on the effectiveness of available anticancer medications. Several novel forms of curcumin have been developed to deal with potential concerns regarding its bioavailability. This indicates greater promise for this natural medicine to gain attention as a cost-effective and safe option for patients with chronic diseases, including cancer, especially for prevention and therapy of colorectal cancer (37).

Flavonoids

Plants generate flavonoids, a category of more than 4,000 polyphenolic compounds, as secondary metabolites. Almost all plant-based foods, including fruits and vegetables, contain them. Their main roles are to protect plants against ultraviolet radiation and attract insects to pollinate. They have been shown to prevent carcinogenesis in vitro. Also, there is strong evidence that they can prevent carcinogenesis in vivo as well. Foods including onions, apples, grapes, peppers and green tea are common sources of it. Because of its anti-inflammatory, anti-diabetic and antioxidant properties, quercetin is the most frequently studied flavonoid (38, 39). Moreover, the chemopreventive properties of quercetin have been shown in a range of cancer types such as lung, ovarian, colon cancers and GBM (40).

Flavonoids and glioblastoma

An important feature of flavonoids, concerning the glioblastoma, is that they can cross the BBB. Transcellular diffusion, carrier-mediated transcellular transport, or paracellular diffusion via tight junctions between BBB endothelial cells are the methods used to accomplish this process (41). Due to their reduced molecular size, the smaller flavonoids are preferred in both forms of diffusion. Quercetin is the most studied flavonoid against glioblastoma. Treatment of glioblastoma cells with quercetin caused apoptosis by triggering caspases 3 and 9 and the mitochondrial death pathway, cell migration and angiogenesis inhibition and lead to cell cycle arrest. Moreover, quercetin decreased cell proliferation and viability (42).

Flavonoids and head and neck cancer

Numerous studies have looked into the connection between flavonoids and cancers of the head and neck (43). In comparison to individuals with the lowest consumption, higher flavonoid intake was linked to a reduced incidence of head and neck cancer, notably oral and pharyngeal cancer (44). The evidence that quercetin enhanced the effectiveness of chemotherapy drugs in killing cancer cells (45) suggests that flavonoids may be beneficial in the treatment of head and neck cancer. In oral cancer, quercetin suppressed cell proliferation, migration and invasion by inducing G1 cell cycle arrest and apoptosis by activating the p38 signaling pathway. Studies performed with dietary flavonoids, namely chalcone, 2-hydroxychalcone and quercetin, on 4-nitroquinolone 1-Oxide (4NQO) induced tongue carcinogenesis in rats, significantly inhibited the development of tongue tumors and they have potential as chemopreventive treatment for oral cancer (46).

Resveratrol (RSV) is another naturally produced polyphenolic substance that exists in a range of fruits, vegetables and plants, including grapes, blueberries and peanuts. Several articles have described the antitumor potential of resveratrol against various cancers, as well as the antitumor strategies, including migration, apoptosis induction, cell cycle disruption, programmed cell death, suppression of angiogenesis and the transition between epithelial and mesenchymal cells (47, 48). Furthermore, RSV has been demonstrated to decrease the expression of a number of genes linked to the development and metastasis of OSCC such as VEGF and matrix metalloproteinases (MMPs) (49). Consequently, it is clear that RSV may play a significant role in the future in the management of head and neck malignancies, including OSCC.

Flavonoids and gastrointestinal cancer

A flavonoid glycoside derived from Pogostemon cablin, apigetrienin can cause autophagy-dependent cell death in gastric cancer cells by activating the PI3K/AKT/mTOR pathway. Additionally, apigetrin's aglycone, apigenin, exhibits superior anticancer action. The B-ring in apigenin's structure is crucial to its anticancer properties. By substituting a methoxy group for C-7 and conjugating aromatic rings, the substituents on the A-ring can also increase the toxic effect and specificity for cancer cells (50). Recent research on the effects of resveratrol on gastrointestinal cancer revealed that men who consumed RSV had a lower incidence of CRC (51). Additionally, RSV may cause gastric cancer cells to undergo cell death in vitro. In summary, it induces apoptosis in cancer cells via activating many pathways, specifically by modifying the activity of the p53 and mitogen-activated protein kinase (MAPK) (52).

Coumarins

A family of substances called coumarins is obtained from plants, which includes fruits, vegetables and herbs. They are synthesized as secondary metabolites and their main role is to aid in iron uptake when iron availability is low. These are lactones, which are fundamentally made up of an a-pyrone ring fused to a benzene ring. A lot of research has explored coumarins as potential therapeutic options for a range of illnesses. Because of its potent pharmacological action, moderate toxicity and high absorption, coumarins play a significant role in pharmaceutical chemistry. The development of coumarin-based anticancer, antibacterial, anti-inflammatory and antineurodegenerative medicines has received substantial attention (53).

Coumarins and glioblastoma

Osthole, umbelliferone, esculin, 4-hydroxycoumarin and 5-methoxypsoralen are coumarinic compounds which have been investigated as potential therapeutic agents in glioblastoma. The results indicated apoptosis induction in glioma cell lines tested. Moreover, 5-methoxypsoralen induced cell cycle arrest, autophagy and signaling pathway inhibition (54, 55).

Coumarins and head and neck cancer

Regarding their effects on head and neck cancer, some studies have suggested that certain coumarins may have a protective effect against this type of cancer. It was discovered that scopoletin, a coumarin derivative, may cause head and neck cancer cells to die in vitro (56). Similar to this, umbelliferone, a different coumarin molecule, has the ability to prevent head and neck cancer cells from developing and induce cell death in vitro (57). To completely grasp the potential advantages of coumarins, additional research is necessary, as there are currently few studies on this topic.

Coumarins and gastrointestinal cancer

Numerous studies have examined the potential of coumarins in the management of gastrointestinal cancer in preclinical models. Some of the most promising coumarins are esculetin and 7-hydroxy-coumarin, which have been demonstrated to block the growth of colon and gastric cancer cells as well (58, 59). Although preclinical studies provide us with valuable insights into the potential therapeutic effects of coumarins, none of them have been approved for gastrointestinal cancer treatment. Thus, additional investigation is required to confirm their safety and efficacy in extensive clinical studies.

Discussion

About 65% of drugs were connected to natural substances throughout the last 40 years, and roughly 33.5% of FDA-approved medications were derived directly from them (60). There has been a notable surge in research on natural compounds, particularly in the treatment of cancer. Many natural substances, such as paclitaxel, camptothecin and homoharringtonine, have been employed in the therapeutic field of cancer. Traditional Chinese medicines, such as hedyotis, malaria and Cephalotaxus fortunei, are all regarded as anticancer medications (17). Furthermore, by triggering RCD, researchers have already discovered a number of naturally occurring compounds that may hinder the proliferation of cancer cells. Consequently, natural substances continue to be a valuable source of anticancer medications.

Natural compounds are constantly gaining ground in treating a range of chronic illnesses, including malignancy. Research efforts have been focusing on them due to their special features consisting of low toxicity and high bioavailability. These compounds have already demonstrated important antitumor activity in vitro, through several mechanisms, including cell viability reduction, inhibition of cell division, promotion of cell death and cell cycle arrest (61, 62). However, further investigation is required, as well as validation in several cancer models and in large clinical trials.

Conclusion

It is important to highlight that natural compounds should not be used as a substitute for conventional cancer treatments and cancer patients should always seek advice from their healthcare provider before starting any new supplement or dietary regimen. However, natural compounds may offer a significant ‘help’ with their anticancer properties in the ‘war’ against cancer in the future. More studies are needed in order to reach safe conclusions.

Conflicts of interest: none declared.

Financial support: none declared.

Authors' contributions: conceptualization – GA and GL.; methodology – GA, GL, AL; formal analysis – GL, AL.; data curation – GL, AL; writing, including original draft preparation – GL AL; writing, including review and editing – GA, MM; supervision – GA, MM.

Acknowledgements: The publication of the article in OA mode was financially supported by HEAL-Link.

FIGURE 1.

Natural compounds and cancer