INTRODUCTION:

A bad object or disease that spreads destructively is cancer. Everyone is affected, and patients, families, and societies are all under a huge strain as a result. According to GLOBOCAN, 9.6 million individuals worldwide passed away from cancer in 2018. The predicted increase in cancer incidence is 29.5 million and mortality is16.3 million by 2040¹. In the United States, experts estimated that there would be 1.3 million newer instances of invasive malignancies and 5,50,000 fatalities by the end of the 20th century, translating to 1,500 cancer deaths every day².

Sadly, this figure grew and in 2015 there were almost 1.6 million new cases and 589,430 deaths, or almost 1,600 deaths every day³. WHO predicted that by 2030, 25% of the global population would have at least one type of cancer. Around 60% of newer cases are anticipated to occur in a lower and middle-income areas⁴. However, cancer was thought to be the cause of 600 000–700 000 deaths in India in 2012. With a predicted increase of 29.8 million DALYs (Disability Adjusted life Years Daily) in 2025, India is likely to have a 26.7 million DALYs AMI higher cancer burden in 2021. The burden was largest among males and in the northern and northeastern areas of the nation. The seven most common cancer sites—lung (10.6%), breast (10.5%), oesophagus (5.8%), mouth (5.7%), stomach (5.2%), liver (4.6%), and cervix uteri (4.3%)—contributed to more than 40% of the overall cancer burden¹. An important issue with women's reproductive health is cervical cancer. It is a disease that can be prevented that poses a serious threat to the public's health, especially in developing nations. Nearly 85% of all cervical cancer fatalities and 83% of the more than 4,93,00 new cases worldwide both occur in poor nations ⁵.After lung and stomach cancer, breast cancer is the third most frequent cancer in the world and the most common malignancy in women, accounting for 23% of all cancers in women globally⁶. According to an intriguing study, 14.1 million Americans overall had a history of cancer. According to a preliminary study, 3,131,440 women in the USA have invasive breast cancer (BC). 232,670 women had invasive BC in 2014 alone, and nearly 72% of them were above 60. There were 231,840 new cases of BC in 2015, according to statistics, whereas experts predicted 246,660 new cases in the year that followed [4]. Atypical lobular hyperplasia, nipple discharge other than milk, high dose breast or chest irradiation, combined oral contraceptive use, early menarche before age 12, late menopause after age 55, obesity, late age of first birth >35 years, null parity, never breastfed, and oestrogen replacement therapy are among the high risk factors for breast cancer. Breast cancer is caused by gene mutations (BRCA-1 or BRCA-2) in 5%–10% of cases^7,8. The most efficient treatment strategy depends on the type of breast cancer. The status of three particular cell surface receptors is the most typical criterion used to categorize breast tumours. Oestrogen receptor (ER), Progesterone Receptor (PR) and HER2/neu receptor, or human epidermal growth factor receptor. Hormone receptor-positive breast cancer, which makes up around 75% of all cases of breast cancer, is the most prevalent kind⁹. In 2021, there was around 1,898,160 cases of cancer diagnosed in the USA, and there will also likely be 608,570 cancer-related fatalities¹⁰. Research on the use of natural products in cancer therapy is ongoing, and earlier studies have shown that a few plant extracts and pure chemicals can effectively treat a variety of malignancies, like garlic and lemon extract¹¹. Other plant extracts that have been used in cancer treatment are Achillea wilhelmsii, Allium sativum, Ammi majus, Artemisia absinthium, Acorus calamus, Aegle marmelos, Agave americana etc^12,13. A tumor suppressor gene called p53 is engaged in several metabolic processes, such as apoptosis initiation, DNA repair, and cell cycle arrest. The protective role of p53 was lost in more than 50% of human malignancies, leading to resistance to apoptosis and uncontrolled cell proliferation¹⁴. Cancer cell growth must be specifically disrupted in order to be selectively inhibited with minimal harm to healthy cells. Given that p53 is mutated in majority of human malignancies, so it is thought to be one of the appropriate targets in this situation¹⁵.

Traditional anticancer treatments' side effects:

Patients with early- or late-stage BC may choose chemotherapy as their first course of treatment and may continue with it. Unfortunately, there are a variety of harmful, unpleasant, and potentially fatal side effects associated with chemotherapy. These medications also fall victim to the MDR, also known as multidrug resistance, which reduces effectiveness of these chemotherapeutic drugs^16,17.

In addition to antimetabolites like fluorouracil, which cause congestive heart failure (CHF) due to vasospasm, anthracyclines and mitoxantrone also produce arrhythmias and congestive heart failure (CHF) with cumulative doses of more than 160 mg/ml, have long been recognised to cause cardiac toxicity. Patients with cancer who receive chemotherapy in conjunction with other antiemetic medications and opioids will become really uncomfortable¹⁸.

Some individuals experience diarrhoea as a result of the drug, oxaliplatin, which generates excessive secretions and triggers apoptosis in colonic crypts. Cisplatin, an anticancer drug that alkylates, produces severe nephrotoxicity by cell death of renal proximal tubules, which in result raises serum creatinine levels after a while. It also causes heart block and ischemia a few administration days. Researchers also found ototoxicity, hepatotoxicity, and a decline in RBCs and WBCs counts in cisplatin users¹⁹.

It was anticipated that radiation-sensitive patients would experience lung and subcutaneous fibrosis. Additionally, breast cancer women who had radial therapy felt emotional distress and suffering. Most of the patients stopped receiving therapy after experiencing severe breast burning once the diagnosis was over. These adverse consequences prompted researchers to look for alternate therapeutics with minimal toxicity and high potential to target malignant cells specifically. Natural compounds made from plants are the best source for these treatments because of their diversity and ability to target many cancerous development pathways^20,21. Herbal treatments have been used for many years all over the world, but they are especially popular in India. Because they may treat a variety of disorders with fewer side effects, herbal medications have become more popular. Natural products (NPs) and herbal treatments have been utilized to treat illnesses since ancient times ²².

What is p53?:

Genes called tumor suppressors control and prevent uncontrolled cellular growth and proliferation. Normal cell growth is lost as a result of gene loss or mutation. The retinoblastoma and p53 genes are two prevalent examples of tumor-suppressor genes. One of the most frequent genetic alterations linked to cancer is p53 mutation. The p53 gene's normal product controls the cell cycle's negative feedback, allowing the cell cycle to pause for repairs, corrections, and reactions to other environmental signals. This checkpoint is eliminated when p53 is inactivated, allowing mutations to take place²³. In over 50% of malignancies and 30% of breast tumors, the DNA binding domain of p53 is mutated, and/or the carboxy-terminal domain is deleted. Both basal-like breast cancer and some poorly differentiated luminal breast cancers likely fall within the category of triple negative breast cancers, which are identified by the absence of expression of the oestrogen receptor, progesterone receptor, and HER2²⁴.

Role of p53 in the development of cancer:

The human p53 gene is capable of encoding 12 distinct isoforms, which are typically created through alternate translation initiation and alternative splicing. The 393 amino acids that make up the p53 protein are divided into six domains. First is the N-terminal region, which is separated into two parts and contains the transcription activation domain (TAD) (TD1 and TD2). The proline-rich region (PRR), which is consistent in most p53s, comes in second.

The DNA-binding portion of the central core domain (p53C), where more than 90% of human mutations occur, is ranked third. A nuclear localization signal domain comes in fourth. A tetramerization (TET) domain comes in fifth. The C-terminal domain (CT), a general DNA-binding domain, comes in at number six. p53 causes cell cycle arrest, apoptosis to stop angiogenesis and DNA repair. Any p53 mutation could have an oncogenic effect. The p53 gene is mutated in the majority of human malignancies, which results in a complete or some loss of function^25,26.

95% of p53 mutations are located in the central region, which is responsible for sequence-specific DNA binding, compared to just 5% in the regulatory domains. Frequently, p53 mutations occur in this area (residues 102–292)²⁷Because of its crucial function in cell survival, p53 is a target for numerous anticancer treatments. Animal models with endogenous p53 expression restored had tumor regression, albeit the type of tumor affected the response. For instance, p53 restoration in lymphoma suppresses cell proliferation while inducing apoptosis²⁸. Burkitt lymphoma receptor BLR-1, which binds to chemokine ligand 13 (CXCL13), is expressed more frequently in BC as a result of p53 inhibition, migrating and spreading. Posttranslational modification, protein stabilization, and protein-protein interactions are just a few of the various ways that the p53 protein can be activated. After all, the primary mechanism involves the destabilizing p53-murine double minute 2 (MDM2) pathway. The MDM2 protein regulates the amounts of p53, a transient tumor suppressor protein. The MDM2 protein binds to the p53 transactivation domain as part of the regulatory process. The first intron of MDM2 links to p53 on a DNA-binding region close to the promoter, inducing the production of the gene. Wild-type p53 (wtp53) promotes the expression of MDM2²⁹.

Function of p53 in apoptosis:

p53 can trigger apoptosis either through transcription-dependent or transcription-independent pathways by activating the caspase-cascade pathway. p53 stimulates the transcription of a gene which encodes a protein, such as the Fas protein, which is necessary for inducing apoptosis³⁰.

The transcription-dependent mechanism, on the other hand, takes place when p53 increases the production of pro-apoptotic proteins like Bax, which is essential for the intrinsic pathway of apoptosis. Targeting p53 with therapeutic methods centered on boosting p53 levels to cause apoptosis, preventing p53 from interacting with MDM2, and regenerating wild-type p53.The oncogene activating genetic mutations can shut down a large number of tumor suppressor genes, resulting in the growth of cancer. The action of p53 is inhibited by tumor-associated p53 mutations, which also cause changes in the activity of proteins that promote apoptosis³¹. Cancer treatment resistance is related to low p53 levels; a clinical research found that tumor cells due to mutation in p53 were resistant to radiation and chemotherapy. Additional clinical investigations have linked the suppression of functioning p53 family proteins like p73 and p63 to poor clinical results in cancer therapy. A mutant-type p53 can also boost the expression of multiple genes including the multidrug resistance-1 (MDR1) gene, which involves in the drug resistance phenomenon. The degree of responsiveness to specific cancer therapy and p53 function were found to be positively correlated. For instance, cancers with mutant p53 showed poor response to chemotherapy, such as lung cancer and prostate cancer^32,26.^.

Fig. 1 The functions of p53 in the normal cells³³.

Hu J, Cao J, Topatana W, Juengpanich S, Li S, Zhang B, Shen J, Cai L, Cai X, Chen M. Targeting mutant p53 for cancer therapy: Direct and indirect strategies. Journal of hematology and oncology. 2021 Dec;14(1):1-9.

Targeting p53 for cancer therapy:

Since p53 was first discovered forty years ago, numerous studies have clarified its functions in the development of tumors. But in addition to losing their tumor-suppressive characteristics, mutant forms of the tumor-suppressor p53 frequently acquire tumor-promoting traits. The development of p53-targeted medications is very difficult since the drug must specifically target mutp53 in cancer cells while having no impact on healthy cells with wtp53^34,33. Furthermore, different mutant p53 protein structures that are challenging to target are produced by numerous p53 mutations. Based on their p53 state, major therapeutic approaches that target p53 may be divided into two groups: regaining wtp53 functions and eliminating mutp53 ^35,33.

Characteristics of Eupatorium adenophorum as a medicine:

Eupatorium adenophorum (E. adenophorum) belongs to the family: Asteraceae, also known as crofton weed, banmara, sticky snakeroot, etc., has been regarded as one of the forest killer plants³⁶. The Asteraceae family is widely found throughout Asia, Eastern Australia, North America, South Africa, New Zealand, India, Nepal, Pakistan, Thailand, Malaysia, the Philippines, and Singapore³⁷. According to tradition, E. adenophorum (E.A) is used to heal wounds, diabetes, inflammation, fever, jaundice, and dysentery. Numerous phytochemicals, including sesquiterpenoids, triterpenes, flavonoids, phenolics, coumarins, steroids, and phenylpropanols, have been extracted and identified from E. adenophorum. Various pharmacological tests revealed that E. adenophorum extract had a range of biological properties, including antioxidant, antibacterial, anticancer, wound healing, analgesic, and antipyretic properties³⁸.

Pharmacological Uses:

Around the world, E. adenophorum has long been utilized as a traditional medicine. Local doctors employ it as a cytotoxic agent, blood coagulant, antipyretic, antibacterial, and antiseptic in many underdeveloped places. E. adenophorum has been used as a traditional Chinese medicine in China for treating injuries, phyma and fever. The raw leaf extract was utilized by indigenous people in the Himalayan region to stop bleeding from cuts, wounds, or bruises by producing clots³⁹. People from the hill towns in the east Himalayas, like Darjeeling and Sikkim, use leaf extract to treat oral and cutaneous ulcers as well as dysentery. Manipur's Naga population typically consumes fresh leaf juice or dry powder to reduce body temperature. E. adenophorum juice or herbal tea was traditionally used to cure indigestion, diabetes, cancer, gallbladder problems, and stomach and liver problems^40,36.

Phytochemistry:

A medicinal plant's abundance of bioactive chemicals is thought to hold great promise for the discovery of novel therapeutics with unique features. The presence of phytochemicals from several families of substances, such as phenolic, flavonoids, glycosides, tannins, lignans, glycosides, terpenoids, proteins, furocoumarins, alkaloids, resins, steroids, and peptides, is essential for the therapeutic qualities of plants. In some studies, pure phytochemicals from E. adenophorum were isolated and identified. These studies revealed 96 different secondary metabolites. Phytochemicals such as phenolics, monoterpenes, sesquiterpenoids, triterpenes, flavonoids, coumarins, steroids, and phenylpropanols make up the majority of it^41,36.

Pharmaceutical processes:

Microbiological Activity:

The antimicrobial agent, which has the ability to either kill or limit the growth of microbes, can be obtained naturally, synthetically, or semi-synthetically (bacteria, viruses, fungi, etc.).

Macranthoin G, 5-O-trans-o-coumaroylquinic acid methyl ester, macranthoin F, and chlorogenic acid methyl ester are the biologically active components of E. adenophorum's aerial part and have demonstrated in vitro antibacterial activity⁴².

Anti-oxidant function:

Because of their strength, it is thought that E. adenophorum leaves may someday be employed as a natural antioxidant. With IC 50 values of 212.2 and 150.2 M, respectively, chlorogenic acid methyl ester and macranthoin G isolated from E. adenophorum tend to demonstrate the scavenging property against the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical, which is less than the positive control resveratrol⁴².

Wound healing process:

E. adenophorum was traditionally used in wound healing activity, which was demonstrated by an experiment in which gel was formulated with the help of plant extract of E. adenophorum. This experiment was done in order to determine the plant's potential for wound healing⁴³.

Antipyretic:

The COX (cyclooxygenase) enzyme is inhibited by the antipyretic drugs, lowering the PG level in the hypothalamus and assisting in lowering the increased body temperature. According to the Naga tribes in Manipur, the aqueous extract of E. adenophorum is said to have antipyretic properties. As a result, an experiment was conducted using albino rats in which yeast was used to produce pyrexia⁴⁴.

CONCLUSION:

EA is a prime candidate for further development to create more potent cancer medicines due to its many health advantages, cost effectiveness, and capacity to target many components of cancer. It's probable that the plant extract also contains anti-cancer properties because the volatile oil of the plant has been investigated for this purpose. By increasing pro-apoptotic proteins (such p53 and Bax) and decreasing anti-apoptotic proteins (such as MDM2 and Bcl-2), this substance may inhibit the growth of cancer. EA may be investigated further to supplement current cancer treatments. Through the literature review it was found that, the plant contains polyphenols, which might be useful in cancer treatment.

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Received on 15.12.2022 Revised on 18.03.2024

Accepted on 15.10.2024 Published on 20.01.2025

Available online from January 27, 2025

Research J. Pharmacy and Technology. 2025;18(1):421-426.

DOI: 10.52711/0974-360X.2025.00065

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.