Natural Product Derived Compounds in Cancer Therapy: Pharmacological Mechanisms and Clinical Applications

Abstract

Natural products have been a necessary starting point in the discovery of anticancer drugs, providing a array of clinically approved agents and providing structurally diverse molecules with the ability to regulate a variety of hallmarks of cancer. This is a review of natural product-derived compounds with anticancer properties with key examples of alkaloids, flavonoids, terpenoids, polyphenols, saponins, glycosides, and other special phytochemicals. The compounds have strong antiprolliferative action due to their wide range of pharmacological actions, which include the induction of apoptosis by intrinsic and extrinsic apoptotic pathways, the inhibition of cell cycle progression, the inhibition of angiogenesis and the inhibition of metastasis and invasion. Besides, natural agents regulate the crucial oncogenic signaling pathways, including PI3K/Akt/mTOR, MAPK/ERK, Wnt/b-catenin, and NF-kB, and also respond to cancer stem cells, affect epigenetic changes, and oxidative stress reactions. Nevertheless, despite their therapeutic potential, there are a number of concerns around them, such as low bioavailability, lack of uniform standardization, lack of mechanistic understanding, and lack of clinical validation, which hinder their acceptance in the mainstream of oncology. The current limitations are being overcome by advances in nanotechnology, systems pharmacology, AI-based drug discovery, and synthetic biology and can be used to improve the clinical translatability of natural products. It can be concluded that natural product-derived compounds have high potential in developing into safe, effective, and accessible anticancer therapeutics by filling the current gaps and using emerging technologies. Their status, mechanistic understanding, limitations and future opportunities are presented in this review with a great importance to the shaping of next-generation cancer treatment plans.

Keywords

Introduction

Fig.1: Stages of Cancer

Fig.2: Natural anticancer agents

Fig.3: Classification of natural product derived anticancer agents

Fig.4: Phytochemicals in cancer therapy

Alkaloids

Alkaloids are heterocyclic compounds that are formed out of nitrogen and they are characterized by strong biological activity as well as wide clinical applications in the treatment of cancer. The vic part of Catharanthus roseus are used in the production of vincristine, vinblastine, vinorelbine, and vindesine which are all vinca alkaloids. These chemicals interfere with the formation of microtubules by binding to tubulin leading to mitotic arrest and apoptosis. Vinblastine and Vinristine are still important agents of chemotherapy in leukemias, lymphomas, breast cancer and sarcomas [46]. The discovery of Camptotheca acuminata as a source of Camptothein as a topoisomerase I inhibitor ushered in a novel generation of topoisomerase I inhibitors. Its semi-syntic analogs, irinotecan and topotecan, circumvent the issues of solubility and toxicity of the parent molecule and are in common use in colorectal, ovarian and cervical cancers. The benzylisoquinoline alkaloids, which were noscapine, berberine, are another important alkaloid group, which show anti-proliferative activity by inducing apoptosis, inhibiting NF-kB, altering microtubule dynamics, and blocking angiogenesis. Besides, the homoharringtonine produced by Cephalotaxus species is approved as omacetaxine and is a protein synthesis inhibitor with some activity against tyrosine kinase-resistant chronic myeloid leukemia. Alkaloids are highly cytotoxic with distinct molecular actions, upon which contemporary therapeutic approaches to cancer are based, and against which they serve to direct the next generation of drugs [47-50].

Flavonoids

Flavonoids are polyphenolic compounds that are highly abundant in fruits, vegetables, tea, and medicinal plants and they have a multimodal anti-cancer effect associated with their antioxidant, anti-inflammatory, and signaling-modulatory properties. One of the most investigated flavonoids is quercetin, which performs apoptosis through mitochondrial pathways, prevents PI3K/Akt and MAPK signaling, suppresses anti-apoptotic proteins, and sensitizes tumor cells to chemotherapy and radiotherapy [51]. It has anti-metastatic action, which is explained by the inhibition of epithelial-mesenchymal transition and matrix metalloproteinases. Kaempferol has a strong antiprolliferative effect by disrupting cell cycle regulators (cyclin D1 and CDK4), altering p53, angiogenesis, and oxidative stress. It also disrupts the growth of tumors by altering EGFR, NF-kB and Wnt/b-catenin signaling. The flavone luteolin (celery, parsley and chamomile) exhibits effective antiprolliferative effects on tumor cells by inhibiting JAK/STAT and Akt signaling, causing ROS-mediated apoptosis, and inhibiting metastasis by regulating integrin and chemokine signaling [52]. Flavonoids mostly serve as multi-target molecules with the ability to modulate redox homeostasis, DNA repair, inflammation, and tumor-microenvironment relationships. Their low toxicity and dietary high concentration favors their use as chemopreventive agents and adjuvants to increase the effectiveness of conventional anticancer agents [53].

Terpenoids

Terpenoids (based on the units of isoprene) form one of the most extensive families of plant metabolites which has significant potential of anticancer. Taxol (paclitaxel), which is a diterpenoid extracted in Taxus brevifolia has transformed the world of cancer treatment by stabilizing microtubules, inhibiting depolymerization and arresting G2/M cell cycles [54]. It cannot be done without in managing breast, ovarian, lung, and pancreatic cancers. Its semi-synthetic counterpart docetaxel but with better solubility and efficacy is acceptable. Artemisinin and its analogs, which were initially used as antimalarial compounds obtained out of Artemisia annua have also shown important anticancer properties [55]. They mediate their activity with endoperoxide bridge cleavage in the presence of intracellular iron to produce cytotoxic free radicals that cause apoptosis, autophagy, ferroptosis, and DNA damage. They also prevent angiogenesis and metastasis and sensitize tumors to chemotherapy. Other attractive terpenoids are limonene, ursolic acid, betulinic acid and andrographolide and each has distinct anticancer mechanisms of PI3K/Akt modulation, STAT3 inhibitor, VEGF signaling, and apoptotic pathways. Terpenoids have good pharmacological properties and structural diversity, thus they are good leads in the development of new anticancer drugs and nanotechnology systems of drug delivery [56-60].

Polyphenols

Polyphenols are a general group of antioxidants which are present in spices, fruits, and pharmaceutical plants and have been known to have strong anticancer, anti-inflammatory, and chemopreventive properties. Curcumin as the major curcuminoid of Curcuma longa is an anticancer agent that can alter the activity of various cellular pathways such as NF-kB, Akt, STAT3, COX-2 and mTOR [61]. It triggers apoptosis through caspases activation, lowers Bcl-2 protein, and produces mitochondrial impairment. Curcumin also prevents angiogenesis, metastasis and cancerous stem cell growth and increases sensibility to chemotherapy agents and radiations. Resveratrol, the stilbene present in grapes, berries, and peanuts, controls the process of apoptosis by activating p53, regulating SIRT1 and blocking the development of mitochondrial dysfunction. It also disrupts the important oncogenic signaling pathways like Wnt/b-catenin, PI3K/Akt, and NF-kB and inhibits the metastatic events by lowering EMT and activity of matrix metalloproteinases. The two compounds also have some issues with bioavailability, which have led to the establishment of nanoformulations, phospholipid complex, and synthetic analogs to enhance clinical applicability. The capacity of polyphenols to act on a broad variety of molecular pathways simultaneously makes them useful in integrative chemotherapy and prevention of cancer [62-65].

Saponins

Saponins are steroidal or glycosylated triterpenoids that occur in the broadest variety of medicinal and edible herbs. They show high anticancer effects due to their membrane-permeabilizing effects, and capability to cause ROS production and apoptotic pathways modulation. Saponins including ginsenosides, dioscin, and saikosaponins have been shown to have the ability to inhibit proliferation, induce mitochondrial depolarization, activate caspase cascades, and arrest the cell cycle [66]. Most saponins inhibit tumor angiogenesis by suppressing VEGF and inhibiting metastasis by suppressing EMT and matrix remodelling enzymes. Others, are also immunomodulatory, boosting the action of NK cells and raising the production of cytokines, thus, adding to anti-tumor immunity. Moreover, saponins may be used to sensitize cancer cells to chemotherapy, inhibit efflux pumps, diminish drug resistance mechanisms, and enhance intracellular drug accumulation. Their amphiphilic nature enables them to be incorporated in new drug delivery systems to enable targeted cancer therapy with enhanced bioavailability [67-70].

Glycosides

Glycosides are made of a sugar molecule that is conjugated to a bioactive aglycone which contributes to a set of diverse anticancer effects that involve cytotoxicity, cellular metabolism, and signal transduction pathway interference. The cardiac glycosids like digoxin, ouabain, digitoxin, and the like have attracted interests due to their anticancer effect in areas outside the heart. Their actions cause downstream inhibition of NF-kB signaling, induction of apoptosis, and impairment of calcium homeostasis by inhibiting Na+/K^- ATPase [71]. PI3K/Akt signaling inhibitors Anthraquinone glycosides such as emodin and aloe-emodin cause ROS-dependent apoptosis and prevent tumor invasion through EMT inhibition. Iridoid glycosides including catalpol and aucubin have anticancer effects through the regulation of oxidative stress, the suppression of inflammatory cytokines and metastasis. Flavonoid glycoside, such as rutin and hesperidin, have antioxidant and cytoprotective properties, as well as proliferation and angiogenesis inhibitor activities. Glycosylation is also relevant in drug delivery since glycosylation may be used to increase solubility, targeting, and pharmacokinetics, and glycosylation-modified compounds are useful in future anticancer therapies [72].

Others

Other classes of phytochemicals such as xanthones, coumarins and lignans have also shown a lot of anticancer effects. Xanthonesa-mangostin and gambogic acid are highly cytotoxic, and their action is based on the mitochondrial dysfunction, activation of caspase, and inactivation of NF-kB and STAT3. They also block angiogenesis and metastasis through the regulation of VEGF, MMPs, and integrins. Coumarins are anti-proliferative and anti-angiogenic compounds and are found in plants like Angelica, Ferula and Citrus species [73]. Esculetin, scopoletin and osthole are compounds that suppress tumor proliferation by modulating cell cycle proteins, triggering the production of ROS, inhibiting the Akt/mTOR pathway and blocking metastasis. Lignans, including podophyllotoxin, enterolactone and arctigenin, cause anticancer effects through the regulation of hormonal metabolism, induction of apoptosis and inhibition of topoisomerase II. Etoposide and teniposide are anticancer drugs that have been identified as clinically significant and their key pharmacologic ingredient is podophyllotoxin. A number of lignans have estrogen-modulating effect, and are especially applicable in the breast, ovarian, and prostate cancers. These phytochemicals have structurally diverse scaffolds to facilitate exchanges with diverse cellular targets and this potential has seen them have a repertoire of therapeutic uses.

Pharmacological Mechanisms of Natural Anticancer Agents

Natural product derived anticancer agents exercise their therapeutic actions in a wide range of molecular and cellular activities that control tumor formation, progression, metastasis and therapeutic resistance. The natural compounds have a wide-spectrum anticancer activity that is less toxic as compared to conventional chemotherapeutic agents, which usually target only one molecular pathway. They are the most useful drug development and adjuvant therapy candidates due to their ability to regulate the apoptotic process, cellular division, angiogenesis, metastasis, oxidative stress, immune reaction, and epigenetics. Significant classes of natural products such as alkaloids, polyphenols, flavonoids, terpenoids and saponins are able to show extraordinary potential in reprogramming cancer cell behaviors by triggering tumor suppressor pathways, silencing oncogenes, and destabilizing the tumor microenvironment. The next section expounds on the major pharmacological mechanisms by which natural compounds act as anticancer agents [74].

Induction of Apoptosis

The process of natural anticancer agents is through apoptosis or programmed cell death whereby the normal tissues are spared and the malignant cells are destroyed. Cancer cells often avoid apoptosis through modulation of intrinsic and extrinsic pathways, which allows them to proliferate out of control and resist treatment. Natural products re-establish apoptotic sensitivity by acting on major regulators of these pathways which results in caspases activation, mitochondrial impairment, fragmentation of DNA and cell death. The pro-survival response regulating the intrinsic pathway is mitochondrial integrity and is determined by the ratio of pro-apoptotic (Bax, Bak, Bad) and anti-apoptotic (Bcl-2, Bcl-xL, Mcl-1) proteins. Natural compounds, including curcumin, berberine, quercetin, resveratrol, and betulinic acid, catalyze the intrinsic pathway by altering this balance in support of pro-apoptotic signals. They cause mitochondrial outer membrane permeabilization (MOMP), release of cytochrome c and caspase-9 and subsequently executioner caspases (caspase-3 and -7). Polyphenols EGCG and luteolin increase mitochondrial ROS production, disrupting the membrane potential, and initiating Bax translocation. A terpenoid such as artemisinin derivatives amplify iron-dependent oxidative stress leading to mitochondrial swelling and apoptosis. Alkaloids like camptothecin and vincristine cause the damage of DNA, which triggers mitochondrial apoptosis that involves p53. All of these together indicate intrinsic pathway as one of the primary targets of natural anticancer agents [75]. Extrinsic pathway occurs through the action of death receptors on the cell surface which include Fas, TRAIL-R1/DR4, TRAIL-R2/DR5 and TNF receptors. The natural products sensitize the cancer cells to extrinsic apoptosis through the increase of the death receptors, the ligand binding affinity, and the caspase-8 activation. It has been demonstrated that curcumin, resveratrol and saponins can enhance the FasL and TRAIL expression, thereby supporting the death receptor-mediated apoptosis. Moreover, some flavonoids prevent FLIP, which is a negative regulator of caspase-8, thus, promoting the formation of DISC (death-inducing signaling complex). Bryostatin and fucoidan are marine compounds that also activate the extrinsic pathway through regulation of immune-mediated apoptotic signalling. It is this combined action on intrinsic and extrinsic pathways that enable natural molecules to work especially well in the circumventing of apoptosis resistance- a characteristic of cancer progression [76].

Cell cycle arrest

Cancer cells display uncontrolled proliferation due to dysregulation of cell cycle checkpoints. Natural anticancer agents exert anti-proliferative effects by regulating cyclins, cyclin-dependent kinases (CDKs), and checkpoint proteins such as p21, p27, and p53. By disrupting the orderly progression of the cell cycle, natural products effectively suppress tumor growth.

G0/G1 phase inhibition

Numerous natural substances decrease the G0/G1 transition with the down-regulation of cyclin D, cyclin E, CDK2, CDK4 and CDK6 and the up-regulation of p21 and p27. The better-known G0/G1 inhibitors include flavonoids (quercetin, kaempferol, apigenin, etc.), that prevent the initial stage of the cell cycle and decrease multiplication. Curcumin and resveratrol regulate the expression of p53, inhibiting the cyclin D and up-regulating the CDK inhibitor transcription. The alkaloids such as berberine prevent the phosphorylation of retinoblastoma (Rb) thus inhibiting the release of E2F transcription factors that allows S-phase entry. By such measures, the natural products are successful in preventing the proliferation of cancer cells at the initial level of the cell cycle [77].

S-phase modulation

The natural compounds disrupt the DNA synthesis, replication fork advancement, and the metabolism of nucleotides, thus preventing the advancement of S-phase. Topoisomerase I is inhibited with camptothecin derivatives, leading to broken DNA strands and S-phase arrest. The curcumin interferes with the DNA polymerase process and reproduction apparatus, and the saponins cripple the nucleotide production. EGCG and resveratrol prevent DNA methyltransferase activity, which changes chromatin structure and has an indirect impact on DNA replication. Natural products cause S-phase arrest through the interference with DNA integrity and replication control, which is why they play a role in the cytotoxicity of fast-growing cancer cells [78].

G2/M blockade

G2/M arrest inhibits the entry of mitosis in the cell, which is a critical phase to the cancer cell. Paclitaxel is a diterpenoid which stabilizes microtubules and inhibits mitotic spindle formation resulting in G2/M arrest and apoptosis. Other terpenoids like derivatives of artemisinin also suppress the mitotic action of cyclin B1/CDK1. Flavonoid luteolin and genistein disruption of tubulin polymerization, interference with Aurora kinases and Plk1, which are important mitotic progression regulators. Alkaloids such as vincristine and vinblastine cause destabilization of the microtubules inducing metaphase arrest. These mechanisms enable the natural compounds to have great anti-proliferative properties by attacking the cancer cells that divide rapidly selectively [79].

Inhibition of metastasis and invasion

The spread of the cancer cells to other body organs, known as metastasis, is considered to cause more than 90 percent of mortality related to cancers. Natural compounds suppress metastasis by attacking epithelial-mesenchymal transition (EMT), extracellular matrix degradation, cell motility, as well as tumor microenvironment interactions. Curcumin and resveratrol are polyphenols that inhibit EMT with the effect of downregulating Snail, Slug, Twist, and ZEB1, and upregulating E-cadherin. Flavonoids prevent the work of matrix metalloproteinases (MMP-2, MMP-9) which decrease the breakdown of the extracellular matrix and invasion. Terpenoids inhibit the expression of integrins and interrupt the rearrangement of the cyto skeleton that is required in motility. Saponins suppress FAK/Src signaling preventing the migration of cancer cells. Natural compounds inhibit metastasis too through a specific action on chemokine receptors (CXCR4), VEGF- mediated vascular permeability, and hypoxia-mediated pathways including HIF-1a. This multi-targeted control of metastasis makes natural products work as the promising agents of preventive treatment of tumor spread and recurrence [80].

Anti-angiogenic mechanisms

The growth and spread of tumors require angiogenesis, a process where new blood vessels are generated by the body using the existing ones. Natural compounds have the anti-angiogenic effects related to proliferation of endothelium, its migration, and tube formation. Curcumin, resveratrol, and EGCG prevent VEGF expression and inhibit VEGFR2 phosphorylation that prevents downstream PI3K/Akt and MAPK signaling required for endothelial cell survival. Terpenoids ursolic acid and andrographolide prevent angiogenesis by suppressing HIF-1a, MMPs and fibroblast growth factors. The fucoidan molecules derived in the sea prevent angiogenesis through the inhibition of the binding of heparan sulfate proteoglycans that bind VEGF. Saponins block endothelial nitric oxide synthase (eNOS) to decrease vascular permeability and angiogenic reactions. Natural agents interfere with angiogenic signaling which deprives tumors of oxygen and nutrients, retarding the development of disease [81].

Modulation of signaling pathways

Natural compounds exert profound anticancer effects by modulating intracellular signaling pathways crucial for survival, proliferation, metabolism, and metastasis. Their ability to regulate multiple signaling cascades simultaneously distinguishes them from single-target drugs.

PI3K/Akt/mTOR pathway

Activation of this pathway is common in cancer that fosters cancer growth and survival, angiogenesis, and resistance to therapy. Natural products interfere with PI3K activation, decrease Akt phosphorylation, and inhibit mTOR signaling, which are curcumin, resveratrol, quercetin, and berberine. The result is a reduction in protein synthesis, the induction of autophagy, apoptosis, as well as the reduction of metastasis. This pathway is also downregulated by the terpenoids such as betulinic acid and ginsenosides. PI3K/Akt/mTOR inhibition increases cancer cells to chemotherapy and radiotherapy, and supports the use of natural compounds as a combination therapy [82].

MAPK/ERK pathway

MAPK/ERK pathway controls the proliferation, differentiation, and stress responses. The polyphenols and flavonoids regulate MEK and ERK phosphorylation resulting in the arrest of cell cycle and apoptosis. Curcumin regulates JNK and p 38 MAPK stimulation, facilitating apoptotic pathways. ERK-regulated transcription factors like c-Myc and AP-1 are inhibited as well by alkaloids like berberine. Inhibition of MAPK lowers the proliferation of tumor cells and inhibits the malignant transformation [83].

Wnt/β-catenin pathway

Wnt signaling is aberrantly activated to promote proliferation, stemness, EMT and metastasis. Natural substances such as resveratrol, luteolin, and EGCG block b-catenin nuclear translocation, down-regulate wnt ligands and induce b-catenin degradation through activation of GSK-3b. This leads to decreased activity of cancer stem cell, reduced EMT and inhibition of metastatic behavior.

NF-κB pathway

NF-kB controls inflammation, resistance to apoptosis, angiogenesis and metastasis. Its sustained expression is a characteristic of a lot of cancers. Curcumin, resveratrol, quercetin, and other saponins prevent the nuclear translocation of NF-kB by inhibiting the IkB kinase (IKK). This lowers the transcription of the genes that are related to survival (Bcl-2, survivin), inflammation (COX-2, TNF-a, IL-6) and metastasis (MMP-9, VEGF). NF-kB inhibition is useful in overturning drug resistance, tumor progression, and tumor sensitization to chemotherapy [84].

Targeting cancer stem cells

CSCs are a special population that initiates, resists, recurs and metastasize tumors. Natural compounds attack CSCs through disabling self-renewal pathways that include Wnt/b-catenin, Notch, hedgehog, and STAT3. Curcumin decreases CSC markers, such as CD44, ALDH1, and Nanog, whereas resveratrol decreases the expression of Oct-4 and Sox2. Flavonoids prevent sphere formation and CSC proliferation by preventing Notch and Hedgehog pathways. Ginsenosides and artemisinin derivatives are terpenoids that inhibit CSC survival by regulating the production of ROS and EMT. CSCs are the primary focus of achieving long-term cancer remission, and natural compounds are excellent to prevent relapse and treatment resistance [85].

Epigenetic regulation

Epigenetic changes such as DNA methylation, histone modification and chromatin remodeling are crucial in cancer progression. Epigenetic processes are controlled by natural compounds to inhibit DNMTs (DNA methyltransferases), HDACs (histone deacetylases), and HATs (histone acetyltransferases). Polyphenals including EGCG block DNMT1 which causes demethylation and reactivation of tumor suppressor genes. Curcumin and resveratrol regulate histone acetylation due to HDACs inhibition and HATs activity enhancement and reinstate normal gene expression patterns. Genistein changes chromatin structure by reversing methylation aberrations in hormone-dependent cancers. These are epigenetic influences which have the effect of inducing apoptosis, reduced proliferation and metastasis suppression. Notably, natural products are non-toxic epigenetic modulators having capabilities of personalized cancer treatment [86].

Oxidative Stress Modulation and ROS Generation

Reactive oxygen species (ROS) have dual effects on cancer firstly, low levels promote cell proliferation, and secondly, excess ROS forms apoptosis. Dozen of natural products cause regulated oxidative stress in cancer cells, and they take advantage of the weakened antioxidant response in cancer cells [87]. Polyphenols include quercetin, resveratrol and curcumin, which control the production of ROS, which activates apoptosis through mitochondrial pathways. Artemisinin is a terpenoid that reacts with iron to form ROS, leading to the damage of DNA and ferroptosis. The effect of the saponins and alkaloids is amplifying the production of ROS by suppressing the action of antioxidant enzymes like glutathione peroxidase and catalase. Other natural products, on the other hand, are antioxidants, and they inhibit the development of cancer by cancelling the effect of free radicals as well as blocking the oxidative injury of DNA. This two-way ROS-modulating feature indicates the situation-dependent therapeutic excellence of natural compounds [88].

Challenges, Research Gaps, and Limitations

Although natural product-derived compounds hold enormous therapeutic potential in cancer management, they are limited to application in mainstream oncology by a number of scientific, technological, clinical, and regulatory concerns. Despite the promising anticancer effects of many phytochemicals and natural metabolites in cell culture and in animal models, very few of them reach the successful phase of clinical approval. This translational disconnect indicates bioavailability, pharmacokinetics, mechanistic, standardization, toxicity-profiling, and extensive-scale production limitations. The need to overcome these barriers is essential to making natural compounds productive as potent, safe and evidence-based anticancer agents. Poor bioavailability is one of the significant problems because it impacts most of the phytochemicals, such as curcumin, resveratrol, quercetin, EGCG, and most terpenoids. They tend to be insoluble in water, have low absorption, undergo rapid metabolism and have low systemic half-lives and as a result, they do not reach sufficient levels in the tumor sites. Several methods have been suggested to enhance pharmacokinetics such as encapsulation strategies, nanoformulations, liposomes, phospholipid complexes, and structural modification, although most are in preclinical phase and need to undergo the extensive clinical test run. Also, individual differences in metabolism can have an influence on the biological activity of natural substances, which makes it more complicated to optimize the dose and have an individual approach to treatment. The other major weakness is irregular quality, standardization and reproducibility of natural extracts. The plant compounds may be diverse depending on the geographical origin, mode of farming, season of harvesting, mode of extracting and storing. The slightest changes in phytochemical make-up may lead to dramatic changes in biological activity. Lack of internationally agreed standards of quality control may usually lead to variation between batch to batch, and so consistency in therapy becomes hard to maintain. Efforts to extract plant materials in a standardized way or to purify active ingredients are still hampered by the complexity of plant matrices and the possibility of synergistic interactions which can be lost in the purification process. The mechanistic knowledge about a large number of natural compounds is still lacking. Though many studies have shown anticancer efficacies, including apoptosis generation, angiogenesis inhibition, and signaling pathway regulation, comparatively few studies have provided an in-depth explanation of either molecular targets or pharmacodynamic networks. Cancer is extremely heterogeneous, whereby there is a combination of genetic and epigenetic aberrations; hence, the effect of natural compounds can be very different among cancer types and patients. Absence of mechanistic clarity also tends to interfere with rational drug design, optimization of therapeutic combinations and prediction of possible off-target interactions. Another challenge is toxicological profiling. Despite the common belief in natural compounds safety, some of them may lead to toxicity, interactions with drugs of herbs or organ-specific effects with therapeutic doses. As an example, a high level of saponins can interfere with cell membranes and certain alkaloids can have a neurotoxic or mutagenic effect. Moreover, natural products have the ability of altering the metabolism of chemotherapeutic agents by modulation of cytochrome P450 enzymes resulting in decreased effect or inhibited toxicity. Extensive toxicological research - such as long term exposure analysis, pharmacokinetic analysis and safety analysis are necessary but not always available.

Sustainability and supply are additional issues that limit the natural anticancer agent development pipeline. Most plants or marine life and microorganisms generating potent bioactive metabolites are rare, slow growing or ecologically sensitive. The harvesting done on large scale can harm the ecosystems, can disorganize the biodiversity, or can be ethically questionable. Semi-synthesis, total synthesis, plant tissue culture and microbial expression system are potential solutions but they need high levels of technological investment and optimization. The second issue is the complicated interaction between natural molecules and the tumor microenvironment. Although, various phytochemicals regulate the process of inflammation, immune response, stromal and oxidative stress, the dynamic nature of the TME makes it hard to predict responses. The pharmacological effects of natural compounds can be affected by cancer-associated fibroblasts, immune cells, hypoxic areas, and elements of the extracellular matrix. This complexity requires refined models, e.g. 3D organoids, co-culture systems and precision oncology platforms to gain insight into context-dependent responses. Lastly, natural anticancer agents cannot be commercially developed due to regulatory and intellectual property issues. Multicomponent extracts cannot be patented and this decreases the motivation to invest in pharmaceuticals. Moreover, there are different approval pathways across the world, and natural products might be classified as dietary supplement, as herbal medicine or pharmaceutical where each has different safety and efficacy data requirements. Such regulatory complexities delay the process of translation between laboratories and the clinic. Summarizing, even though natural products have enormous potential to promote cancer treatment, the best way to make the products achieve their full potential is to overcome huge obstacles in the form of bioavailability, mechanistic explanation, quality control, toxicology, sustainable sourcing and clinical validation. The only way that these research gaps can be bridged will be through interdisciplinary collaboration, high level of analytical technologies, new delivery systems and solid regulatory frameworks. By this kind of work, natural product-derived compounds can eventually be useful, readily available, and safer substitutes or supplements to traditional cancer therapies.

FUTURE PERSPECTIVES

The future of natural product-based cancer therapeutics is actually very bright as a result of the rapid increase in technology, better mechanistic insights as well as the increasing interest on the usage of multi-targeted therapeutic responses. The natural compounds with their structural diversity and pleiotropic biological activity provide incomparable source of safer and more effective anticancer strategies as cancer is a highly heterogeneous and adaptive disease. Nevertheless, to fully leverage their therapeutic capabilities, new approaches, interdisciplinary teams, and tactical partnership with contemporary drug development platforms will have to be introduced. The combination of novel drug delivery systems, especially nanotechnology-based preparations, is one of the most important future directions. Nanocarriers, including liposomes, polymeric nanoparticles, dendrimers and lipid-based vesicles, have been demonstrated to enhance the solubility, stability, bioavailability and targeted delivery of natural compounds, which have a poor pharmacokinetic profile. Nanoformulated curcumin, resveratrol, paclitaxel and artemisinin analogs exhibit increased therapeutic effect and lowered systemic toxicity in preclinical trials. Precision and therapeutic index can be further increased by the development of smart delivery systems, which in response to tumor-specific stimuli can be pH, enzymes, redox gradients, or temperature. The natural products research will also be transformed by the advancements in computational biology, artificial intelligence, and system pharmacology. Machine learning can be used for predicting drug-target interactions, optimization of molecular structure, and synergistic interactions with conventional treatments. Network pharmacology provides information about multi-target processes, so it is possible to discuss the identification of important signaling hubs that are controlled by phytochemicals. Molecular docking, virtual screening, and pharmacophore modeling with AI are supremely useful in the discovery of new bioactive molecules in large natural product collections. The technologies will be used to solve the historical difficulties in the natural product drug discovery, including the complexity of the structure and inability to elucidate the mechanism. The other significant direction of the future is the targeting of cancer stem cells and the tumor microenvironment. Numerous natural products have been shown to prevent CSC renewal, prevent EMT, and regulate the immune-inhibitory tumor environment. The combination therapies which prevent recurrence and metastasis and resistance can be developed in further exploration. Such compounds as curcumin, resveratrol, ginsenosides, and flavonoids demonstrate high potentials in shifting TME components, such as macrophages, fibroblasts towards an anti-tumor phenotype. There will also be more interest in the epigenetic modification of cancer. The promising results of DNMT or HDAC-inhibitors in natural compounds are a source of future safer epigenetic drugs. The future research must target epigenetic signature profiling to phytochemicals, which can be used to target epigenetic therapy with an individual tumor profile.

CONCLUSION

The natural product-based anticancer agents still remain one of the most useful and effective assets in the field of oncology, as they provide a treasury of structurally diverse compounds that can be used to drive various hallmarks of cancer. Contrary to the traditional chemotherapeutic drugs that often interact with a specific molecular process, natural compounds are pleiotropic in nature, influencing apoptosis, cell cycling, angiogenesis, metastasis, oxidative stress, inflammation, and epigenetics at the same time. It is especially beneficial in the context of treating the complexity, adaptability, and heterogeneity of cancer, which in most cases makes single-pathway blocking agents inadequate or susceptible to resistance. Years of preclinical studies indicate that alkaloids, flavonoids, terpenoids, polyphenols, saponins, glycosides, and other metabolites found in plants have potent anticancer effects with well-defined molecular targets. The basis of several successful chemotherapeutic agents, such as paclitaxel, vincristine, etoposide, and camptothecin derivatives, can be attributed to many of these compounds and are still key constituents of a current treatment regimen. At the same time, dietary phytochemicals such as curcumin, resveratrol, EGCG, and quercetin are still promising to be used as chemopreventive agents and adjuvant therapy due to their good safety and ability to be used in combination with conventional therapy. Although it has this potential, there are a number of limitations that prevent smooth translation of natural compounds into clinical oncology. Issues related to low bioavailability, rapid metabolism, inconsistent standardization of extract, lack of mechanistic understanding, and lack of large-scale clinical trials are still a major obstacle. Besides, sustainability concerns, toxicological loopholes, and regulatory challenges contribute to additional barriers on the wide-scale therapeutic usage. These drawbacks will have to be overcome by unified principle of extraction, increased delivery systems, strict pharmacokinetic and toxicological testing, and more robust clinical data. In the future, nanotechnology, systems pharmacology, synthetic biology, metabolic engineering, and AI-assisted drug discovery, are promising vastly to overcome these difficulties. These technologies will increase the accuracy, solubility, and clinical scalability of natural products and allow natural products to be produced at large scale. Further investigations of cancer stem cells, interactions between tumor microenvironment, and epigenetic control can also be used to find out new therapeutic strategies based on natural product pharmacology. To sum up, natural product-derived compounds will continue to play an indispensable role in the treatment of cancer. They have the potential to become mainstream, evidence-based anticancer therapeutics, complementary agents can become mainstream, improved standardization, and strategic scientific innovation can improve them to meet unmet clinical needs and enhance overall cancer treatments in the world.

REFERENCES

1. Talib WH, Alsalahat I, Daoud S, Abutayeh RF, Mahmod AI. Plant-derived natural products in cancer research: extraction, mechanism of action, and drug formulation. Molecules. 2020 Nov 14;25(22):5319.
2. Dehelean CA, Marcovici I, Soica C, Mioc M, Coricovac D, Iurciuc S, Cretu OM, Pinzaru I. Plant-derived anticancer compounds as new perspectives in drug discovery and alternative therapy. Molecules. 2021 Feb 19;26(4):1109.
3. Chaudhry GE, Md Akim A, Sung YY, Sifzizul TM. Cancer and apoptosis: The apoptotic activity of plant and marine natural products and their potential as targeted cancer therapeutics. Frontiers in pharmacology. 2022 Aug 10;13:842376.
4. Ali Abdalla YO, Subramaniam B, Nyamathulla S, Shamsuddin N, Arshad NM, Mun KS, Awang K, Nagoor NH. Natural products for cancer therapy: a review of their mechanism of actions and toxicity in the past decade. Journal of tropical medicine. 2022;2022(1):5794350.
5. Scaria B, Sood S, Raad C, Khanafer J, Jayachandiran R, Pupulin A, Grewal S, Okoko M, Arora M, Miles L, Pandey S. Natural health products (NHP’s) and natural compounds as therapeutic agents for the treatment of cancer; mechanisms of anti-cancer activity of natural compounds and overall trends. International Journal of Molecular Sciences. 2020 Nov 11;21(22):8480.
6. Khan AW, Farooq M, Haseeb M, Choi S. Role of plant-derived active constituents in cancer treatment and their mechanisms of action. Cells. 2022 Apr 13;11(8):1326.
7. He M, Xia L, Li J. Potential mechanisms of plant-derived natural products in the treatment of cervical cancer. Biomolecules. 2021 Oct 18;11(10):1539.
8. Rajabi S, Maresca M, Yumashev AV, Choopani R, Hajimehdipoor H. The most competent plant-derived natural products for targeting apoptosis in cancer therapy. Biomolecules. 2021 Apr 3;11(4):534.
9. Chunarkar-Patil P, Kaleem M, Mishra R, Ray S, Ahmad A, Verma D, Bhayye S, Dubey R, Singh HN, Kumar S. Anticancer drug discovery based on natural products: from computational approaches to clinical studies. Biomedicines. 2024 Jan 16;12(1):201.
10. Lin SR, Chang CH, Hsu CF, Tsai MJ, Cheng H, Leong MK, Sung PJ, Chen JC, Weng CF. Natural compounds as potential adjuvants to cancer therapy: Preclinical evidence. British journal of pharmacology. 2020 Mar;177(6):1409-23.
11. Wang Y, Chen M, Yu H, Yuan G, Luo L, Xu X, Xu Y, Sui X, Leung EL, Wu Q. The role and mechanisms of action of natural compounds in the prevention and treatment of cancer and cancer metastasis. Frontiers in Bioscience-Landmark. 2022 Jun 15;27(6):192.
12. Huang M, Lu JJ, Ding J. Natural products in cancer therapy: Past, present and future. Natural products and bioprospecting. 2021 Feb;11(1):5-13.
13. Anwar S, Almatroudi A, Alsahli MA, Khan MA, Khan AA, Rahmani AH. Natural products: implication in cancer prevention and treatment through modulating various biological activities. Anti-Cancer Agents in Medicinal Chemistry-Anti-Cancer Agents). 2020 Nov 1;20(17):2025-40.
14. Mohd Zaid NA, Sekar M, Bonam SR, Gan SH, Lum PT, Begum MY, Mat Rani NN, Vaijanathappa J, Wu YS, Subramaniyan V, Fuloria NK. Promising natural products in new drug design, development, and therapy for skin disorders: An overview of scientific evidence and understanding their mechanism of action. Drug design, development and therapy. 2023 Dec 31:23-66.
15. Sun W, Shahrajabian MH. Therapeutic potential of phenolic compounds in medicinal plants—Natural health products for human health. Molecules. 2023 Feb 15;28(4):1845.
16. Najmi A, Javed SA, Al Bratty M, Alhazmi HA. Modern approaches in the discovery and development of plant-based natural products and their analogues as potential therapeutic agents. Molecules. 2022 Jan 6;27(2):349.
17. Sauter ER. Cancer prevention and treatment using combination therapy with natural compounds. Expert review of clinical pharmacology. 2020 Mar 3;13(3):265-85.
18. Naeem A, Hu P, Yang M, Zhang J, Liu Y, Zhu W, Zheng Q. Natural products as anticancer agents: current status and future perspectives. Molecules. 2022 Nov 30;27(23):8367.
19. Dasari S, Njiki S, Mbemi A, Yedjou CG, Tchounwou PB. Pharmacological effects of cisplatin combination with natural products in cancer chemotherapy. International journal of molecular sciences. 2022 Jan 28;23(3):1532.
20. Qin R, You FM, Zhao Q, Xie X, Peng C, Zhan G, Han B. Naturally derived indole alkaloids targeting regulated cell death (RCD) for cancer therapy: from molecular mechanisms to potential therapeutic targets. Journal of hematology & oncology. 2022 Sep 14;15(1):133.
21. Yap KM, Sekar M, Fuloria S, Wu YS, Gan SH, Mat Rani NN, Subramaniyan V, Kokare C, Lum PT, Begum MY, Mani S. Drug delivery of natural products through nanocarriers for effective breast cancer therapy: A comprehensive review of literature. International journal of nanomedicine. 2021 Dec 2:7891-941.
22. Singh S, Pandey VP, Yadav K, Yadav A, Dwivedi UN. Natural products as anti-cancerous therapeutic molecules targeted towards topoisomerases. Current Protein and Peptide Science. 2020 Nov 1;21(11):1103-42.
23. Garcia-Oliveira P, Otero P, Pereira AG, Chamorro F, Carpena M, Echave J, Fraga-Corral M, Simal-Gandara J, Prieto MA. Status and challenges of plant-anticancer compounds in cancer treatment. Pharmaceuticals. 2021 Feb 14;14(2):157.
24. Zhao LY, Mei JX, Yu G, Lei L, Zhang WH, Liu K, Chen XL, Ko?at D, Yang K, Hu JK. Role of the gut microbiota in anticancer therapy: from molecular mechanisms to clinical applications. Signal Transduction and Targeted Therapy. 2023 May 13;8(1):201.
25. Su XL, Wang JW, Che H, Wang CF, Jiang H, Lei X, Zhao W, Kuang HX, Wang QH. Clinical application and mechanism of traditional Chinese medicine in treatment of lung cancer. Chinese Medical Journal. 2020 Dec 20;133(24):2987-97.
26. Talib WH, Alsayed AR, Barakat M, Abu-Taha MI, Mahmod AI. Targeting drug chemo-resistance in cancer using natural products. Biomedicines. 2021 Sep 29;9(10):1353.
27. Rahman MA, Hannan MA, Dash R, Rahman MH, Islam R, Uddin MJ, Sohag AA, Rahman MH, Rhim H. Phytochemicals as a complement to cancer chemotherapy: Pharmacological modulation of the autophagy-apoptosis pathway. Frontiers in Pharmacology. 2021 May 7;12:639628.
28. Ren X, Xie X, Chen B, Liu L, Jiang C, Qian Q. Marine natural products: A potential source of anti-hepatocellular carcinoma drugs. Journal of medicinal chemistry. 2021 Jun 15;64(12):7879-99.
29. Mirza MA, Mahmood S, Hilles AR, Ali A, Khan MZ, Zaidi SA, Iqbal Z, Ge Y. Quercetin as a therapeutic product: evaluation of its pharmacological action and clinical applications—a review. Pharmaceuticals. 2023 Nov 20;16(11):1631.
30. Melfi F, Carradori S, Mencarelli N, Campestre C, Gallorini M, Di Giacomo S, Di Sotto A. Natural products as a source of new anticancer chemotypes. Expert Opinion on Therapeutic Patents. 2023 Nov 2;33(11):721-44.
31. Asma ST, Acaroz U, Imre K, Morar A, Shah SR, Hussain SZ, Arslan-Acaroz D, Demirbas H, Hajrulai-Musliu Z, Istanbullugil FR, Soleimanzadeh A. Natural products/bioactive compounds as a source of anticancer drugs. Cancers. 2022 Dec 15;14(24):6203.
32. Naeem A, Hu P, Yang M, Zhang J, Liu Y, Zhu W, Zheng Q. Natural products as anticancer agents: current status and future perspectives. Molecules. 2022 Nov 30;27(23):8367.
33. Sarker SD, Nahar L, Miron A, Guo M. Anticancer natural products. InAnnual reports in medicinal chemistry 2020 Jan 1 (Vol. 55, pp. 45-75). Academic Press.
34. Shaik BB, Katari NK, Jonnalagadda SB. Role of natural products in developing novel anticancer agents: a perspective. Chemistry & biodiversity. 2022 Nov;19(11):e202200535.
35. Barreca M, Spanò V, Montalbano A, Cueto M, Díaz Marrero AR, Deniz I, Erdo?an A, Luki? Bilela L, Moulin C, Taffin-de-Givenchy E, Spriano F. Marine anticancer agents: An overview with a particular focus on their chemical classes. Marine drugs. 2020 Dec 4;18(12):619.
36. Dehelean CA, Marcovici I, Soica C, Mioc M, Coricovac D, Iurciuc S, Cretu OM, Pinzaru I. Plant-derived anticancer compounds as new perspectives in drug discovery and alternative therapy. Molecules. 2021 Feb 19;26(4):1109.
37. Chunarkar-Patil P, Kaleem M, Mishra R, Ray S, Ahmad A, Verma D, Bhayye S, Dubey R, Singh HN, Kumar S. Anticancer drug discovery based on natural products: from computational approaches to clinical studies. Biomedicines. 2024 Jan 16;12(1):201.
38. Matulja D, Wittine K, Malatesti N, Laclef S, Turks M, Markovic MK, Ambroži? G, Markovi? D. Marine natural products with high anticancer activities. Current Medicinal Chemistry. 2020 Mar 1;27(8):1243-307.
39. Ahmad R, Khan MA, Srivastava AN, Gupta A, Srivastava A, Jafri TR, Siddiqui Z, Chaubey S, Khan T, Srivastava AK. Anticancer potential of dietary natural products: a comprehensive review. Anti-Cancer Agents in Medicinal Chemistry-Anti-Cancer Agents). 2020 Jan 1;20(2):122-236.
40. Aljabali AA, Obeid MA, Bashatwah RM, Qnais E, Gammoh O, Alqudah A, Mishra V, Mishra Y, Khan MA, Parvez S, El?Tanani M. Phytochemicals in cancer therapy: a structured review of mechanisms, challenges, and progress in personalized treatment. Chemistry & Biodiversity. 2025 Aug;22(8):e202402479.
41. Choudhari AS, Mandave PC, Deshpande M, Ranjekar P, Prakash O. Phytochemicals in cancer treatment: From preclinical studies to clinical practice. Frontiers in pharmacology. 2020 Jan 28;10:1614.
42. Zhang Y, Liu X, Ruan J, Zhuang X, Zhang X, Li Z. Phytochemicals of garlic: Promising candidates for cancer therapy. Biomedicine & Pharmacotherapy. 2020 Mar 1;123:109730.
43. Rudzi?ska A, Juchaniuk P, Oberda J, Wi?niewska J, Wojdan W, Szklener K, Ma?dziuk S. Phytochemicals in cancer treatment and cancer prevention—review on epidemiological data and clinical trials. Nutrients. 2023 Apr 14;15(8):1896.
44. Zheng Z, Zhang L, Hou X. Potential roles and molecular mechanisms of phytochemicals against cancer. Food & Function. 2022;13(18):9208-25.
45. Motallebi M, Bhia M, Rajani HF, Bhia I, Tabarraei H, Mohammadkhani N, Pereira-Silva M, Kasaii MS, Nouri-Majd S, Mueller AL, Veiga FJ. Naringenin: A potential flavonoid phytochemical for cancer therapy. Life Sciences. 2022 Sep 15;305:120752.
46. Yadav N, Parveen S, Banerjee M. Potential of nano-phytochemicals in cervical cancer therapy. Clinica chimica acta. 2020 Jun 1;505:60-72.
47. Dong L, He J, Luo L, Wang K. Targeting the interplay of autophagy and ROS for cancer therapy: an updated overview on phytochemicals. Pharmaceuticals. 2023 Jan 8;16(1):92.
48. Rizeq B, Gupta I, Ilesanmi J, AlSafran M, Rahman MM, Ouhtit A. The power of phytochemicals combination in cancer chemoprevention. Journal of Cancer. 2020 May 18;11(15):4521.
49. Paudel S, Mishra N, Agarwal R. Phytochemicals as immunomodulatory molecules in cancer therapeutics. Pharmaceuticals. 2023 Nov 26;16(12):1652.
50. Khan AQ, Uddin S. Anticancer activity of natural compounds. Asian Pacific Journal of Cancer Prevention. 2021 Feb 1;22(S1):1-2.
51. Lee SG. Molecular target and action mechanism of Anti-cancer agents. International journal of molecular sciences. 2023 May 4;24(9):8259.
52. Chaudhry GE, Md Akim A, Sung YY, Sifzizul TM. Cancer and apoptosis: The apoptotic activity of plant and marine natural products and their potential as targeted cancer therapeutics. Frontiers in pharmacology. 2022 Aug 10;13:842376.
53. Liu ZB, Zhang T, Ye X, Liu ZQ, Sun X, Zhang LL, Wu CJ. Natural substances derived from herbs or plants are promising sources of anticancer agents against colorectal cancer via triggering apoptosis. Journal of Pharmacy and Pharmacology. 2022 Feb 1;74(2):162-78.
54. Chimento A, De Luca A, D’Amico M, De Amicis F, Pezzi V. The involvement of natural polyphenols in molecular mechanisms inducing apoptosis in tumor cells: A promising adjuvant in cancer therapy. International Journal of Molecular Sciences. 2023 Jan 14;24(2):1680.
55. Nan Y, Su H, Zhou B, Liu S. The function of natural compounds in important anticancer mechanisms. Frontiers in Oncology. 2023 Jan 4;12:1049888.
56. Yuan L, Cai Y, Zhang L, Liu S, Li P, Li X. Promoting apoptosis, a promising way to treat breast cancer with natural products: A comprehensive review. Frontiers in Pharmacology. 2022 Jan 28;12:801662.
57. Carneiro BA, El-Deiry WS. Targeting apoptosis in cancer therapy. Nature reviews Clinical oncology. 2020 Jul;17(7):395-417.
58. Siddiqui AJ, Jahan S, Singh R, Saxena J, Ashraf SA, Khan A, Choudhary RK, Balakrishnan S, Badraoui R, Bardakci F, Adnan M. Plants in anticancer drug discovery: from molecular mechanism to chemoprevention. BioMed Research International. 2022;2022(1):5425485.
59. Kubczak M, Szustka A, Rogali?ska M. Molecular targets of natural compounds with anti-cancer properties. International Journal of Molecular Sciences. 2021 Dec 20;22(24):13659.
60. Petroni G, Formenti SC, Chen-Kiang S, Galluzzi L. Immunomodulation by anticancer cell cycle inhibitors. Nature Reviews Immunology. 2020 Nov;20(11):669-79.
61. Sharma V, Kumar D, Dev K, Sourirajan A. Anticancer activity of essential oils: Cell cycle perspective. South African Journal of Botany. 2023 Jun 1;157:641-7.
62. Khan H, Alam W, Alsharif KF, Aschner M, Pervez S, Saso L. Alkaloids and colon cancer: molecular mechanisms and therapeutic implications for cell cycle arrest. Molecules. 2022 Jan 28;27(3):920.
63. Chaudhry GE, Md Akim A, Sung YY, Sifzizul TM. Cancer and apoptosis: The apoptotic activity of plant and marine natural products and their potential as targeted cancer therapeutics. Frontiers in pharmacology. 2022 Aug 10;13:842376.
64. Shaik BB, Katari NK, Jonnalagadda SB. Role of natural products in developing novel anticancer agents: a perspective. Chemistry & biodiversity. 2022 Nov;19(11):e202200535.
65. Matthews HK, Bertoli C, de Bruin RA. Cell cycle control in cancer. Nature reviews Molecular cell biology. 2022 Jan;23(1):74-88.
66. Alhmied F, Alammar A, Alsultan B, Alshehri M, Pottoo FH. Molecular mechanisms of thymoquinone as anticancer agent. Combinatorial Chemistry & High Throughput Screening. 2021 Nov 1;24(10):1644-53.
67. Singh S, Varshney M. Exploring the pharmacological potential of chlorogenic acid as an anti-cancer agent and a call for advance research. Combinatorial chemistry & high throughput screening. 2025 Aug;28(12):2047-72.
68. Subbaraj GK, Kumar YS, Kulanthaivel L. Antiangiogenic role of natural flavonoids and their molecular mechanism: An update. The Egyptian Journal of Internal Medicine. 2021 Dec;33(1):29.
69. Vafopoulou P, Kourti M. Anti-angiogenic drugs in cancer therapeutics: A review of the latest preclinical and clinical studies of anti-angiogenic agents with anticancer potential. Journal of Cancer Metastasis and Treatment. 2022 May 6;8:N-A.
70. Filippelli A, Ciccone V, Donnini S, Ziche M, Morbidelli L. Molecular mechanisms of resistance to anti-angiogenic drugs. Critical Reviews™ in Oncogenesis. 2021;26(2).
71. Haibe Y, Kreidieh M, El Hajj H, Khalifeh I, Mukherji D, Temraz S, Shamseddine A. Resistance mechanisms to anti-angiogenic therapies in cancer. Frontiers in oncology. 2020 Feb 27;10:221.
72. Iksen, Pothongsrisit S, Pongrakhananon V. Targeting the PI3K/AKT/mTOR signaling pathway in lung cancer: an update regarding potential drugs and natural products. Molecules. 2021 Jul 5;26(13):4100.
73. Figueiredo da Silva M, Lins AA, Gomes MC, de Jesus Marinho WP, de Araújo RS, de Moura RO, Zhan P, dos Santos Nascimento IJ, da Silva Júnior EF. Anticancer drug discovery from natural compounds targeting PI3K/AKT/mTOR signaling pathway. Current Medicinal Chemistry. 2024 Oct 10.
74. Hasan AM, Al Hasan MS, Mizan M, Miah MS, Uddin MB, Mia E, Yana NT, Hossain MA, Islam MT. Quercetin promises anticancer activity through PI3K-AKT-mTOR pathway: a literature review. Pharmacological Research-Natural Products. 2025 Mar 17:100206.
75. Ali ES, Akter S, Ramproshad S, Mondal B, Riaz TA, Islam MT, Khan IN, Docea AO, Calina D, Sharifi-Rad J, Cho WC. Targeting Ras-ERK cascade by bioactive natural products for potential treatment of cancer: an updated overview. Cancer cell international. 2022 Aug 8;22(1):246.
76. Shi A, Liu L, Li S, Qi B. Natural products targeting the MAPK-signaling pathway in cancer: overview. Journal of Cancer Research and Clinical Oncology. 2024 Jan;150(1):6.
77. Xing L, Zhang C, Yuan J, Zhu K, Tomás H, Sheng R, Yang XH, Tu Q, Guo R. Progress of ERK Pathway-Modulated Natural Products for Anti-Non-Small-Cell Lung Cancer Activity. Pharmaceuticals. 2025 Sep 12;18(9):1371.
78. Cui J, Qian J, Chow LM, Jia J. Natural products targeting cancer stem cells: a revisit. Current Medicinal Chemistry. 2021 Oct 1;28(33):6773-804.
79. Gairola K, Gururani S, Bahuguna A, Garia V, Pujari R, Dubey SK. Natural products targeting cancer stem cells: Implications for cancer chemoprevention and therapeutics. Journal of Food Biochemistry. 2021 Jul;45(7):e13772.
80. Erkisa M, Sariman M, Geyik OG, Geyik C, Stanojkovic T, Ulukaya E. Natural products as a promising therapeutic strategy to target cancer stem cells. Current Medicinal Chemistry. 2022 Feb 1;29(4):741-83.
81. Vallejo MJ, Salazar L, Grijalva M. Oxidative stress modulation and ROS?mediated toxicity in cancer: a review on in vitro models for plant?derived compounds. Oxidative Medicine and Cellular Longevity. 2017;2017(1):4586068.
82. Larbi A, Kempf J, Pawelec G. Oxidative stress modulation and T cell activation. Experimental gerontology. 2007 Sep 1;42(9):852-8.
83. Roquito T, Colaco M, Costa JP, Borges O. Curcumin-encapsulated glucan nanoparticles as an oxidative stress modulator against human hepatic cancer cells. Colloids and Surfaces B: Biointerfaces. 2025 Jan 1;245:114326.
84. Özdemir K, Demir Y. Phenolic compounds in exercise physiology: dual role in oxidative stress and recovery adaptation. Food Science & Nutrition. 2025 Aug;13(8):e70714.
85. Rao MJ, Duan M, Zhou C, Jiao J, Cheng P, Yang L, Wei W, Shen Q, Ji P, Yang Y, Conteh O. Antioxidant defense system in plants: Reactive oxygen species production, signaling, and scavenging during abiotic stress-induced oxidative damage. Horticulturae. 2025 Apr 29;11(5):477.
86. Sebghatollahi Z, Yogesh R, Mahato N, Kumar V, Mohanta YK, Baek KH, Mishra AK. Signaling Pathways in Oxidative Stress-Induced Neurodegenerative Diseases: A Review of Phytochemical Therapeutic Interventions. Antioxidants. 2025 Apr 12;14(4):457.
87. Wang C, Li G, Chen S, Li R, Wang M, Wang X, Ding N, Sun Y. Mitigation of PFOA/PFOS toxicity in zebrafish (Danio rerio) by oxidative stress modulation and gut microbial metabolism through the use of aquatic probiotic Lactobacillus rhamnosus. Water Cycle. 2025 Jan 1;6:71-81.
88. Reed S, Taka E, Darling-Reed S, Soliman KF. Neuroprotective effects of metformin through the modulation of neuroinflammation and oxidative stress. Cells. 2025 Jul 11;14(14):1064.