INTRODUCTION:

Nature provides an infinite and inexhaustible source of novel effective drugs, chemotypes, and pharmacophores¹. Medicinal herbs are widely used around the world and have become increasingly important in the treatment of diseases in recent years. Bioactive molecules, which are components of the plant's chemical core, play a therapeutic role². Natural compounds have played an important role in the treatment and prevention of various pathologies since ancient times, forming the backbone of the traditional system of healing^3-4.

Furthermore, because plant-derived compounds comprise a large portion of current therapeutic approaches, terrestrial plants (e.g., Artemisia annua L., Camptotheca acuminata Decne., Gingko biloba L., Curcuma longa L., Podophyllum peltatum L., Taxus brevifolia, Taxus baccata, Combretum caffrum, Euphorbia peplus, etc^5-7.

The most recent review published by Newman and Cragg thoroughly explains the role of natural compounds as drugs or as a basis for the development of new drugs. According to their data, 929 of the 1881 new approved drugs (antibacterial, antifungal, antiviral, antiparasitic, antitumor, etc.) in the last four decades have natural origin and are classified as biological macromolecules, unaltered natural products, botanical drugs, or derivatives of natural products or vaccines, while the other 952 are classified as synthetic drugs, synthetic drugs with natural product pharmacophores, or drugs that mimic a natural product^8-10.

Herbal medicines have been widely accepted as a complementary or alternative option in the field of oncology (Catharanthus roseus, Podophyllum peltatum L., Taxus brevifolia Nutt., Taxus baccata, and others). As a result, several novel cytotoxic compounds isolated from plants each year represent new possibilities for cancer treatment. Many researchers focus their efforts on the study of naturally occurring molecular entities that could be useful to the pharmaceutical industry. Those who discover antitumor compounds in preclinical studies seek clinical efficacy confirmation as well¹¹.

METHODS:

Materials:

Carcinogenesis, the process by which cancer arises and develops, is a step-by-step process characterized by the accumulation of distinct molecular changes, the accumulation of mutations and epigenetic alterations that activate oncogenes, the inactivation of tumor suppressor genes, the hindrance of DNA repair machinery, and the disruption of apoptosis mechanisms, which forces cells to undergo uncontrolled cellular division. A single change cannot promote tumorigenesis, but a combination of multiple changes that affect cellular homeostasis is required to cause cells to lose control of proliferation¹². Cells undergo fundamental changes with each disturbance, leading to tumor initiation, promotion, and progression. Tumor initiation is a rapid and irreversible process that begins with exposure to a carcinogenic agent, which is then transported to tissues where it can cause cancer¹³.

The advantages of natural compounds, such as reduced side effects and the ability to influence multiple signaling pathways involved in the carcinogenesis process, may explain why, of the 240 antitumor drugs approved in the last 40 years, only 29 are strictly synthetic. Furthermore, in the last ten years, synthetic compounds with natural pharmacophores that mimic the natural product effect have been approved as antitumor drugs¹⁴.

Phytochemicals have been at the forefront of cancer research since its inception, as they were among the first anticancer drugs discovered (e.g., leucovorin in 1950, carzinophilin in 1954, vincristine in 1963, actinomycin D in 1964, etc.). Furthermore, their research has been carried on to the present day. It is critical to note that natural compounds are used not only as chemotherapeutic agents, but also as adjuvants in cancer treatment¹⁵.

Chemoprevention is defined as a pharmacological intervention, and several compounds, ranging from natural sources such as plants, fruits, and vegetables to synthetic molecules, are capable of inhibiting, delaying, or reversing tumorigenesis and preventing cancer recurrence by blocking carcinogenic agents, increasing the capacity of the DNA repair system, or acting directly against cells that carry DNA modifications by decreasing cell cycle It usually focuses on the discovery of agents that specifically affect the early stages of cellular transformation and is directed at people who have already developed cancer as well as those who are predisposed to any type of cancer. Phytochemicals play a role in cancer prevention¹⁶.

Major phytochemicals used for ameliorating or preventing Cancer:

Relevant in vitro studies based on natural compounds with antitumor properties

Natural Compound	Cancer Type	Findings	Cell Death Type
Resveratrol	Breast cancer	Cell cycle inhibition; S-phase arrest; ↑ cell apoptosis rate	Apoptosis
	Osteosarcoma	Cleavage of PARP, and caspase-3; ↑ Bax; ↓ Bcl-2 and Bcl-xL; JAK2/STAT3 pathway inhibition	Apoptosis
	Cervical cancer	↑ content of LAMP1, Atg7, LC3B, PINK1 and PARK2 proteins; ROS overload; ↓ glycolysis; ↓ oxidative phosphorylation protein contents and fluxes	Autophagy
	Colorectal cancer	inducing cell cluster formation; ↓ cell viability	Apoptosis
Curcumin	Melanoma	inhibition of cell invasion; G2/M phase cell-cycle arrest; suppression of the AKT, mTOR and P70S6K activation	Autophagy
	Breast Cancer	↓ phosphorylation of Akt and MAPK; ↓ HER-2 oncoprotein; ↓ NF-κB	-
	Cervical Cancer	DNA damage and fragmentation; chromatin condensation; ↑ amounts of p-ATM, p-ATR, p53, MDM2, BRCA1, DNA-PK, MDC1 and p-H2A.X, PARP and MGMT proteins	Apoptosis
	Colon Cancer	inhibition of the cellular invasive activity; ↓ uPA and MMP9 expression; ↓ NF-κB activation	-
EGCG	Colorectal Cancer	↓ number and size of cell sphe-roids;inhibition of the Wnt/β-catenin pathway; ↓ pro-tein levels of Cyclin D1 and PCNA; ↓ Bcl-2; ↑ Bax, Caspase-8, Caspase-9, and Caspase-3	Apoptosis
	Colorectal Cancer		Apoptosis
	Lung Cancer	↓ survival rate; loss of the adhe-sion ability; ↓ Bcl-xL	Apoptosis
	Breast Cancer	↓ expression of β-catenin, p-Akt, and cyclin D1; inactivation of the β catenin signaling pathway; ↓ cell proliferation; disrupted adherence junction formation	-
Quercetin	Pancreatic Cancer	modulation of ROS production and mitochondrial membrane potential; interference with MAPK, Akt, and NF-κB signaling pathways	Apoptosis Necrosis
Quercetin	Cervical Cancer	↑ expression of caspases and pro-apoptotic genes; DNA fragmentation; ↓ cell migration; G2-M cell cycle arrest; blockage of the PI3K, MAPK and WNT pathways	Apoptosis
	Colorectal Adenocarcinoma	NF-κB pathway inhibition; ↑Bax; ↓Bcl-2 increased cell membrane permeability; nuclear condensation	Apoptosis
Rutin	Colon Cancer	↑ cleaved caspases-3, -8 and -9; ↓ Bcl 2; ↑ Bax; cell shrinkage; chromatin condensation; rounding, blebbing and an increased density of apoptotic bodies	Apoptosis
Betulinic acid	Melanoma	G0/G1 cell cycle arrest; ↓ cell proliferation	Apoptosis
	Ovarian Cancer	↑ levels of cleaved caspase-8, -3, -9; ↑ Bax; ↓ Bcl-2; nuclear Condensation	Apoptosis
	Colon Cancer	↑ Bax; ↑ cleaved caspase-3; ↑ ROS production; ↓ Bcl-2; ↓ mitochondrial membrane potential	Apoptosis
Artemisinin (Artesunate)	Breast Cancer	↓ Bcl-2; ↑ Bax; G2/M-phase arrest; ↓ Cyclin-B1 and Cyclin-D1; agglutinated heterochromatin; degenerated mitochondrial vacuoles; nuclear swelling; ↓ number of intracellular organelles	Apoptosis Autophagy
	Colon Cancer	Cell elongation; membrane foaming; nuclear condensation and fragmentation; chromatin shrinkage; ↓ Bcl 2 and BclxL; ↑ Bax; ↑ cleaved procaspase-3 to active caspase-3; ↑ levels of beclin 1, LC3 I/II, and Atg5; ↑ complexation of Atg12-Atg5	Apoptosis Autophagy
	Cervical Cancer	↓ Telomerase activity; ↓ hTERT and hTR expression; ↓ E6 and E7 oncogenes; chromatin condensation; ↑ p53 expression	Apoptosis
Ginseng extract	Breast Cancer	↓ Bcl-2; ↑ Bax, cytochrome c, and cleaved caspase-3; ↑ ROS production	Apoptosis
Ginseng extract	Lung Cancer	Punctate cytoplasmic expression of LC3, Beclin-1 and ATG5; G2/M phase arrest; ↑ expression of LC3-II; ↑ p-Akt; ↓ mTOR-4EBP1	Autophagy

DISCUSSION:

Numerous cellular effects of phytochemicals have been discovered, and their chemopreventive activities can be attributed to their abilities to stop carcinogens from reaching specific sites, support the detoxification of highly reactive molecules, improve innate immune surveillance, improve the elimination of transformed cells, or have a variety of effects on intrinsic DNA repair mechanisms by influencing tumor suppressors or obstructing cellular proliferation pathways. Other chemoprevention strategies include suppressing inflammatory events, inducing cell death through autophagy or apoptosis, and inhibiting the epithelial-mesenchymal transition, in addition to directly inactivating carcinogens by either acting as free radical scavengers or inducing enzymes involved in scavenging^17-18. Plants are a never-ending source of secondary metabolites that are increasingly used as treatments for a variety of cancers. Research on flavonoids is one such secondary metabolite that has significantly advanced the development of anticancer drug discoveries. The pharmacokinetics of flavonoids, their ability to reach the biological site of action, and their chemical structure all play a significant role in how effective they are at chemoprevention. Furthermore, flavonoids have a high availability due to their abundant presence in foods that we consume, such as fruits, vegetables, teas, and wine. They also possess powerful antioxidant potential, estrogenic regulatory effects, antimicrobial activity, and the ability to inhibit several stages of cancer progression, such as invasion, metastasis, and angiogenesis^19-35.

CONFLICT OF INTEREST:

The author has no conflicts of interest.

ACKNOWLEDGMENTS:

The author would like to thank NCBI, PubMed and Web of Science for the free database services for their kind support during this study.

REFERENCES:

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Received on 24.12.2022 Modified on 29.04.2023

Asian J. Research Chem. 2023; 16(6):443-447.

DOI: 10.52711/0974-4150.2023.00073