Signal Transduction Targeting of Cancer Stem Cells Using Natural Compounds: Mechanisms, Challenges, and Nano-Enabled Solutions

Signal Transduction Targeting of Cancer Stem Cells Using Natural Compounds: Mechanisms, Challenges, and Nano-Enabled Solutions

Anusha S

Department of Biotechnology St Joseph’s College of Engineering, Chennai, Tamil Nadu 600119, India

Rashmitha V

Department of Biotechnology St Joseph’s College of Engineering, Chennai, Tamil Nadu 600119, India

Sridevi R

Department of Biotechnology St Joseph’s College of Engineering, Chennai, Tamil Nadu 600119, India

Abstract – Cancer stem cells (CSCs) have an essential function in cancer spread, tumor reappearance, and treatment resistance, which creates major difficulties for traditional cancer treatment methods. Natural products that exhibit anti-CSC activity include flavonoids and alkaloids and polyphenols which include curcumin and resveratrol as they disrupt Wnt and Notch and Hedgehog vital signaling pathways. The compounds stop CSCs from growing while they kill CSCs and stop epithelial- mesenchymal transition and drug resistance development. The clinical usage of these natural compounds encounters obstacles because of their poor solubility and low bioavailability and unstable nature. The natural product-based drug delivery systems developed through nanotechnology enhance both product stability and their ability to deliver drugs to specific targets while increasing their treatment power, which results in better CSC removal. Scientists can develop safer yet more powerful treatments to stop tumor recurrence and drug resistance through the combination of natural compound nanoformulation and current medical treatments. The upcoming preclinical and clinical trials need to establish optimal nanocarrier formulations while researchers continue to study CSC biology to develop new cancer treatments.

Keywords – Cancer Stem Cells, Natural Products, Nanotechnology, Drug Resistance, Curcumin, Flavonoids

1. INTRODUCTION

   Cancer stands as the primary global cause of death across all nations. Cancer functions as a major worldwide social and economic challenge at present. The cancer disease presents an exceptionally dangerous combination of high disease rates and high death rates according to reference [1]. The treatment of cancer becomes difficult because of its high level of complicated characteristics which need complex treatment methods.

   Modern cancer treatment methods provide physicians with one specialized method to treat specific genetic changes within tumors. The approach works successfully for instances but fails for most others. The method fails to achieve cancer eradication because of its operational limitations. Cancer cells possess the ability to switch their operational methods after we establish an interruption in one pathway by creating a genetic change. One drug treatment shows effectiveness against one target but fails to deliver lasting benefits because of cancer’s tendency to return. The combination of multiple medications enabled the doctors to attack multiple cancer cells at the same moment. The body requires immunotherapy to strengthen its defense system because this treatment helps fight against cancer cells. Current medical treatments show numerous limitations which restrict their effectiveness. Multiple medications produce stronger cancer cell destruction effects which also result in different unwanted medical effects. The immune system may become excessively active, leading to damage to healthy tissues. Doctors need to identify body damage before they start treating side effects because this step helps determine treatment success [2]. Most cancer treatments fail because of four main problems: cancer spreading to other body parts, cancer returning after treatment, cancer cells showing different characteristics, and patients developing resistance to both chemotherapy and radiation treatments.

   Cancer stem cells which exist as a small subset of tumors create treatment difficulties because their unique abilities grant them protection from standard medical procedures. The factors mentioned here cause both recurrence and metastasis along with creating resistance against pharmaceuticals and radiation treatment. The process increases heterogeneity while enabling the system to fend off immune assaults [3]. The development of cancer stem cells occurs through the transformation of normal tissue stem cells or the specialized

   cells which constitute them. Both types of cells develop mutations through exposure to toxins and infectious agents and radiation and metabolic stress which leads to their infinite cell division. The process of cell transformation results in oncogene activation and loss of tumor suppressor genes which makes the cells act like stem cells. Stem cells possess the primary ability of self-renewal. Stem cells require fewer genetic changes than differentiated cells to achieve CSC status. The degree of tumor aggressiveness depends on cancer type because different cancers arise from distinct cell origins [4]. Tumors develop hypoxic environments which protect against drug treatment while CSCs exhibit genetic variability that enables them to resist treatment [5]. The development of cancer treatment resistance and tumor spread depends on the actions of CSCs. The plasticity mechanism enables CSCs to establish treatment resistance by utilizing tumor microenvironment elements as their protective barriers. The two main factors which lead to cancer recurrence establish the relationship between these two elements. The development of effective cancer therapies requires scientists to focus on CSCs because these cells play vital roles in tumor spread and recurrence [6]. Researchers need to establish innovative methods which can specifically target CSCs for their direct elimination. Natural products (NPs) can be used in this scenario.

   The drug discovery process benefits from natural products which produce medicines that target various cellular mechanisms throughout the body. The main advantage of NPs is that they have fewer side effects than conventional therapies. Researchers have identified CSCs as potential targets for drug development because they show promise in overcoming existing treatment barriers [7]. Researchers conducted tests using numerous compounds which revealed their capacity to explore subsequent outcomes. The study tested multiple compounds which included quercetin and glucosamine and carvedilol and aloe-derived substances to determine their impact on breast cancer MCF7 cells which showed effective suppression of CSC growth. Most of these compounds possess a common characteristic which allows them to inhibit mitochondrial respiration, thus establishing a pathway to eliminate CSCs [8].

   Your training data extends until the month of October in the year 2023. Natural compounds including turmeric and green tea and grapes and broccoli and black pepper block the growth signals of CSCs. The process results in two outcomes because it decreases drug resistance while boosting immune response capabilities. Natural products derive their main characteristic from their ability to impact several biological pathways at the same time which enables them to effectively combat the complex characteristics of CSCs. Numerous disadvantages exist in this situation. The body shows

   restricted bioavailability together with stability problems which stop the body from receiving natural products [9]. The major limitation exists because research shows that natural products function actively in cancer cells yet there exists a lack of studies that examine their effects on CSCs which creates a research gap [10]. NPs lack patient-specific characteristics, and they do not possess clinical evidence which has been proven to show their effectiveness in medical applications. The true therapeutic power of NPs remains unknown until doctors determine which patients will gain benefits from NP treatment and until clinical trials measure CSC-related results like recurrence and metastasis [11]. To enhance their overall efficiency, the system requires solutions for three challenges that include poor absorption and low availability in the body and the absence of specific targeting systems [12]. The NPs bioavailability plays a crucial role in determining how much drug reaches the bloodstream and the target area after the drug is administered. The basic approach uses nano formulations of natural products to solve all existing limitations in this situation [13].

   NPs face limitations which nanotechnology overcomes because they improve their operational performance. The process of loading natural products into nanodrug delivery systems results in smaller particle sizes which enhance both solubility and stability while making it easier for cells and tissues to absorb the product. The process using nanocarriers enables natural compounds to reach their target site directly which increases their effectiveness while decreasing their potential side effects [14].

   The natural products curcumin and resveratrol and flavonoids and alkaloids exhibit strong potential to fight cancer stem cells through their effects on Wnt and Notch and EMT signaling pathways. The pathways result in drug resistance and tumor recurrence for patients. The methods present limited application because their absorption issues create bioavailability problems and they cannot achieve targeted delivery to locations. The combination of natural products with nanocarriers through nanotechnology provides a safer and more effective method for developing CSC-targeted cancer therapies.

   play crucial roles in CSC self-renewal, making them attractive targets for the development of CSC-directed therapies [17].

   • Notch Signalling

   Figure 1: Overview of how CSC-targeted treatment overcomes the limitations of conventional therapy [15]

2. CANCER STEM CELLS IN TUMOR BIOLOGY AND CLINICAL CHALLENGES:

   The cells that make up a tumor begin their existence from cancer stem cells which function as the primary genetic source for the complete tumor cell population. They possess the same fundamental capability which allows them to create all the different cell types needed for tumor formation just like regular stem cells. Tumor cells emerge from CSCs which produce tumor cells at a constant rate despite their slow division rate. The standard cancer treatments which include chemotherapy and radiotherapy primarily focus on attacking fast-growing cells, but this approach falls short of complete success against CSCs. Cells that endure treatment will eventually produce fresh tumors which results in cancer returning for patients. The reason why cancer keeps coming back after treatment is because CSCs endure between therapies which let the disease remain hidden from detection until visible tumor cells disappear [16].

   1. Signaling Pathway Regulators

      Signaling pathways are essential communication networks within cells that regulate the growth, survival, and maintenance of cancer stem cells (CSCs). Several studies have shown that inhibiting certain pathways or activating others can slow CSC proliferation and ultimately lead to their elimination. These effects can be achieved using small- molecule drugs, which are relatively easy to design, have good mobility within the body, and offer favorable safety and effectiveness profiles. Due to their affordability and efficiency, small-molecule drugs are among the most practical cancer treatment options in developing countries. Key pathways such as Wnt, Hedgehog (Hh), Notch, and Hippo

      The Notch signaling pathway plays a central role in regulating cell growth, differentiation, and division during both embryonic development and adult tissue maintenance. Activation of this pathway begins when a ligand from a neighboring cell binds to the Notch receptor, triggering receptor cleavage and the release of the intracellular domain. This domain then translocates into the nucleus, where it activates target gene expression through the canonical Notch pathway. In addition, Notch can signal through non-canonical mechanisms by interacting with other pathways, including NF-B, PI3K/AKT, and Wnt. Notch signaling has a dual role in cancer, functioning either as an oncogene or a tumor suppressor depending on the cellular context. For example, aberrant Notch activation drives the progression of T-cell acute lymphoblastic leukemia (T-ALL) and colorectal cancer, whereas loss of Notch activity has been linked to the development of squamous cell carcinoma and liver cancer [18].

      Notch signaling is particularly important for maintaining stem-like cell populations in lung, colorectal, and breast cancers. In lung cancer, ALDH cells display strong CSC characteristics and show elevated activity of NOTCH1, NOTCH2, and NOTCH3. Inhibition of Notch signaling, either through the -secretase inhibitor DAPT or by NOTCH3 knockdown, significantly reduces ALDH CSC populations, cell cycle progression, and colony-forming ability [19]. In colorectal cancer, Notch signaling is normally required for maintaining stem cells in intestinal crypts; however, its abnormal activation promotes metastasis, treatment resistance, and the survival of CD133 CSCs. Targeting the Notch pathway in this context effectively decreases CSC numbers and suppresses tumor growth [20].

      In breast cancer, particularly in triple-negative breast cancer, breast cancer stem cells (BCSCs) commonly exhibit a CD24/CD44 phenotype, with high NOTCH4 activity associated with increased invasiveness and resistance to chemotherapy. Overall, Notch signaling plays a critical role in CSC maintenance across these cancers: NOTCH13 primarily support lung CSC survival, Notch hyperactivation contributes to metastasis in colorectal cancer, and

      NOTCH4 sustains aggressive stem-like populations in breast cancer [21].

      • Hedgehog (Hh) Signalling

        Hedgehog (Hh) signaling controls embryonic development and tissue healing and stem cell preservation. The Ptch receptor prevents smoothened (SMO) activity during its normal operational mode. The process allows SMO to operate by removing its restriction which causes GLI protein to be released. The proteins enter the nucleus to start the activation of genes that control growth. The process malfunctions which result in multiple types of cancer that assist cancer stem cells to survive while tumors continue to grow. This condition occurs frequently in leukemia cases including AML and CML combined with basal cell carcinoma and various solid tumors. The study found that blocking Hedgehog signaling resulted in a significant decrease of cancer stem cell activity which also hindered tumor development [16]. Hedgehog signaling establishes its specific function to control cancer stem cells within every different cancer type. The HHGLI activation pathway serves as the fundamental mechanism that enables colon cancer CSCs to survive. GLI activity increase results in CD133 stem cell population growth because this population drives the primary force behind tumor development [22]. Breast cancer resistance to treatment arises from CD44/CD24/ALDH1 CSC populations, which hedgehog signaling enables to regenerate after chemotherapy treatment. The upregulation of HH ligands and GLI factors by Np63 creates an enhancement of sphere formation [23]. NSCLC cancer stem cells (CSCs) use SHH activation through HHAT to create an autocrine loop for CD133 CSC self-maintenance, while CAFtumor cell contact causes HH activity increase which leads to greater metastatic potential. The research results demonstrate that colon, breast, and lung cancers employ distinct mechanisms, which results in cancer-secific Targeted therapies becoming essential despite the fact that hedgehog signaling functions as a universal CSC sustaining mechanism [24].

      • Wnt Signalling

        The Wnt pathway operates as an essential mechanism for stem cell renewal and cell growth while maintaining tissue homeostasis. The canonical pathway Wnt proteins achieve their operation by establishing connections with Frizzled and LRP5/6 receptors. The process leads to the protection of – catenin because its degradation gets prevented from occurring. The process leads to the protection of -catenin because its degradation gets prevented from occurring. The – catenin protein establishes a stable state which results in its nuclear transfer to activate essential growth and division genes. APC or -catenin mutations result in permanent pathway activation which causes cells to grow uncontrollably. The disease first appeared in colorectal cancer cases, but it now functions as a principal factor in prostate and lung

        cancers and melanoma and blood diseases including AML CML ALL and multiple myeloma [16].

        The Wnt/-catenin pathway controls the stemness and self- renewal capacities of cancer stem cells in multiple types of cancer. The process leads to -catenin hyperactivation which causes EpCAM liver cancer stem cells to grow and form tumors through their nuclear -cateninTCF/LEF system which controls c-myc and cyclin gene transcription. The process leads to tumorigenesis in liver cancer [25]. In breast cancer, CSC-rich mammospheres elevate Wnt signaling and correlate with estrogen receptor status, where Wnt ligands such as Wnt3a promote mammosphere formation [26]. The DKK1 protein prevents CSC growth while functioning as an active growth suppression factor. The abnormal activation of Wnt/-catenin signaling pathway exists in colorectal cancer. The primary cause of the condition exists because of APC or CTNNB1 mutations [27]. The canonical Wnt pathway sustains cancer stem cell existence across all three cancers while simultaneously driving tumor growth. The approach targets Wnt pathway elements which lead to a major reduction in both cancer stem cell growth and their ability to survive, that proves its value as a treatment method. The pathway maintains stemness across all tissues, yet it specifically boosts tumor aggressiveness through its complete route. The development of CSC-targeted treatments for different cancers depends on our understanding of these pathways.

   2. Hallmarks of Cancer

      Cancer progression and treatment failure can be better understood through several defining hallmarks of cancer. These hallmarks play a central role in tumor initiation, progression, recurrence, and resistance to therapy, highlighting the complex nature of cancer biology.

      • Role of CSCs in Drug Resistance

        Drug resistance represents a major challenge in cancer treatment, particularly in therapies targeting cancer stem cells (CSCs). CSCs enable tumors to withstand chemotherapy and radiotherapy, often leading to metastasis and disease recurrence. Drug resistance may be either primary or acquired and arises through multiple mechanisms. One of the most significant mechanisms involves the overexpression of ATP- binding cassette (ABC) transporters, which actively pump therapeutic drugs out of CSCs, thereby reducing intracellular drug accumulation and diminishing treatment efficacy. In addition, CSCs possess highly efficient DNA repair systems that allow them to repair therapy induced DNA damage and survive treatment. CSCs can also evade therapy by entering a dormant or quiescent state, making them less susceptible to

        drugs that target rapidly dividing cells. Autophagy further supports CSC survival under therapy-induced stress and reduces the effectiveness of immunotherapies. Moreover, CSCs upregulate anti-apoptotic proteins and activate pro- survival signaling pathways, such as PI3K/AKT, collectively contributing to resistance against conventional therapies [28].

      • Role of CSCs in Tumor Heterogeneity

        Tumor heterogeneity refers to the diversity observed among cancer cells and can occur between different tumors (intertumoral heterogeneity) or within a single tumor (intratumoral heterogeneity). Intertumoral differences allow cancers to be classified into distinct subtypes, whereas intratumoral heterogeneity arises from ongoing genetic and epigenetic alterations that generate subpopulations with varying growth rates, metastatic potential, and drug resistance profiles. This cellular diversity complicates cancer diagnosis and treatment, as a single biopsy may not accurately represent the entire tumor, increasing the risk of relapse and treatment failure. Growing evidence indicates that effective cancer therapy requires combination strategies that target both CSCs and the bulk tumor cell population, especially since treatments such as radiation can unintentionally enhance CSC activity [29].

      • Role of CSCs in Immune Evasion

        The ability of CSCs to evade immune surveillance significantly limits the success of cancer immunotherapy. CSCs impair antigen presentation, leading to reduced tumor antigen expression and altered recognition by immune cells such as natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). In addition, CSCs promote the release of immunosuppressive cytokines, including IL-6 and TGF-, and upregulate immune checkpoint proteins. Together, these mechanisms create an immunosuppressive tumor microenvironment that protects CSCs from immune mediated elimination. Because these processes act in concert, targeting CSC-driven immune evasion may be more effective than focusing on individual pathways. Other contributing factors, such as hypoxia, altered tumor metabolism, and epithelial mesenchymal transition (EMT), further enhance immune resistance and should be considered in the development of future therapeutic strategies [30].

      • Role of CSCs in Tumor Recurrence

        The survival ability of CSCs enables them to withstand both chemotherapy and radiotherapy which leads to tumor recurrence. The treatment process destroys most of the tumor cells but leaves behind a collection of cells which possess tumorigenic properties and can initiate tumor growth.

        Epithelial-mesenchymal transition (EMT) constitutes the primary mechanism which drives this process. The process of circulating tumor cells results in higher chances of both invasion and metastasis. Breast and liver cancer studies show that cancers have a high occurrence rate of mesenchymal CTCs between 62 to 85 percent. Recurrences begin after treatments create CSC populations because therapies destroy all cancer cells except for CSCs. Breast cancer biopsies demonstrate this finding through their evidence of increased CSC-like gene signatures which occur after chemotherapy or endocrine therapy. The surgical studies which investigated stemness-inhibiting molecules demonstrated that therapies which target stemness-related pathways successfully reduced relapse rates. The findings present CSCs as essential therapeutic targets which can help prevent cancer recurrence [31].

        Figure 2: Schematic representation of the role of cancer stem cells in tumour biology and related clinical challenges.

3. Natural Products as Anti-CSC Agents

   The pharmaceutical industry depends on Natural Products (NPs) as its primary source for developing new drugs. Researchers developed paclitaxel and vinca alkaloids and anthracyclines into successful anti-cancer treatments after discovering their plant and microbial origins. The introduction of synthetic targeted therapies during the 1990s caused a dramatic decrease in interest in natural product-based medicines. The natural product anti-cancer drug market has recovered its previous value because the therapies show two key deficiencies which include resistance and low efficacy [32]. Natural ompounds together with their derivatives serve as the base for numerous authorized medical treatments which the medical field utilizes [33]. The compounds achieve their high effectiveness because they contain multiple phytochemicals which include flavonoids and alkaloids and saponins and tannins and phenolics. The CSCs receive their

   treatment through a combination of pathways that target the cancer’s altered signaling and metabolic systems [34, 35].

   1. Flavonoids

      Flavonoids stand as crucial compounds which nature provides in fruits, vegetables, nuts, tea, and some medicinal plants. Their classification system includes four primary categories which are flavanols, flavones, isoflavones, and catechins. Most of these categories demonstrate capacity to fight cancer [36-39]. Flavonoids demonstrate capacity to inhibit cancer stem cell (CSC) growth according to scientific studies which have been conducted [40-41]. Quercetin exists as a plant- based substance that contains high amounts of flavonoids while it demonstrates powerful anticancer effects through its ability to kill cancer cells and decrease cancer stem cell markers (CD24 and CD133) and regulate -catenin pathway activities. Luteolin exists as one dietary flavone which studies demonstrate to block CSC persistence and capacity to self- generate and ability to develop into different forms and capacity to spread through breast and oral and liver cancer types. Medication inhibits both the IL-6/STAT3 and JNK pathways while it enhances radiotherapy success rates. Apigenin exists as a flavonoid which people find in various herbal sources and vegetable plants. They cause CSCs to die and stop their movement through their apoptosis activation and their PI3K/Akt/NF-B pathway activation. Wogonin, genistein, myricetin, epigallocatechin gallate (EGCG), and fisetin represent additional flavonoids which demonstrate capacity to stop CSCs from growing while they prevent EMT and stem cell marker expression. Flavonoids exist as a broad collection of natural compounds which interact with CSC related pathways in cancer cells while they decrease cancer treatment resistance. They show potential as effective cancer treatment agents [7].

   2. Alkaloids

      Alkaloids are a diverse group of naturally occurring organic compounds characterized by the presence of nitrogen atoms within aromatic or heterocyclic ring structures. They are distributed as higher plants in the plant kingdom and are well known for their strong biological activity and therapeutic potential [47]. Alkaloids have contributed significantly to medicine, ranging from quinine in malaria to vinblastine in cancer treatment. Several alkaloids have been clinically established as anti-cancer agents. This highlights their potential therapeutic value. Interestingly, these alkaloids can also distinguish between normal and cancerous DNA, selectively blocking cancer DNA synthesis while sparing only healthy cells, suggesting their potential for treatments with reduced side effects [48]. Ongoing investigations have shown that alkaloids are antineoplastic, anti-metastatic, and MDR-

      inhibiting [49]. These results suggest that alkaloids have the potential to eliminate CSCs. Three main alkaloids help combat CSCs. Dihydrocapsaicin (DHC) induces autophagic or caspase-3-mediated apoptosis in colon and breast cancers. This provides a dual pathway to overcome CSC resistance [50]. Piperine helps lower ALDH expression and Wnt signaling in breast CSCs. This acts only on CSCs and spares differentiated cells. This demonstrates selective CSC inhibition [51]. Liposome-encapsulated berberine induces caspase-dependent apoptosis in CD44+/CD24 breast CSCs and enhances chemotherapy response by inhibiting ABC transporters [52-53].

   3. Polyphenols

      Polyphenols are aromatic rings attached to hydroxyl groups. Many natural pharmaceutical products are derived from polyphenols. Polyphenols can be divided into flavonoids, stilbenes, tannins, lignans, and phenolic acids. In vitro, they significantly impact several important cancer-related processes, such as inflammation, angiogenesis, cell proliferation, invasion, and apoptosis [54]. Resveratrol and curcumin are important polyphenols with cytotoxic effects, making them ideal for CSC targeting.

   4. Resveratrol

      Resveratrol is a natural polyphenolic compound of the stilbenoid class. The structure of resveratrol contains two phenolic rings connected through an ethylene bridge [55]. Resveratrol exhibits strong activity against CSCs. It induces caspase-3/7mediated apoptosis in CD44/CD24/ESA pancreatic CSCs and suppresses stemness regulators, such as

      Nanog and Oct-4. It also reduces EMT drivers, such as Snail and Slug, while inhibiting the

      ABCG2 efflux pump. This process sensitizes CSCs to chemotherapy [53]. In breast CSCs (CD24/CD44/ESA), FAS-dependent apoptotic pathways are activated by resveratrol, which decreases tumor formation in nude mice. This confirms the potential of resveratrol to impair

      CSC-driven tumor growth [56]

   5. Curcumin

   The orange-red substance known as curcumin exists as a natural compound which comes from turmeric and serves as the main bioactive element in dried turmeric root. The compound exists as CHO and displays both water insolubility and sensitivity to light while lacking any flavor [57]. The compound demonstrates its capacity to destroy

   cancer stem cells which exist in breast cancer through its complete ability to prevent breast CSCs from producing mammospheres through total blockade of all epithelial- mesenchymal transition (EMT) processes at micromolar levels [52]. The curcumin structural analog GO-Y030 reduces tumor burden in colon CSC xenograft models by approximately 50% because it induces apoptosis while blocking STAT3 signaling [58]. The combination of curcumin and FOLFOX chemotherapy produces more powerful effects on colon CSC survival and epithelial mesenchymal transition (EMT) than chemotherapy alone [59].

4. LIMITATIONS OF NATURAL PRODUCT

   Wnt/-catenin, Notch, Hedgehog, Hippo, STAT3, and NF-B are the key pathways that regulate both CSCs and normal

   stem cells [60, 61]. Natural compounds mainly target CSCs without affecting normal cells at therapeutic doses; however, at high concentrations, they may cause hepatotoxicity or mild gastrointestinal issues [62, 63]. This makes dose-finding clinical trials essential. However, there are some limitations, such as poor solubility, low bioavailability, instability, rapid metabolism, and difficulties in isolating active components [64-67]. These limitations are overcome by innovative strategies such as nanoparticle formulations, which improve delivery and selectivity [68, 69], and synthetic analogs, which aim to overcome stability and solubility issues [70-72]

   Natural Compound	Class	Target Cancer Type	Pathway Affected	Effect on CSCs
   Curcumin	Polyphenol	Breast, colon	STAT3, EMT	Mammosphere , apoptosis
   Resveratrol	Stilbene	Breast, pancreas	EMT, ABC transporters	Stemness
   Quercetin	Flavonoid	Pancreas, cervical	Wnt/-catenin	CD24/44
   Piperine	Alkaloid	Breast	Wnt, ALDH	CSC-specific inhibition
   Berberine	Alkaloid	Breast	ABC transporters	Chemoresistance

   Table I: Overview of Natural Products and Their Anti-CSC Mechanism

5. CELLULAR MECHANISMS BY WHICH NATURAL PRODUCTS TARGET CSCS</p

   The Classical Cancer stem cell hypothesis states that tumors arise from a group of cells with stem cell properties. These cells possess the capacity for endless self-renewal and develop into a variety of cell types that eventually form tumors. This creates a hierarchical organization and heterogeneity observed in cancer [73]. Tumor initiation, progression, metastasis, and resistance to therapy are heavily dependent on the complex signaling of CSCs. Molecular pathways such as Wnt/- catenin, Notch, Hippo, Hedgehog, PI3K/Akt/mTOR, JAK/STAT, and NF-B help sustain these properties [74-83]. Natural products target these cellular mechanisms to eliminate CSCs.

   1. Induction of CSC Apoptosis and Autophagy

      Programmed cell death, also known as apoptosis, is a key mechanism used as a defense against cancer. This pathway is often disrupted during tumor progression [84, 85]. One promising approach to cancer treatment is the induction of apoptosis in CSCs [86]. Both extrinsic and intrinsic apoptotic pathways exist in the body. Numerous organic substances activate caspases and reactive oxygen species to induce apoptosis. This includes oxyresveratrol from Morus alba, angelicin, gambogic acid, and extracts from Melandrium firmum, Dioscorea nipponica, and Saussurea lappa. These studies underscore apoptosis signaling as an important vulnerability of CSCs and a viable therapeutic target [87]. Studies suggest that a combination of autophagy modulators

      and standard chemotherapy can improve cancer treatment. However, different cell types and conditions lead to different roles of autophagy. However, further research is required to confirm this hypothesis. Conventional therapies combined with drugs, such as chloroquine and hydroxychloroquine, have produced promising results in clinical trials [88]. The main reason for tumor relapse is drug resistance, which is due to the presence of CSCs. Chloroquine is an autophagy inhibitor. This reduces pancreatic CSCs by blocking CXCR4 and modulating hedgehog signaling [89]. Salinomycin, a natural antibiotic, and metformin, a metabolic regulator, have been reported to eliminate CSCs, either alone or in combination with chemotherapy [90-92]. These results highlight that targeting CSC autophagy with natural products enhances therapeutic responses and helps overcome drug resistance.

   2. Epigenetic Regulation

      Epigenetics is the study of how genes are turned on and off without changing the DNA code. DNA methylation, histone protein modification, and energy-driven chromatin remodeling to open or close DNA regions are just a few of the ways in which gene expression can be regulated. The regulation of epigenetic changes plays a major role in cancer development and CSC maintenance [93].

      Natural compounds aid in the epigenetic regulation of cancer stem cells. For example, polyphenols are the largest group of plant metabolites, which include compounds such as EGCG (green tea), resveratrol (grape skin), and curcumin (turmeric). They possess strong antioxidants, anti-inflammatory, and anti-cancer properties. Tumor suppressor genes are silenced by abnormal epigenetic modifications induced by natural polyphenols. Polyphenols influence tumor DNA methylation, histone modifications, and microRNA. These are the key regulators of CSC self-renewal and proliferation. EGCG induced apoptosis and reduced CSC colony formation. Curcumin focuses on epigenetic reprogramming, as demonstrated in clinical studies. Other compounds, such as genistein (soy isoflavone), sulforaphane, lycopene, and resveratrol, can also remodel the tumor microenvironment. Dietary phytochemicals influence all stages of cancer progression by modifying the epigenome. This remodels the epigenetic machinery, making them promising candidates for CSC-targeted prevention and therapy [94].

      Another example is flavonoids, which alter cancer development by acting on epigenetic mechanisms. Enzymes such as DNMT and HDAC, which silence tumor suppressor genes, are blocked by EGCG. This helps turn protective genes back on. EGCG, in combination with other epigenetic drugs or natural products, has a stronger effect on controlling

      enzymes. Studies have shown that they help restore ER expression in triple-negative and ER-negative breast cancers by inhibiting HDAC. Another flavonoid, genistein, blocks DNMT activity. Genistein reduces DNA methylation in triple-negative breast cancer by increasing BRCA1 and ER expression. These findings help us understand that flavonoids can switch on key tumor suppressor genes by altering DNA methylation and histone modifications [95].

   3. Targeting the CSC Niche and Microenvironment
   1. • Angiogenesis and Metastasis

        Angiogenesis is the process by which new blood vessels grow from existing ones. This occurs when the body is still growing, tissues are being repaired to obtain oxygen and nutrients, and wounds are healing. Tumors in cancer take over this process and create their own blood supply. This helps them grow and move to other parts of the body [96]. Angiogenesis is crucial for tumor growth and its spreading.

        Natural compounds have shown great potential in blocking these processes by interfering with key proteins and signaling pathways. For example, in prostate and breast cancer models, tumor volume and proteins such as VEGF, MMP-2/9, COX- 2, and NF-B were suppressed by curcumin. This process reduces metastasis. Similarly, a compound called methyl anticinate A from Antrodia camphorata boosted p53 expression and acted as an antimetastatic agent. Therefore, the stress protein Hsp27 is reduced, and breast CSC self- renewal is limited.

      • CSC Microenvironment Modulation

        CSCS surrounding CSCS are modified by natural compounds such as resveratrol, pterostilbene, wogonin, and baicalin. Resveratrol directly suppresses CSC growth and lowers stemness and oncogenic markers, such as c-Myc, SOX2, and CD44. Pterostilbene enhances the immune response by activating T, NK, and B cells. This process occurs during the conversion of tumor-supporting immune cells into tumor- fighting immune cells. Wogonin and

        Scutellaria extracts help reduce the immunosuppressive effects of TGF1. This restores the body’s natural defense against CSCs. These compounds help make the tumor microenvironment unsuitable for tumor spread and growth [97].

      • Drug Resistance

   P-glycoprotein is a protein pump present at higher concentrations in CSCS. This is why they undergo chemotherapy. This pump works by throwing chemotherapy drugs out of the cell, making the medicines less effective, and the cancer returns. Some natural compounds, such as celafolin A-1, sesquiterpene ester 1, and celorbicol ester, which are sesquiterpene derivatives from the Celastraceae plant family, can block this pump. They work by attaching to the part of P- gp that uses ATP. Blocking the pump causes the drug to remain inside the cell, making chemotherapy effective [9].

   Oxymatrine is another natural compound that helps overcome drug resistance in CSCs. It works by opting for different

   mechanisms. It inhibits epithelial-mesenchymal transition, a process that makes CSCs more resistant to chemotherapy. In colon CSCs, which no longer respond to 5-fluorouracil (5- FU), the NF-B signaling pathway is blocked by oxymatrine. This reversed EMT sensitizes cells to chemotherapy [98].

   Argablin is another example of a compound that can kill acute myelogenous leukemia (AML) cells, making it a possible approach for treating blood cancer. The most important fact is that it works against AML cells that no longer respond to doxorubicin. This explains why argablin can overcome the common drug resistance mechanisms linked to CSCs. This ability makes it a promising therapeutic option for cancer therapy [99].

   Mechanism	How It Works	Natural Products </td	Effect on CSCs
   Apoptosis & Autophagy	Activates caspases, ROS Inhibits autophagy	Oxyresveratrol, Angelicin, Gambogic acid, Chloroquine, Salinomycin, Metformin	CSC death, reduced drug resistance
   Epigenetic Regulation	Modifies DNA methylation & histones Inhibits DNMT/HDAC	EGCG, Curcumin, Resveratrol, Genistein, Sulforaphane	Restores tumor suppressor genes, reduces CSC self-renewal
   Targeting Microenvironment	Blocks angiogenesis & metastasis Modulates immune cells	Curcumin, Resveratrol, Pterostilbene, Wogonin	Reduced CSC growth, suppressed metastasis
   Overcoming Drug Resistance	Inhibits P-gp pumps Reverses EMT	Celafolin A-1, Oxymatrine, Arglabin	Increased drug sensitivity, reduced chemoresistance

   Table II: Effect of Natural products on CSCs

6. Therapeutic Opportunities and Future Perspectives:

   CSCs pose a significant challenge in oncology due to their rapid ability to relapse, differentiate, and divide at a very fast rate. Natural products are novel therapeutic opportunities that may help improve cancer management and provide a new perspective for effective CSC-directed therapies in oncology.

   A. A. Role of Nanocarrier in improving Natural product therapy

   Nanocarrier-based delivery of natural products is a promising approach for targeting CSC to prevent cancer recurrence, metastasis, and drug resistance. This enhances the bioavailability of the compounds. Many clinical studies have shown that the use of nanocarriers with natural products boosts their anti-cancer activity. These carriers help compounds such as curcumin, paclitaxel, cyclopamine, all-trans retinoic acid, resveratrol, and silibinin to be stable and bioavailable until they reach their target site, and they help in

   releasing them in a very controlled manner directly on CSCs. This leads to a much stronger therapeutic effect. They use ligand modification for precise targeting. These systems reduce CSC stemness and work positively for chemotherapy, making them a safer and more effective treatment option. Nano formulations also act as effective tools, where their movement and distribution in the body heavily depend on the nanocarriers rather than the drugs properties [100]

   Combination Therapy Strategies

   Chemotherapy and radiotherapy are costly and have harmful side effects during cancer treatment. Therefore, researchers have begun to explore natural products as alternatives. They are easy to access and are tolerated.

   Figure 3: Schematic representation of cellular mechanisms of natural products targeting Cancer stem cells.

   Compounds such as curcumin, EGCG (green tea extract), resveratrol, quercetin, and apigenin have demonstrated anti- cancer effects in basic laboratory studies. However, converting these into effective human treatments is challenging. These include differences between animals and humans, poor solubility, low absorption, and short activity time of these compounds.

   Curcumin has low bioavailability; however, when combined with other drugs, such as lenalidomide, bortezomib, or paclitaxel, it improves survival and reduces cancer progression in patients. The main success was that it had fewer side effects than other drugs. Similarly, EGCG and indole-3-carbinol combined with chemotherapy improved the survival rate in patients with ovarian cancer and reduced recurrence. EGCG also lowers the side effects of radiation induced esophagitis in lung cancer patients. Other natural compounds, such as vincristine, bryostatin-1, sulforaphane (from broccoli), and fisetin, have also been tested in clinical trials, showing benefits such as reduced inflammation, improved remission, and slowed progression of cancer. Overall, Natural products have a strong potential when paired with other therapies as a combination therapy for the effective treatment of cancer without any major side

   effects [12].

7. Future Perspectives

   In the future, research should focus on optimizing drug delivery systems, including nanoparticle-based or liposomal-based formulations. These formulations may enhance stability, bioavailability, and target delivery of natural compounds to CSCs. It is important to explore combination therapies that include natural compounds. It is necessary to gain deeper insights into CSCs characteristics, identify reliable biomarkers, and effectively target the tumor microenvironment. Furthermore, extensive preclinical and clinical trials must be conducted to validate the safety and therapeutic potential of these compounds [101]. Future research should also focus on the effectiveness of these compounds. Improving drug delivery systems and creating modified versions also helps in increasing the drug activity and absorption in the body.

8. CONCLUSION:

   Cancer therapy struggles due to the presence of Cancer stem cells. It faces various challenges and obstacles due to the presence of CSCs. These factors drive tumor heterogeneity, therapy resistance, metastasis, and recurrence. They have self-renewal and differentiation potentials that enable them to survive standard treatments, such as chemotherapy and radiotherapy, escape from immune cells, and repopulate tumors. Their capacity to activate survival mechanisms, repair DNA damage, and enter a dormant state makes them an important barrier to long-term therapeutic success. This highlights the importance of therapies that effectively target CSCs.

   Natural compounds are a therapeutic goldmine that can function as potential anti-CSC agents, as they possess the potential to treat CSC with reduced toxicity. Flavonoids, alkaloids, polyphenols, curcumin, and resveratrol have exhibited maximum efficacy in inhibiting the self-renewal of CSCs, inducing apoptosis and autophagy. They also regulate epigenetic regulators and interfere with CSC- supportive microenvironments. For example, flavonoids such as quercetin and luteolin inhibit -catenin and STAT3 signaling; alkaloids such as piperine reduce CSC markers; and polyphenols such as resveratrol and curcumin exacerbate EMT and enhance CSC sensitivity to chemotherapy. This provides NPs with a therapeutic advantage over CSCs. Nevertheless, NPs are hindered by their limited solubility, poor bioavailability, rapid metabolism, and lack of sufficient targeting. Combining this with nanotechnology, including liposomes, polymeric nanoparticles, and ligand-modified carriers, may be a stable and effective remedy for CSCs. This also helps increase the bioavailability of NPs and drug delivery targeting. Nano formulated NPs have proven to be more efficient in reducing cancer stem cell stemness, bypassing drug resistance, and combination treatments with traditional anti- cancer agents. The integration of sophisticated delivery systems with natural compounds is a promising approach for providing long-term, safe, and targeted CSC-guided cancer therapy. This will improve patient outcomes and minimize the risk of tumor recurrence.

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