Plant-Derived Anticancer Agents: From Traditional Medicine To Modern Therapeutics

5.1 Induction of Apoptosis

Plant-derived compounds kill cancer cells through the mechanism of programmed cell death (apoptosis), which is one of the most significant mechanisms. Apoptosis occurs in normal tissues to eliminate damaged, old or abnormal cells. Cancer cells, however, are frequently resistant to apoptosis, thereby surviving, proliferating and being able to withstand treatment. Numerous phytochemicals used to inhibit cancer restore apoptotic signaling and selectively kill cancer cells. There are two main pathways of inducing apoptosis: the intrinsic mitochondrial pathway and the extrinsic death receptor pathway. Phytochemicals may open up the permeability of the mitochondrial membrane, release cytochrome c, activate the caspase enzymes and induce cell death in intrinsic pathway. They can also act as regulators of proteins like Bax, Bcl-2, Bcl-xL and p53. An increase in Bax and decrease in Bcl-2 is proapoptotic. In the extrinsic pathway, compounds could be able to activate death receptors, like Fas and TRAIL receptors, resulting in the death of cancer cells by caspase-mediated mechanisms. Some of the plant based compounds that cause apoptosis include curcumin, resveratrol, quercetin, paclitaxel, vincristine, camptothecin derivatives and podophyllotoxin derivatives. These agents induce activation of caspase-3, caspase-8 and caspase-9, DNA fragmentation, and decreasing of the survival signal. The induction of apoptosis is crucial because it allows the destruction of cancer cells without triggering a lot of inflammation, as would necrotic cell death [53].

5.2 Cell Cycle Arrest

One of the characteristics of cancer is uncontrolled cell growth. The cell cycle has several phases, G0, G1, S, G2 and M phase. Cell cycle checkpoints help ensure the accurate replication of DNA and division of cells in normal cells. Because of mutations in checkpoint proteins, cyclins, cyclin-dependent kinases, and p53, cancer cells can evade these checkpoints. Plant-based anticancer agents may stall cancer cells in various stages of the cell cycle and stop them from dividing. For instance, vinca alkaloids and taxanes are typical inhibitors of the M-phase of the cell cycle, which block the function of the microtubules. Camptothecin derivatives could block the cells in the S phase as a result of damage to DNA replication, and podophyllotoxin derivatives could arrest cells in the S phase and G2 phase by inhibiting the activity of topoisomerase II. Quercetin, apigenin, luteolin, curcumin, and epigallocatechin gallate are flavonoids and polyphenols that can help control cyclins, CKs and checkpoint proteins. They can also cause them to up-regulate the expression of the natural inhibitors of cell cycle progression, p21 and p27. These compounds block cancer cells at certain checkpoints, which slow their proliferation and helps to promote cell death. Therefore, the ability to arrest the cell cycle is a major way by which phytochemicals can inhibit the growth of tumors [54].

5.3 Inhibition of Angiogenesis

Angiogenesis the development of new blood vessels from the existing blood vessel. Tumors need angiogenesis to get oxygen, nutrients and remove waste. Tumor growth is limited without the formation of new blood vessels. Pro-angiogenic factors like vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and matrix metalloproteinases (MMPs) are secreted by cancer cells to promote blood vessel growth. Plant-derived compounds can inhibit angiogenesis by decreasing the production or action of these pro-angiogenic factors. A large number of phytochemicals are known to block expression of vascular endothelial growth factor, inhibit proliferation of endothelial cells, decrease migration, and prevent tube formation. This restricts the blood flow to tumors and helps to reduce the growth of cancerous cells. Plant-derived substances that have anti-angiogenic properties include curcumin, resveratrol, genistein, epigallocatechin gallate, luteolin, apigenin and plumbagin. They may exert their effects through the inhibition of various pathways such as the VEGF pathway, the hypoxia-inducible factor 1 alpha (HIF-1α) pathway, the NF-κB pathway, the PI3K/Akt pathway, and the MAPK pathway. Other compounds also inhibit inflammation-mediated angiogenesis; chronic inflammation is a key element in supporting vascularization of tumors. Plant-based agents can prevent the development of new blood vessels, which can help to inhibit the growth of tumors and limit their spread [55].

5.4 Suppression of Metastasis and Invasion

The spread of cancer cells from the primary tumour to other parts of the body is called metastasis. It is responsible for most cancer-related deaths. The process of metastasis requires several steps: loss of cell to cell adhesion, degradation of extracellular matrix, invasion into surrounding tissue, entry into blood or lymph vessels, survival in blood or lymph, attachment to distant tissues, formation of secondary tumors. Cancer-causing compounds in plants can inhibit cell migration and invasion, epithelial–mesenchymal transition, extracellular matrix degradation, and adhesion molecule changes, which are all mechanisms that prevent metastasis. The extracellular matrix-degrading enzymes known as matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, play a significant role in the process of invasion and metastasis of cancer cells. A number of phytochemicals have been found to decrease the expression and activity of MMPs. Experimental studies have demonstrated anti-metastatic effects for compounds like curcumin, resveratrol, quercetin, epigallocatechin gallate, berberine, plumbagin and ursolic acid. They are able to block EMT process via modulating proteins like E-cadherin, N-cadherin, vimentin and transcription factors like Snail, Slug and Twist. They may also inhibit pathways like NF-κB, Wnt/β-catenin, STAT3, and PI3K/Akt related to invasion and metastasis. Hence, the inhibition of metastasis is an added favorable effect of plant based anticancer drugs [56].

5.5 Modulation of Oxidative Stress

Oxidative stress is a double edged sword in the fight against cancer. When excess amounts of ROS are produced they can damage DNA, proteins and lipids causing mutations and the initiation of cancer. On the other hand, the very high level of ROS may destroy cancer cells through oxidative damage and apoptosis. Compounds from plants may be able to modulate oxidative stress in the context of each cell, depending on the concentration and depending on the type of cancer. Numerous flavonoids, polyphenols, tannins and phenolic acids are antioxidants. They neutralize free radicals, decrease DNA damage, block lipid peroxidation and improve cellular antioxidant defense systems. Compounds like curcumin are known to enhance the activity of antioxidant enzymes like Superoxide Dismutase, Catalase and Glutathione Peroxidase.Compounds like curcumin are known to enhance the activity of antioxidant enzymes like Superoxide Dismutase, Catalase and Glutathione Peroxidase. This anti-oxidative effect is significant especially in cancer prevention. Some anticancer agents derived from plants, however, when applied to the cancer cell become pro-oxidants. Reactive oxygen species and/or oxidative stress-mediated apoptosis can be produced by quinones like plumbagin and shikonin. Basal reactive oxygen species (ROS) levels are already high in cancer cells, and increasing ROS may further drive them toward cell death. So, the action of modulation of oxidative stress is a complicated but significant mechanism which may prevent the development of cancer or even eliminate existing cancer cells by plant compounds [57].

5.6 Inhibition of Topoisomerases

Topoisomerases are important enzymes that control DNA topology in a wide range of biological processes such as replication, transcription, recombination, and chromosome segregation. They open up the DNA and create temporary breaks in the strands of the DNA to relieve supercoiling and then re-join the fragments. Topoisomerases are critically involved in the proliferation of cancer cells. Thus, the inhibition of topoisomerase is one of the important anticancer mechanisms. Plant-based compounds have been very important for the development of topoisomerase targeting chemotherapy. Topoisomerase I inhibitors include camptothecin derivatives like topotecan and irinotecan. They block the re-ligation of single strand DNA breaks and stabilize the topoisomerase I-DNA complex. These lesions are converted into double strand breaks during replication, which causes damage to the DNA, cell cycle arrest and apoptosis. Etoposide, Teniposide, etc. are derivatives of podophyllotoxin that act as inhibitors of topoisomerase II. These drugs block the re-ligation of double-strand DNA breaks, leading to the buildup of DNA damage and killing of cancer cells. Other phytochemicals, such as flavonoids, quinones, and alkaloids, have been reported to have an impact on topoisomerase function in experimental models. Inhibitors of topoisomerases are very potent, but can also be toxic to normal proliferating cells, particularly bone marrow cells. However, topoisomerase inhibitors are still important anti-cancer drugs that are derived from plants [58].

5.7 Microtubule Stabilization and Disruption

Tubulin proteins are the components of microtubules and they are dynamic structures. They are vital to cell shape, to moving material within a cell and to separating chromosomes in mitosis. Cancer cells grow quickly and are very sensitive to substances that interfere with the dynamics of microtubules. Microtubule targeting agents are one of the most effective clinically used anticancer drugs derived from plants. Vincas interfere with microtubules by binding tubulin and inhibiting the ability of tubulins to polymerize, including vincristine, vinblastine and vinorelbine. This prevents the formation of mitotic spindle and prevents cancer cells entering metaphase. Cells die as a result of unsuccessful mitosis. Taxanes like paclitaxel and docetaxel work in a reverse manner. They inhibit depolymerization and help to stabilize microtubules. They act in a different way than vinca alkaloids but produce a similar effect of abnormal microtubule dynamics resulting in cell death and mitotic arrest. This mechanism is particularly crucial in breast, ovarian, lung and prostate cancers. The most effective agents are those that target the microtubules, but although these drugs are effective, they have drawbacks, such as causing peripheral neuropathy, myelosuppression, hypersensitivity reactions, and drug resistance by changes in tubulin and/or increased drug efflux [59].

5.8 Regulation of Cancer Signaling Pathways

Several abnormal signaling pathways control cancer progression, including cell growth, survival, inflammation, angiogenesis, invasion and immune escape. Compounds derived from plants may be multi-target agents that can affect several signaling pathways simultaneously. These are useful in cancer, a complex disease in which many molecular pathways are affected. Signaling pathways that are important for cancer, and impacted by phytochemicals include PI3K/Akt/mTOR, MAPK/ERK, NF-κB, JAK/STAT, Wnt/β-catenin, Notch, Hedgehog and p53 pathways. As a case in point, curcumin is capable of suppressing NF-κB, STAT3, COX-2, and inflammatory cytokines. Resveratrol is able to modulate the PI3K/Akt, p53, and apoptosis-related pathways. Quercetin and apigenin have the ability to inhibit kinase signaling, decrease cell proliferation, and cause cell death by apoptosis. Other compounds, such as berberine, plumbagin, luteolin and epigallocatechin gallate, have a range of effects on several oncogenic pathways. Plant compounds can regulate signaling pathways to inhibit the growth of cancer cells, block cancer survival signaling, suppress inflammation, induce apoptosis and limit metastasis. Multitarget action is particularly beneficial because it is possible for cells to become resistant if a single pathway is blocked. This multi-targeted nature does however pose problems in identifying exact mechanisms and setting a standard for therapeutic effects [60].

5.9 Immunomodulatory Effects

The immune system is important in identifying and destroying abnormal cells. Cancer cells, on the other hand, can evade immune surveillance via immune suppression, the expression of immune checkpoint molecules, alteration in cytokine production, and the creation of an immunosuppressive microenvironment. Natural products from plants can modulate immune responses, cytokines, inflammatory factors, and tumor-associated immune responses to promote anticancer immunity. There are a number of phytochemicals that can act to boost the activity of natural killer cells, cytotoxic T lymphocytes, macrophages and dendritic cells. They can also control cytokines like interleukins, interferons, tumour necrosis factor-alpha and transforming growth factor-beta. Some compounds are anti-inflammatory; because chronic inflammation is a risk factor for the development and progression of cancer. Plants with immunomodulatory activities have been investigated to determine their immune-regulatory properties, including Withania somnifera, Tinospora cordifolia, Curcuma longa, Panax ginseng, Astragalus membranaceus, and Ganoderma species. Plant Extracts can also modulate the tumor environment by decreasing the number of tumor-associated immunosuppressive cells, increasing antigen presentation, and increasing the killing of tumor cells by the immune system. As part of supportive oncology, some medicinal plants are investigated for their ability to support immune function, lessen complications of therapy and improve quality of life, while reducing fatigue. Immunomodulatory effects, though, need to be thoroughly assessed as over stimulation or inappropriate immune activation can lead to undesirable effects or compromise the use of standard treatments. In conclusion, the anti cancer properties of plant based agents are multifaceted and related to each other. One compound can affect multiple biological processes, such as inducing apoptosis, arresting the cell cycle, inhibiting angiogenesis, decreasing metastasis, regulating oxidative stress, and also influencing signaling pathways. This poly-targeted nature renders plant-derived compounds good candidates for cancer prevention, as adjuvant agents and new anti-cancer drugs. Additional studies are needed to establish their safety, bioavailability, molecular targets, clinical efficacy and potential interactions with currently available anti-cancer drugs [61].

6. Role of Plant-Derived Agents in Modern Therapeutics

Herbal agents have significant applications in the modern era of cancer therapy in terms of clinically useful drugs, lead compounds, adjuvants, chemopreventive agents and combination therapy. Surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy and hormonal therapy are just some of the many treatment methods that have been developed for cancer, but there are still some drawbacks, including toxicity, drug resistance, recurrence, metastasis and the high cost of treatment.While cancer treatment has progressed significantly through surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy, and hormonal therapy, challenges such as toxicity, drug resistance, recurrence, metastasis, and the high cost of treatment continue to drive the need for safer, more effective therapeutic approaches. Plant-derived compounds are useful due to their ability to have multiple chemical structures with the ability to work on multiple molecular targets involved in cancer growth and progression. A number of clinically used cancer therapeutics have evolved from plants or are based on naturally derived plant compounds. Besides the direct cytotoxic chemicals, there are numerous phytochemicals that are being explored for their supportive, preventive and synergic aspects in the management of cancer [62].

6.1 Chemotherapeutic Agents of Plant Origin

One of the most promising areas of natural product contributions to oncology is the use of plant-derived chemotherapies. Numerous plants have been used in the development of clinically proven anticancer drugs and currently remain in use in cancer treatment. These include vinca alkaloids, taxanes, derivatives of vinca alkaloids, derivatives of camptothecin, derivatives of podophyllotoxin and other plant based compounds. Their significance is that they exhibit strong inhibitory activity against all major processes in the cell including protein synthesis, topoisomerase activity, DNA replication and mitosis. Catharanthus roseus is a source or inspiration for vinca alkaloids, including vincristine, vinblastine, and vinorelbine. They work by blocking the polymerisation of microtubules to block the formation of the mitotic spindle and to stall the development of cancer cells in the middle of their cell division. They are used to treat leukemia, lymphoma, breast cancer, lung cancer and other cancers. The taxanes, which include paclitaxel, docetaxel, are derived from the Taxus species, and function by stabilizing microtubules. This results in failing to breakdown normal microtubules and arrests the dividing cell in metaphase, resulting in apoptosis. Taxanes are generally used for breast, ovarian, lung, prostate, gastric and head and neck cancer [63].

Camptothecin is derived from the tree Camptotheca acuminata and the camptothecin derivatives irinotecan and topotecan are developed. These drugs block topoisomerase I and cause DNA damage in the rapidly growing cancer cells. Irinotecan is applied to widespread use in colorectal cancer, while topotecan is applied to small cell lung cancer and cervical cancer. Podophyllum species are the source of podophyllotoxins, which are used to make a number of drugs, including etoposide and teniposide. They are inhibitors of topoisomerase II and used in testicular cancer, lung cancer, lymphoma, leukemia and other cancers. As seen through these examples, the compounds found in plants have not just traditional or alternative medicine applications, but have also become part of the available evidence-based modern chemotherapy. They can, however, have adverse effects like myelosuppression, neurotoxicity, gastrointestinal toxicity, alopecia, hypersensitivity reactions and organ specific toxicity, as with other cytotoxic drugs. Hence, current research is directed towards increasing their selectivity, formulation, delivery and safety. The use of adjuvant therapy and combination treatment [64].

6.2 Adjuvant Therapy and Combination Treatment

Plant derived agents are also of significance in cancer management as adjuvants. Adjuvant therapy is the use of auxiliary treatment in addition to the main treatment to improve therapeutic outcome, reduce recurrence, improve patient recovery and reduce complications. Today, in the modern field of oncology, plant-derived compounds can be utilized as supportive agents, sensitizers, protective agents or as complementary substances, if they have been scientifically proven and properly monitored. Phytochemicals possess antioxidant, anti-inflammatory, immunomodulatory and cytoprotective effects. These may play a role in minimizing treatment-related side effects and enhance cancer patients' quality of life. Some compounds like curcumin, resveratrol, quercetin, epigallocatechin gallate, withanolides, ginsenosides, and berberine are known to exert anti-inflammatory, anti-oxidative, anti-immuno, and anti-cancer effects. Certain phytochemicals can help minimize side effects of chemotherapy treatment like mucositis, fatigue, oxidative tissue damage and inflammation, but clinical trials are required before they are widely used. Another key area where plant-based agents are becoming a focus for combination treatment. Cancer is a complex disease and so may not always be possible to use only one drug. Co-treatment of plant-derived compounds with conventional chemotherapy, radiotherapy, targeted therapy and/or immunotherapy may increase anticancer effects. These combinations can make cancer cells more sensitive, lower the dose of toxic drugs needed and prevent resistance, and enhance the effectiveness of the treatment. But combination treatment should be carefully evaluated. Herbal extracts or phytochemicals can interact with anticancer drugs by changing how the drug is absorbed, metabolized, distributed or eliminated. They can affect Cytochrome P450 enzymes, drug transporters, platelet function or immune responses. Thus, chemotherapy shouldn't be used with plant-derived agents on a whim, before scientific evidence and medical guidance. Future of adjuvant plant-based therapy relies on regulation of the extracts, identification of active compounds, precise dosage, clinical trials, and safety [65].

6.3 Chemopreventive Potential

Chemoprevention is the prevention, delay, or reversal of cancer using natural or synthetic chemicals. Plants contain compounds with high chemopreventive activity as many of them can affect early stages of cancerous process. The process of cancer develops in multiple steps, including initiation, promotion and progression. At these times, oxidative DNA damage, inflammation, abnormal cell growth, and failure of programmed cell death, or apoptosis, and genetic instability are important factors. There are many phytochemicals that could target these processes, and the risk of malignant transformation can be lowered. Cancer protective effects of polyphenols, flavonoids, carotenoids, organosulfur compounds, lignans, tannins and phenolic acids have been studied extensively. Experimental studies indicate that compounds like curcumin (from turmeric), resveratrol (from grapes), epigallocatechin gallate (from green tea), sulforaphane (from cruciferous vegetables), lycopene (from tomatoes), quercetin (from onions and apples) and genistein (from soy) have promising chemopreventive properties. They can neutralize free radicals, boost detoxification enzymes, inhibit carcinogen activation, decrease chronic inflammation, promote DNA repair, trigger the death of abnormal cells and control cell proliferation. Some phytochemicals also regulate transcription factors and signal molecules including NF-κB, Nrf2, STAT3, COX-2, p53, PI3K/Akt and MAPK pathways. Control of these pathways could help to lower cancer risk and slow the early development of tumors, while plant-derived compounds may have beneficial effects. Chemoprevention is particularly important for the prevention of cancers in high-risk populations, such as those with genetic susceptibility, chronic inflammation, environmental exposure, precancerous conditions, and lifestyles that increase the risk. In the case of plant derived agents as chemopreventives, however, strong evidence on clinical benefit, long-term use, effective dose and safety must be established. Eating foods with phytochemicals is good for you, but foods containing high amounts of individual phytochemicals may not be safe. Thus, there is a critical need to move beyond presumption and rely on scientific evidence for chemoprevention [66].

6.4 Overcoming Multidrug Resistance

One of the big reasons for cancer treatment failures is multidrug resistance. Structurally and functionally distinct anticancer drugs can become ineffective because cancer cells can become resistant to them. This resistance may be manifested in multiple ways such as the reduction of drug uptake, increase in drug efflux, activation of survival pathways, epithelial–mesenchymal transition, changes in the tumor microenvironment, mutation of drug targets, and decreased apoptosis. Compounds extracted from plants may be useful in overcoming multidrug resistance by targeting various mechanisms of resistance. Overexpression of ATP-binding cassette transporters (P-glycoprotein, multidrug resistance-associated proteins, and breast cancer resistance protein) is one of the most prevalent mechanisms of drug resistance. Such transporters actively excrete the anticancer drugs out of the cancer cells, thereby lowering the intracellular drug levels. Some phytochemicals, including curcumin, quercetin, resveratrol, berberine, piperine, epigallocatechin gallate and a few terpenoids have been studied for their drug efflux inhibitory properties and their capacity to enhance the levels of drugs within cancer cells. Plant-based compounds can also re-establish apoptosis in resistant cancer cells. The resistance of many cells to apoptosis is mediated by increased expression of anti-apoptotic proteins like Bcl-2 and survivin, or decreased expression of pro-apoptotic proteins like Bax and caspases. Phytochemicals can alter this balance to promote apoptosis and render resistant cells more susceptible to treatment. They also can block survival pathways like PI3K/Akt/mTOR, NF-κB, STAT3 and MAPK, pathways that are often activated in drug-resistant cancers. An additional mechanism is the inhibition of epithelial–mesenchymal transition that is associated with metastasis and resistance. Various compounds including curcumin, resveratrol, quercetin, luteolin and sulforaphane may inhibit epithelial–mesenchymal transition markers and inhibit invasion. Agents derived from plants can act on several resistance pathways at the same time, which could make them more effective than the conventional forms of chemotherapy. Yet, the majority is still preclinical and clinical trials of good design are required to validate this in overcoming MDR [67, 68].

6.5 Synergistic Effects with Conventional Anticancer Drugs

A combination of two agents acting together is more effective than each agent alone and is known as synergy. Phytochemicals may exhibit synergistic activity with the use of conventional anti-cancer agents through several mechanisms: increase in the effects of the drugs, induction of apoptosis, downregulation of survival signaling, increased delivery of the drugs and enhance sensitivity of the tumor cells to the drugs. This is desirable, as it could mean fewer doses of standard chemotherapy and thus less toxicity with equal or greater cancer-killing effects. Curcumin, for instance, has been investigated with drugs such as paclitaxel, cisplatin, doxorubicin and gemcitabine due to its ability to inhibit NF-κB, STAT3, COX-2 and anti-apoptotic pathways. Resveratrol can also improve the effectiveness of chemotherapy, by inducing apoptosis and decreasing damage caused by oxidative stress and inhibiting survival pathways. In experimental models quercetin has been reported to sensitize cancer cells to the action of doxorubicin, cisplatin and other chemotherapy drugs. Epigallocatechin gallate can modulate the pathways of apoptosis, proliferation and angiogenesis, thus enhancing the response to anticancer treatment. Another possible method of overcoming dose-limiting toxicity is to use synergistic combinations [69]. A phytochemical may make a cancer cell more susceptible to a chemotherapeutic agent, which could allow for a lower dose of the drug to be used. This may reduce side effects like myelosuppression, neuropathy, nephrotoxicity and gastrointestinal toxicity. Other plant-based chemicals may also help to prevent the oxidative damage of normal cells while killing cancer cells, but the selective protection needs to be carefully verified. These benefits, however, must be scientifically proven to be the case in synergy. Some of the combinations of plants and drugs are not beneficial. Others may hinder chemotherapy, via rapid metabolism of the drugs or by blocking them from getting into the cancer cells, or by shielding the cancer cells from the drug by consuming its antioxidants prior to it reaching them. A few others can make the drug more poisonous, either by interfering with how a drug is cleared from the body or by changing liver enzymes. Thus, combination therapy with plant-derived medications should be based on pharmacological evidence, standardized formulations, known dosages, and clinical trials. In general, plant derived agents have several applications in current therapies. They are directly used as chemotherapeutic agents, supportive co-adjuvants, chemopreventive agents, resistance modifying agents, and synergistic agents when used with established chemotherapy agents. They are especially useful in cancer, a disease in which multiple and interconnected molecular abnormalities underlie the disease. They must be standardized and mechanistically evaluated, pharmacokinetically studied, safely assessed, and clinically validated, however, for their successful incorporation into modern oncology practice [70].

FUTURE PERSPECTIVES

The potential of plants as source of anticancer drugs looks bright with the rising demand for safer, effective, cost effective and multi-targeted cancer therapeutics. A number of plant-derived drugs are already in clinical use including vincristine, vinblastine, paclitaxel, docetaxel, irinotecan, topotecan, etoposide and teniposide, but many medicinal plants and phytochemicals are not yet studied. Systematic screening of traditional medicinal plants, isolation of bioactive compounds, identification of molecular targets and validation of the anticancer mechanisms through advanced experimental models, are suggested for future research. The integration of artificial intelligence, molecular docking, network pharmacology and systems biology into natural product drug discovery is one of the future directions. These tools are currently available and can be useful to predict the interaction between phytochemicals and cancer targets, discover signaling pathways and to represent and select interesting compounds for further research. In particular, the function of many plant-derived compound is multi-target and is important in a complex disease such as cancer, making network pharmacology a very useful tool. Nanotechnology will also be important in enhancing the therapeutic properties of the plant-based anticancer agents. The clinical application of many of the phytochemicals is limited by low bioavailability, rapid metabolism, poor water solubility and instability. Nanoformulations like liposomes, polymeric nanoparticles, solid lipid nanoparticles, nanoemulsions, micelles and phytosomes can help to enhance the solubility of the drug, therapeutic efficacy, target the tumor and decrease its toxicity. These "delivery systems" could prove useful in turning beneficial phytochemicals into viable anti-cancer drugs. Combination therapy is also a field that should be explored in the future. Plant compounds can help conventional drug therapy, radiation, targeted therapy, and immunotherapy work better by promoting apoptosis, overcoming drug resistance, suppressing inflammation, and controlling immune responses. Combinations of these, however, need to be carefully assessed for safety, drug-herb interaction, optimization of dosage, and effectiveness. Production, another key area, is sustainable production. Excessive extraction of medicinal plants can be a threat to biodiversity. Hence, the development of plant tissue culture, semi-synthesis, synthetic biology and biotechnological production methods to guarantee continuous and eco-friendly supply of important anticancer compounds. Although they have promise, these plant-based agents must be thoroughly studied before they can be used clinically. Standardization of extracts, quality control, toxicity and pharmacokinetic studies as well as well-designed clinical trials are necessary. The use of traditional knowledge combined with modern pharmaceutical science in the future can potentially bring about the discovery of new plant-based anticancer drugs and enhance the efficacy of cancer treatment.

CONCLUSION

Cancer therapy has gained a tremendous boost in cancer treatment from plant-derived anticancer agents, connecting traditional and modern medicine. Medicinal plants contain a wide variety of bioactive compounds such as alkaloids, terpenoids, taxanes, flavonoids, polyphenols, lignans, quinones, saponins, glycosides, and coumarins, which can target several mechanisms involved in cancer development and progression. These compounds can act as apoptosis inducers, cell cycle arresters, angiogenesis inhibitors, metastasis suppressors, oxidative stress regulators, topoisomerase inhibitors, microtubule disruptors, cancer signaling pathway modulators and immune response enhancers. There are several clinically used anticancer drugs such as vincristine, vinblastine, paclitaxel, docetaxel, irinotecan, topotecan, etoposide and teniposide that clearly illustrate the therapeutic relevance of plant-derived molecules. These drugs have been an indispensable part of modern chemotherapy and are employed for the treatment of different types of hematological and solid tumors. In addition to direct chemotherapy, numerous phytochemicals have been found to have a variety of other therapeutic potential as adjuvants, chemopreventive agents, resistance-modifying agents, and synergistic agents with conventional anticancer drugs. Although plant-based anticancer drugs show great potential, they have been hindered by low bioavailability, poor solubility, toxicity, lack of standardization, variability of phytochemical content, limited clinical studies and potential herb–drug interactions. Thus, before their routine clinical application, it is necessary to validate them scientifically. To overcome these challenges and facilitate clinical translation, modern techniques like nanotechnology, molecular docking, network pharmacology, artificial intelligence, metabolomics, synthetic biology, and advanced formulation strategies can be used. In general, anticancer agents derived from plants still provide an abundant and valuable source for novel anticancer agents. The use of traditional medicine in conjunction with the modern pharmacological, molecular and clinical studies can enable the development of safer, effective, cost-effective and multipurpose approaches for cancer prevention and treatment.

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