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Next-generation strategies against prostate cancer: natural products and nanomedicine targeting prostate cancer stem cells
1Department of Biochemistry, Research and Publications, Kampala International University, P.O. Box 20000, 10417 Kampala, Uganda
2Department of Biochemistry, Faculty of Basic Medical Sciences, College of Medicine, Federal University of Health Sciences, 972211 Otukpo, BEN, Nigeria
3Department of Medical Laboratory Sciences, College of Health Technology, 540001 Calabar, CRS, Nigeria
*Corresponding Author(s):daniel.ejimuti@kiu.ac.ug (Daniel Ejim Uti)
| History | Submitted: 24 July 2025 | Accepted: 18 September 2025 | Published: 30 January 2026 |
| Copyright: | ©2026 The Author(s). Published by MRE Press. |
Recurrence, metastasis, and treatment resistance are significant issues in prostate cancer management. Evidence increasingly substantiates the notion that prostate cancer stem cells (PCSCs) initiate cancer, facilitate its progression, and complicate therapy. Thus, targeting PCSCs may provide a feasible strategy for addressing incurable or recurrent illnesses. Research indicates that natural compounds derived from medicinal plants and foods may combat cancer, particularly by targeting cancer stem cells via modulation of signals from the Wnt/β-catenin, Notch, Hedgehog, and Phosphoinositide 3-kinase (PI3K)/Protein kinase B (AKT)/Mechanistic target of rapamycin (mTOR) signaling pathway. Nonetheless, the majority of these bioactive chemicals exhibit low solubility in water, inadequately penetrate the circulation, and are rapidly eliminated by the body before they can be effectively used in medical applications. Nanotechnology has enhanced the delivery, production, and targeting of certain natural products. Phytochemicals may be effectively administered to PCSCs inside tumours using liposomes, polymeric nanoparticles, dendrimers, micelles, and exosomes. Moreover, stimuli-responsive nanoplatforms may be constructed to concurrently administer several pharmaceuticals. This review analyses the function of PCSCs in prostate cancer, identifies key natural chemicals that target PCSCs, and evaluates the potential of nanotechnology to amplify the efficacy of these natural products. Furthermore, we examine current obstacles, unresolved enquiries, and anticipated trajectories for the implementation of natural nanomedicine therapies in PCSCs.
Cite this article
Daniel Ejim Uti, Wilson Achu Omang, Esther Ugo Alum, Inalegwu Bawa, Okechukwu Paul-Chima Ugwu, Simeon Ikechukwu Egba. Next-generation strategies against prostate cancer: natural products and nanomedicine targeting prostate cancer stem cells.Journal of Men's Health,2026,22(1):27-47 DOI:10.22514/jomh.2026.003
1. Introduction
Prostate cancer (PCa) is one of the most common cancers in men around the world, with a significant impact on the health of the population [1, 2, 3]. It is the second most reported cancer and the fifth killer-cancer of men in the whole world. As indicated by the Global Cancer Observatory (GLOBOCAN), over 1.46 million estimated cases of prostate cancer were recorded in 2022 alone, and about 396,000 of them died [4]. Prostate cancer incidence is highly variable in different parts of the world, with those in the West, especially North America, Northern, and Western Europe as well as Australia recording high incidences [3, 5]. The causes of such disparities remain widely spread, including variations in healthcare accessibility, genetics, environment, and the popularity of using the prostate-specific antigen (PSA) test [5]. In low- and middle-income countries, the reported incidence is low, but the mortality rates are unbalanced as people are not diagnosed timely, screening programs are insufficient, and treatment facilities are weak. Since there is a tendency of life expectancy going up, the increasing burden of prostate cancer all over the world is inevitable, hence the need to come up with the best prevention and treatment methods [6].
Though there have been tremendous innovations in the diagnosis and treatment of prostate cancer, especially with the advent of androgen deprivation therapy (ADT), radiations, and surgery, as well as newer generation anti-androgen based drugs, there has not been a long term disease management in a high number of patients [7]. Therapeutic resistance, culminating in poor outcomes, is one of the major challenges of prostate cancer arising in the form of recurrence and its progression to a disease-resistant condition, castration-resistant prostate cancer (CRPC), which is fatal [8]. Recent studies have increasingly pointed to a minor fraction of tumor-initiating cells, the so-called prostate cancer stem cells (PCSCs), creating resistance to conventional therapies [3, 9]. These PCSCs have distinguishing features like self-renewal, multi-lineage differentiation, and quiescence, with the possibility to rise therapeutic attacks that normally wipe millions of bulk tumor cells away. They are able to re-seed the tumor and enable the occurrence of metastasis that leads to treatment failure and illness relapse [10]. In addition, PCSCs are resistant to chemotherapeutic drugs and radiation therapy due to high expression of drug efflux pump, resistance paths, and increased DNA repair [11].
Since PCSCs are so instrumental in the progression of prostate cancer, as patients develop resistance to treatment, it follows that an attack on this persistent subpopulation is highly promising to break therapeutic resistance and enhance patient outcomes [12]. But the straightforward destruction of the PCSCs is a significant challenge because they are resistant, with a unique microenvironment, and their molecular pathways are complex [13]. There has been a growing interest recently in the use of natural products as the future agents of targeted cancer stem cells. Natural products, including c-curcumin, resveratrol, epigallocatechin-3-gallate (EGCG), and quercetin, which are used as diets, and medicinal plants; have displayed anticancer activity in numerous malignancies, including prostate cancer [14, 15]. The known targets of action of these compounds include modulation of important signaling pathways that relate to stemness, including Wnt/β-catenin, Notch, Hedgehog, and PI3K/AKT [16]. Unlike other synthetic drugs, natural products tend to be less toxic and can be used long term with negligible side effects. They have a potential to be used as combination drugs with the current therapeutic methods because they can modulate the tumor microenvironment, which helps in interfering with the self-renewal machinery of PCSCs [17].
However, many of these potential natural-derived compounds have suffered limitations due to very low solubility, low bioavailability, and rapid metabolism accompanied by systemic clearance when attempting clinical reality [18]. These pharmacokinetic shortcomings limit their therapeutic effectiveness and bench to bedside translation. Nanotechnology has offered a good option to mitigate these hurdles by means of targeting bioactive constituent delivery to cancer cells and specifically to shred cancer stem cells [19]. Nanoparticle-based drug delivery systems, including liposome, polymeric nanoparticles, dendrimers, micelles, and solid lipid nanoparticles, have been developed to improve the aqueous solubility, loading capacity, and targeted delivery of natural products [20]. The recognition of surface markers on PCSCs is possible by ligands or antibodies in functionalizing these nanosystems and thus guarantee specificity and reduce the off-target effect [21]. In addition, nanoparticles are able to be tuned to react to the appropriate stimuli within the tumor environment, e.g., pH or tissue enzymatic activity, to provide a controlled and enhanced delivery and gathering of therapeutic loads at the tumor location [22].
The combination of natural compounds and nanocarrier systems is a synergistic integration of strategy to combat cancer cells and target PCSCs as it manages both mechanistic and pharmacological weaknesses of conventional treatment regimens [23]. This innovative strategy allows enhancing bioavailability and suitability index of natural agents and helps them break the process of tumor initiation driven by PCSC, tumor progression, and resistance. As our body of knowledge of PCSC biology and tumor microenvironment broadly expounds, the fact that phytochemicals in conjunction with highly developed nanotechnologies may transform the landscape of the therapeutic market in prostate cancer cannot be ignored. This review, thus, seeks to discuss the existing knowledge of PCSCs in prostate cancer, the potentials of using natural compounds against these cells, as well as how nanotechnology can be used as the tool to deliver these agents and make them more effective, ultimately providing a bright prospect on how drug resistant prostate cancer can be overcome and its long-term outcomes improved.
2. Prostate cancer stem cells: biology and therapeutic resistance
2.1 Definition and characteristics of prostate cancer stem cells
Prostate cancer stem cells (PCSCs) are a small, specific population of cells in prostate tumors which have stem-like qualities (self-renewal, differentiation, and even the ability to cause cancer) [12]. This type of cells are thought to be on the top of the chain in the tumor cells, and it is core to the creation, preservation, and growth of prostate cancer [3]. In contrast to bulk tumor, the PCSCs have the capacity to regenerate new tumors upon transplantation into immunodeficient mice, and are thus central to the development of cancer [3].
The PCSCs have much in common with normal stem cells: they can develop asymmetrically, i.e., give way both to similar unilateral stems (self-renew) and to differentiated progenitors that add to tumor heterogeneity [24]. This dynamic ability permits PCSCs, in this way, to keep a supply of tumor-initiating cells, even as non-stem cancer cells proceed with the proliferation. These features add to the plasticity and flexibility of tumors, and PCSCs are especially risky in the context of clinical practice [24]. Notably, PCSCs are defined by their non-sensitivity to standard treatment approaches that include chemotherapy, radiotherapy, and androgen deprivation therapy (ADT) [25, 26]. Although such therapies are successful in shrinking tumor mass they do not always eliminate PCSCs which are capable of survival and repopulation, resulting into tumor recurrence and metastases. These resistances are because PCSCs are characterized by some inherent factors, such as quiescence (low proliferation status), the presence of efficient repair mechanisms of a DNA strand break (DNA damage), high expression rate of drug efflux pumps (like the ATP-binding cassette transporters (ABC)), and considerable neutralization of reactive oxygen species (ROS) [27].
Another aspect that makes stem cells resilient is the PCSC niche, which is the special microenvironment in which they are sustained [28]. The factors that maintain the PCSC phenotype include hypoxia, stromal support, inflammatory cytokines, and the components of extracellular matrix. Besides that, PCSCs are capable of responding to environmental stressors, and can live even in the presence of nutrient deprivation or therapeutic insult [29].
The oncogenic transformation of normal prostate stem/progenitor cells may be a foundation source of PCSCs, or PCSCs may be developed by the acquisition of stem-like properties by more differentiated cancer cells in the same manner, such as an epithelial to mesenchymal transition (EMT) [30]. In whatever way they appear, PCSCs presence in prostate tumors is characterized by poor prognosis, aggressive nature of disease development, as well as decreased effectiveness of treatment. To target PCSCs, a full picture of their biological characteristics and regulatory networks is needed. The latest findings aim toward perturbation of important signaling pathways, particular surface markers, and methods of treatment, which can destroy the PCSCs without destroying the normal stem cells. The understanding of the peculiarities of PCSCs presents a rewarding way out in the treatment and prevention of prostate cancer relapse.
2.2 Prostate cancer stem cells surface markers
The isolated PCSCs identification and isolation strongly depend on the application of surface and functional markers. Such markers can be used in differentiating PCSCs with bulk tumor cells as well as normal prostate cells and have been useful in elucidating their biology, in addition to being used in the development of precision medication. The cluster of differentiation 44, 133 (CD44, CD133) and aldehyde dehydrogenase (ALDH) are some of the most widely-researched PCSC markers, but others, including integrin 21, Epithelial Cell Adhesion Molecule (EpCAM) and ATP-Binding Cassette Sub-Family G Member 2 (ABCG2), have also been suggested [31].
CD44 is a plasma membrane glycoprotein primitively in cell-cell cooperation, cell adhesion, and movement [32]. CD44-positive cells are more tumorigenic and have clonogenic capacity besides being chemoresistant and ADT resistant in prostate cancer [33]. CD44 is linked to epithelial-to-mesenchymal transition (EMT) which augments cell mobilities and invasions, thus facilitating metastasis [33]. CD44+ and PCSCs are more flexible to drug stress and more expressive of stemness related genes [33]. CD133 (Prominin-1) has also been found to be another important marker that has been extensively used to define PCSCs. CD133+ prostate tumor or prostate cell line-derived cells have much better in vitro formation of prostaspheres and form tumors much earlier in xenografts than parental or CD133-negative cell lines [34]. CD44 is frequently co-expressed with these cells and the CD44+/CD133+ phenotype has been demonstrated to purify population of highly tumorigenic PCSCs. CD133 is associated with resistance to therapy, especially in CRPC and can be viewed as a possible prognostic marker [35].
Aldehyde dehydrogenase (ALDH), and specifically Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1) isoform, is an intracellular aldehyde oxidase that takes part in the cellular detoxification and retinoic acid biosynthesis [3]. The most characteristic feature of stem-like cancer cells, such as PCSCs, is the high activity of ALDH that leads to greater resistance to radiation and chemotherapeutic drugs, as a result of an increased ability to detoxify and regulate reduction and oxidation processes [3]. Another indicator is integrin alpha 2 beta 1 which is a receptor of laminin and is involved in cell attachment and invasion. Higher expression of integrin alpha 2 beta 1, especially when combined with CD44, imparts improved stem cell characteristics and displays tumor-initiating potential by cells [36]. Enrichment of epithelial-like PCSCs can also be done by epithelial cell adhesion molecule (EpCAM), which has been shown to be associated with enhanced proliferation and metastasis [37]. Nevertheless, all of them are limited to the therapeutic targeting of PCSCs, yet they are not specifically PCSCs-related. The specificity and the effectiveness of PCSC isolation can be enhanced by combining several markers and functional assays (side population analysis, dye exclusion, or sphere formation) [3]. These markers are significant research tools portraying a hope of dynamic benefits in diagnosis and treatment of prostate cancer.
2.3 Tumor initiation, metastasis and therapy resistance role
The PCSCs are considered to be central to the whole chain of the development of prostate cancer: initiation of the tumor, its growth and development, metastasis, and re-development during or after the treatment [38]. They form a major source of heterogeneity and other causes of prostate cancer therapy failure and clinical recurrence, and are, therefore, an important intervention point. On tumor initiation, PCSCs have the special capability to form self-renewal and differentiation, which gives them the ability to create all the cellular diversity of prostate tumors [3]. This is particularly manifested in investigations during which even small amounts of 100–1000 PCSCs when xenografted in the immunocompromised mice may germinate into a complex multifaceted comprehensively developed tumor [39]. The way they can recolonize tumors after primary treatment points to their central importance in the creation and sustenance of prostate cancer.
PCSCs also play a big role in metastasis, they can cause secondary tumors in the metastatic sites because they have high motility, are more resistant to death during circulation, and can colonize other organ areas [40]. The epithelial-to-mesenchymal transition (EMT) process plays a pivotal part in this respect, imparting on the PCSCs the mesenchymal qualities of greater invasive capabilities and resistivity to anoikis [41]. In a secondary organ, PCSCs have the potential to go through mesenchymal-epithelial transition (MET) to reenter proliferative epithelial growth, resulting in the formation of metastatic tumor cells [42].
The problem, that is also extremely dangerous, when it comes to PCSCs is their resistance to therapy. In contrast to heterogeneous cancer cells that tend to be susceptible to both chemotherapy or ADT, PCSCs would survive as a result of a number of mechanisms. Such are their quiescent character, enabling them to avoid drugs that kill divide cells; increased Adenosine Triphosphate (ATP)-binding cassette (ABC) pumps that expel cytotoxic substances; more rapid DNA repair; and an increase in the levels of antioxidants, and can neutralize the drugs produced in response thereto, sequestering potentially dangerous reactive oxygen species [3]. Moreover, PCSCs are able to modify the tumor microenvironment to establish the niches leading to their survival and stemness, and it usually entails interactions with stromal cells, immune cells, and extracellular matrix elements [43]. The PCSCs resistance to treatment is one of the principal causes of tumor recurrence and CRPC [44, 45]. Apparently, subsided PCSCs may persist in a dormant state and will finally reactivate, relapsing into an aggressive condition and producing a treatment-resistant condition [46]. Therefore, effective therapy of prostate cancer would require an approach that could not only decrease tumor load but one that also targets PCSC population.
2.4 Signaling pathways in PCSCs (Wnt/β-catenin, notch, hedgehog)
The multiple evolutionarily conserved signaling pathways which control the maintenance, self-renewal, and therapeutic resistance of PCSCs are the Wnt/transduction (β-catenin), Notch, as well as Hedgehog (Fig. 1) [47]. These pathways play key roles in embryonic formation and homeostasis of adult tissues and their misregulation in cancer, and results in uncontrolled growth and cancer stem cell (CSC) states of tissues [47].
Fig. 1.Key signaling pathways regulating prostate cancer stem cells (PCSCs) (created in https://BioRender.com). This figure illustrates the major signaling pathways: Wnt/β-catenin, Notch, and Hedgehog that regulate the maintenance, self-renewal, proliferation, and therapy resistance of prostate cancer stem cells (PCSCs). (A) The Wnt/β-catenin pathway stabilizes β-catenin, allowing its nuclear translocation and transcriptional activation of genes such as c-Myc, Cyclin D1, and Axin2, thereby promoting PCSC survival and epithelial-to-mesenchymal transition (EMT). (B) In the Notch pathway, ligand binding triggers proteolytic cleavage of the receptor, releasing the Notch intracellular domain (NICD), which translocates to the nucleus and activates downstream genes like Hes1 and Hey1, maintaining the undifferentiated state of PCSCs. (C) Activation of the Hedgehog pathway involves binding of Sonic Hedgehog (Shh) to the Patched (PTCH) receptor, lifting inhibition of Smoothened (SMO) and enabling GLI-mediated transcription of stemness-associated genes. These core pathways are interconnected with additional signaling axes, such as PI3K/AKT, STAT3, and TGF-β, which further enhance PCSC survival and treatment resistance. TCF/LEF, T-cell factor/lymphoid enhancer factor; NICD, Notch intracellular domain; Shh, Sonic Hedgehog; PTCH, Patched receptor; SMO, Smoothened receptor; GLI, glioma-associated oncogene homolog; SUFU, Suppressor of Fused; ADAM, A Disintegrin and Metalloproteinase; NECD, Notch Extracellular Domain; Co-A, Co-Activator; Co-R, Co-Repressor; MAM, Mastermind-like Protein; CSL, CBF1/Su(H)/Lag-1; CKIα, Casein Kinase I Alpha; GSK, Glycogen Synthase Kinase (commonly GSK-3β in Wnt signaling); LRP, Low-Density Lipoprotein Receptor-Related Protein (commonly LRP5/6).
Wnt/β-catenin regulation is the key pathway to the control of PCSC. In normal conditions, β-catenin is phosphorylated and degraded. However, in prostate cancer, aberrant Wnt signaling leads to β-catenin stabilization and nuclear translocation, where it binds to T-cell Factor (TCF)/Lymphoid Enhancer-Binding Factor (LEF) transcription factors to activate genes involved in proliferation and stemness, such as c-Myc, Axin2, and Cyclin D1 [48, 49]. Activation of the Wnt pathway enhances the development of prostaspheres, induction of EMT, and develops therapeutic resistance [49]. Inhibiting this route by the use of Wnt inhibitors or β-catenin antagonists is currently being studied to annihilate PCSCs.
The second pathway involved in cell fate determination and the undifferentiated state is the Notch signaling. In prostate cancer, expression of both Notch ligands, e.g., Jagged1, Delta-like ligand 1 and Notch receptor (Notch1–4) have been negatively correlated with patient survival and influence PCSCs proliferation [50]. After this ligand binding, the Notch receptor is cleaved proteolytically to release the Notch intracellular domain (NICD), which migrates to the nucleus where it induces target gene activation, such as of Hes1 and Hey1. Notch signaling can be inhibited by the use of γ-secretase inhibitors (GSIs) and decrease the PCSC survival and tumorigenicity [51].
The ligand-activated Hedgehog (Hh) pathway is when the Patched (PTCH) receptor is bound by ligands that include Sonic Hedgehog (Shh) then the suppression of Smoothened (SMO) is released and this causes the downstream Glioma-associated oncogene homologs (GLI-) mediated transcription [52]. Hedgehogs are over-expressed in CRPC and are linked with amplified construction of stemness standard genes. Blocking of this pathway with SMO antagonist, such as vismodegib or sonidegib, has demonstrated potential to decrease the frequency of PCSC and increase reversal of therapy resistance [53]. Also, Wnt, Notch, Hedgehog interacts with Phosphoinositide 3-Kinase (PI3K)/Protein Kinase B (AKT), Signal Transducer and Activator of Transcription 3 (STAT3), and Transforming Growth Factor Beta (TGF-β) to enhance the PCSC functions. Activation of PI3K/AKT cascade through depletion of Phosphatase and Tensin Homolog (PTEN) in prostate cancer vehicles promotes cell survival and induction of apoptotic resistance [54]. Activating of STAT3, by cytokines such as (Interleukin 6) IL-6, assists tumor growth and stemness. EMT and stemness in the advanced prostate cancer can be promoted by the TGF-β that is a tumor inhibitor at an early stage [55].
While critical pathways such as Wnt, Notch, Hedgehog, PI3K/AKT, STAT3, and TGF-β have been individually implicated in prostate cancer progression and stemness, their biological relevance lies not only in their independent functions but also in their extensive crosstalk and convergence on shared downstream targets [56]. For instance, Wnt and Notch signaling synergize to maintain prostate cancer stem cell self-renewal, while aberrant activation of Hedgehog can potentiate Wnt-driven transcriptional programs, amplifying tumorigenic potential. Similarly, the PI3K/AKT pathway interacts with STAT3 signaling to enhance survival and evade apoptosis, thereby reinforcing a microenvironment that favors therapy resistance [56]. TGF-β, though context-dependent, often cooperates with PI3K/AKT and STAT3 to promote EMT, thereby facilitating invasion, metastasis, and resistance to ADT and chemotherapy. The convergence of these pathways creates a highly redundant signaling network, such that inhibition of one axis may be compensated by activation of another, explaining the limited efficacy of monotherapies targeting single pathways [57]. Thus, a deeper understanding of the interconnectivity among Wnt, Notch, Hedgehog, PI3K/AKT, STAT3, and TGF-β underscores the need for combinatorial therapeutic strategies that disrupt these cooperative networks and overcome resistance mechanisms in prostate cancer management.
Besides the well-understood Wnt/β-catenin, Notch, and Hedgehog signaling pathways, there is currently a growing number of molecular pathways that are indispensible to the survival, self-renewal, plasticity, and resistance to treatment of PCSCs. These are the PI3K/AKT/mTOR, Janus Kinase (JAK)/STAT, Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB), TGF-5, and Hippo pathway/Yes-Associated Protein (YAP) signaling axis, and other epigenetic regulators which form a complex regulatory network to maintain the biology of PCSC [58]. In prostate cancer, the PI3K/AKT/mTOR pathway is one of the most often activated pathways, particularly in prostate cancer with PTEN loss, a tumor suppressor regularly mutated in high-stage prostate cancer [59]. Stimulation of this pathway encourages cell survival, proliferation, metabolic adaptation, and resistance to apoptosis. PI3K/AKT signaling contributes to a maintenance of undifferentiated phenotype, provides resistance to ADT and/or chemotherapy. mTOR is a downstream effector that is important in controlling the protein synthesis and cell growth [60]. Dual targeting of PI3K and mTOR has demonstrated the ability to cooperate in lowering viability of PCSC, and rendering cancer treatment-susceptible [61].
Central to the immune evasive, stem cell like, and resistance functions of PCSCs is the JAK/STAT3 pathway that frequently becomes activated by inflammatory cytokines such as IL-6 [62, 63]. The stimulation of gene expression of self-renewal hNANOG (Homeobox protein NANOG), SOX2 (SRY-box 2), Oct4 (Octamer-binding transcription factor 4), proliferation, and anti-apoptotic signaling results in constitutive STAT3 activation [64, 65]. High concentrations of STAT3 activities correlate with aggressive prostate cancer and unfavourable treatment outcome. JAK kinase inhibitors, or direct STAT3 inhibition, can both block the formation of prostaspheres and tumor-initiating activity [66]. An additional inflammatory pathway relevant to PCSCs survival and immune evasion is the NF-κB signalling. NF-κB encourages the expression of anti-apoptotic genes (B-cell lymphoma-2 (Bcl-2), Survivin) and inflammation mediators, which favors the tumor promoting microenvironment [67]. Its crosslinking with the pathways of STAT3 and PI3K also enhance PCSC resistance. NF-κB blockers are being tried out with a view that it can interfere with this support system and decrease stemness [68].
TGF-β, though serving as a tumor suppressor at an early stage of prostate cancer, ironically activates metastasis, EMT and stem-like characteristics at an advanced stage. It causes transcriptional shifts which contribute to plasticity and resistance to therapy [69]. TGF-β boosts colonization and mesenchymal transition within PCSCs at the metastatic sites. One can attack TGF-β or downstream regulators such as Mothers Against Decapentaplegic Homolog 2/3 (SMAD2/3) and thereby decrease PCSC-caused metastasis [70].
Hippo/YAP signaling plays a critical role in regulating organ size, stem cell proliferation, and tissue homeostasis. When organ sizes are measured, Hippo/YAP signaling is commonly recognized as a key regulator of organ growth [71]. The transcriptional coactivator Yes-associated protein (YAP), when dysregulated, translocates to the nucleus where it drives stem-related gene expression, survival genes, and drug resistance genes [72]. The prostate cancer overexpression of YAP is associated with a malignant tumor and treatment resistance. Pharmacological YAP/TAZ inhibitors or the transcriptional partners of the YAP/TAZ, e.g., TEADs (TEA Domain transcription factors) are being developed as PCSC targets [73]. Beside the traditional signaling cascades, PCSC gene expression is also controlled by epigenetic changes through DNA methylation, histone modifications, and chromatin restructuring. Enzymes, such as EZH2 (Polycomb Repressive Complex 2 component), DNMTs (DNA methyltransferases) and HDACs (histone deacetylates), are commonly upregulated in prostate cancer and contribute to the cancerous shutdown of tumour suppressor-genes and the maintenance of stemness programmes [74]. You can reprogram PCSCs through differentiation into epigenetic inhibitors (e.g., EZH2 or HDAC inhibitors) and make them more susceptible to treatment. Lastly, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) have become central regulators of the post-transcription network of signaling in PCSC [75]. An example is that miR-34a, miR-200c are tumor suppressors that inhibit genes related to stemness, whereas HOX Transcript Antisense Intergenic RNA (HOTAIR), lncRNA, and Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) encourage EMT and metastasizing [76].
Hence, the biology of PCSCs is dictated by complex interactions between signaling and epigenetic networks. Sabotaging only one cell signaling pathway may not be enough to destroy PCSCs since there is compensatory pathways. Hence, multiplexed signaling axis combinatorial targeting, in addition to standard treatment, holds potential in the elimination of PCSCs and resistance to treatment in prostate cancer.
3. Natural products with anti-cancer stem cell activity in prostate cancer
Natural products have become prolific compounds in attacking PCSCs, special cells believed to be responsible for therapeutic resistance, metastasis, and recurrence of prostate cancer [12, 27, 77]. All of these compounds, both dietary and medicinal, or phytochemical in nature have multi-targeted effects, such as interference of signaling pathways, apoptosis, EMT inhibition, and self-renewal capacity suppression. Table 1 (Ref. [78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97]) showcases in detail a series of the selected natural compounds, their source and origin, mechanism of actions toward PCSCs in particular, preclinical evidence, in vitro models, significant findings, and shortcomings.
| Serial number | Compound | Class of Compound | Source/Origin | Mechanism of Action | Preclinical Evidence | Experimental Model | Limitations | References |
| 1 | Curcumin | Polyphenol | Curcuma longa (Turmeric) | Inhibits Wnt/β-catenin, NF-κB, and PI3K/AKT | ↓ sphere formation | PC3, DU145 cells, xenograft mice | Low bioavailability | [78] |
| 2 | Resveratrol | Stilbene | Grapes, berries | Suppresses STAT3, Notch, and EMT pathways | ↓ CD44+ cell populations | DU145, LNCaP cells | Rapid metabolism | [79] |
| 3 | EGCG | Catechin (Flavonoid) | Green tea (Camellia sinensis) | Targets Hedgehog and Notch; induces apoptosis | ↓ self-renewal | TRAMP model, PC3 cells | Requires high doses | [80] |
| 4 | Sulforaphane | Isothiocyanate | Broccoli, cruciferous vegetables | Inhibits ALDH1, Wnt/β-catenin | ↓ tumor initiation | PC3, DU145 CSCs | Poor stability in vivo | [81] |
| 5 | Genistein | Isoflavone | Soybeans | Blocks AKT/NF-κB, reduces stemness markers | ↓ prostasphere size | TRAMP mice, LNCaP, PC3 | Estrogenic side effects | [82] |
| 6 | Withaferin A | Steroidal Lactone | Withania somnifera | Induces ROS, inhibits vimentin and EMT | ↓ invasion & spheres | PC3, DU145 | Cytotoxicity at high doses | [83] |
| 7 | Berberine | Isoquinoline Alkaloid | Berberis vulgaris | Inhibits AKT/mTOR, suppresses EMT | ↓ ALDH+ CSCs | LNCaP, PC3, xenografts | Poor systemic absorption | [84] |
| 8 | Quercetin | Flavonol (Flavonoid) | Onions, apples | Inhibits YAP/TAZ, modulates cell cycle | ↓ CD133+ cells | DU145, TRAMP mice | Moderate oral bioavailability | [85] |
| 9 | Parthenolide | Sesquiterpene Lactone | Tanacetum parthenium | Blocks NF-κB, induces CSC apoptosis | ↓ tumorigenic cells | DU145 CSC-like cells | Limited clinical data | [86] |
| 10 | Honokiol | Biphenolic Lignan | Magnolia bark | Inhibits STAT3, reduces CSC frequency | ↓ colony formation | PC3, DU145, mice | Rapid clearance | [87] |
| 11 | Apigenin | Flavone (Flavonoid) | Parsley, celery | Downregulates β-catenin and Oct4 | ↓ sphere size | PC3 CSCs, TRAMP mice | Weak in vivo effect | [88] |
| 12 | Luteolin | Flavone (Flavonoid) | Green pepper, celery | Modulates miR-21/PTEN, inhibits CSC migration | ↓ migration/invasion | PC3 CSCs | Synergism with chemo not tested | [89] |
| 13 | Fisetin | Flavonol (Flavonoid) | Strawberries, apples | Inhibits PI3K/AKT and induces apoptosis | ↓ PCSC survival | DU145 cells | Limited in vivo data | [90] |
| 14 | Baicalein | Flavone (Flavonoid) | Scutellaria baicalensis | Suppresses stemness-related transcription | ↓ CD44+/CD133+ cells | PC3 spheres | Dose-dependent toxicity | [91] |
| 15 | Thymoquinone | Monoterpene Quinone | Black seed (Nigella sativa) | Suppresses STAT3 and c-Myc | ↓ ALDH+ cell pool | DU145 CSC-like cells | Solubility issues | [92] |
| 16 | Nimbolide | Triterpenoid Lactone | Azadirachta indica | Inhibits Notch and NF-κB; induces apoptosis | ↓ clonogenicity | PC3 CSCs | Incomplete pharmacokinetics | [93] |
| 17 | Garcinol | Polyisoprenylated Benzophenone | Garcinia indica | Inhibits Wnt/β-catenin; histone acetylation | ↓ sphere-forming cells | PC3, TRAMP model | Requires formulation enhancement | [94] |
| 18 | Diosgenin | Steroidal Saponin | Fenugreek, yam | Disrupts Hedgehog signaling, ↓ ALDH activity | ↓ tumorspheres | PC3 CSC-like cells | Variable potency | [95] |
| 19 | Silibinin | Flavonolignan | Milk thistle | Suppresses EMT and CD44 expression | ↓ metastasis | DU145, LNCaP, mice | Low aqueous solubility | [96] |
| 20 | Betulinic acid | Pentacyclic Triterpenoid | Birch bark | Induces mitochondrial apoptosis in CSCs | ↓ tumor initiation | PC3, DU145 | Poor oral bioavailability | [97] |
| ↓: Decreased/reduced. PCa, Prostate Cancer; PCSCs, Prostate Cancer Stem Cells; CSC, Cancer Stem Cells; TRAMP, Transgenic Adenocarcinoma of Mouse Prostate (mouse model); ALDH, Aldehyde Dehydrogenase (stemness marker enzyme); STAT3, Signal Transducer and Activator of Transcription 3; EMT, Epithelial-to-Mesenchymal Transition; NF-κB, Nuclear Factor kappa-light-chain-enhancer of activated B cells; PI3K, Phosphoinositide 3-Kinase; AKT, Protein Kinase B; mTOR, Mechanistic Target of Rapamycin; ROS, Reactive Oxygen Species; YAP/TAZ, Yes-Associated Protein/Transcriptional co-Activator with PDZ-binding motif; Oct4, Octamer-binding Transcription Factor 4; miR, MicroRNA (e.g., miR-21); PTEN, Phosphatase and Tensin Homolog; c-Myc, Proto-oncogene Myc (transcription factor); CD, Cluster of Differentiation cell surface markers. |
4. Nanotechnology-enabled delivery of natural products in prostate cancer therapy
Nanotechnology is revolutionary in cancer therapeutics and has introduced new methods for effective delivery of bioactive agents [23, 98]. Nanotechnology offers a potential platform to improve the efficacy of natural products in prostate cancer in which therapeutic resistance and tumor recurrence have always been a significant issue. The plants, marine or microbial origin of these natural compounds are potent anti-cancer agents but tend to be lowly bioavailable, unstable and non-specific in terms of their targets [20, 99]. These limitations can be overcome by using nanocarriers in their delivery system; this enhances solubility, prevents the exposure of compounds to degradants, their pharmacokinetics are improved, and there is a possibility to selectively deliver them to tumor tissues [77, 100].
Nanocarriers are nanometric-size construct nanomaterials that are design to confine, protect and move therapeutic agents [101]. Nanocarriers of various types in drug delivery have been developed, and each type of nanocarrier has dedicated structural and functional characteristics that suit a determined therapeutic purpose. Liposomes are containers made up of the phospholipid bilayers in spherical shapes which have the capability to transport hydrophilic chemicals and amphiphilic drugs [102]. They are biocompatible and have a structural similarity to biological membranes; hence they can be used in precision cancer treatment. Polymeric nanoparticles usually incorporate biodegradable polymers including, but not restricted to, those of Poly(lactic-co-glycolic) acid (PLGA) that have controlled release and increased stability. The same nanoparticles have the potential to be surface-functionalized to be able to target known tumor markers, enhancing targeted delivery to prostate cancer cells [103].
Solid lipid nanoparticle (SLN) is a combination between the strength of lipid-based systems and nanoparticles made of polymers [104]. SLNs are solidified lipids influenced by stabilizers, which are surfactants and may enclose the lipophilic natural products, which have low drug loading ability and perfect regulation of drug release [104]. Dendrimers are well defined three-dimensional tree-like macro-molecules with a clear architecture and surface functionalities [105]. Their multi-terminal groups can be used to conjugate natural products and targeting ligands which makes the Antibody-Drug Conjugates (ADCs) favorable in multivalent interactions with tumor cells. In aqueous solutions, the self-assembly (micelles) of block copolymers of amphiphilic nature can effectively solubilize the poorly water-soluble natural products. They increase the circulation time of the system and the concentration of therapeutic compounds in tumor tissues through the phenomenon of enhanced permeability and retention (EPR) [106].
The newest type of nanocarriers are exosomes and biomimetic carriers that take advantage of the communication system of the body to deliver drugs [107]. Exosomes refer to naturally occurring extracellular vesicles secreted by a cell and have an intercellular communication role [108]. Such vesicles would be suited to containing therapeutic natural products and presenting a targeting capability due to a natural targeting capability that cell type provides. Immune evasion and better biocompatibility, especially important in systemic administration during cancer therapy, are also provided by biomimetic carriers, e.g., nanoparticles coated with cell membranes [109]. The enhanced bioavailability of nanoformulated natural products is one of the first benefits of such natural products. Numerous natural products, e.g., curcumin and resveratrol, are poorly water-soluble and their bioavailability is undermined by fast metabolism, thus restricting their utility as therapeutics. Nanoformulations make them soluble, stable and resistant to enzymatic degradation and make them stay longer in the blood stream [110]. Also, nanocarriers can be altered to have targeting ligands, e.g., antibodies or peptides, that recognise prostate cancer-specific markers (e.g., prostate-specific membrane antigen (PSMA) and integrins), which would allow them to accumulate in prostate cancer tissue and minimise systemic toxicity [111].
Many research findings point that nanoformulated natural products are effective in prostate cancer models. In one example, curcumin-encapsulated liposomes exhibit cellular internalization and pro-apoptotic effect on prostate cancer cells, exhibiting higher cellular take up than free curcumin [112]. As well, encapsulation of resveratrol in polymeric nanoparticle has shown better anti-proliferative and anti-metastatic effect in vitro and in vivo [113]. A Green tea Polyphenol, Epigallocatechin gallate (EGCG), has also been effectively loaded into SLNs and dendrimers, enhancing its therapeutic index against prostate cancer xenografts. These nanoformulations are not only able to increase the pharmacological activities of natural products, but also could overcome the drug resistance processes through targeting cancer stem cells and regulating the important signaling processes [114] (Table 2, Ref. [115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131]).
| Serial number | Nanocarrier | Strengths | Weaknesses | Prostate-specific challenges/translational notes | Representative preclinical examples (natural + chemo) | Representative clinical/translational studies | References |
| 1 | Liposomes | Biocompatible; clinical precedent; load hydrophilic/amphiphilic drugs; PEGylation improves circulation | Limited payload for very hydrophobic drugs; heterogeneous tumour penetration; opsonization (unless stealth) | Good for systemic delivery but EPR in prostate tumours is variable; bone metastases require additional targeting | Curcumin-liposomes; honokiol-liposomes showing improved uptake and apoptosis in PCa models. | Liposomal platforms have entered clinical studies for various tumors; PSMA-targeted liposomal docetaxel (BIND-014) reached phase I/II in mCRPC (shows activity/tolerability). | [115, 116] |
| 2 | Polymeric nanoparticles (e.g., PLGA) | Controlled/sustained release; robust surface functionalization; good for co-delivery | Potential biodegradation variability; scale-up and GMP complexity | Allow ligand targeting (PSMA, CD44), helpful to reach PCSC niches; careful design needed for bone tropism | Resveratrol-polymeric NPs + paclitaxel (preclinical co-delivery improved tumour control). | Several polymeric platforms evaluated in early translational studies and oncology trials; no widely adopted polymeric phytochemical product in PCa yet. | [117, 118] |
| 3 | Solid lipid nanoparticles (SLN) | Good for lipophilic natural products; enhanced circulation; relatively simple formulation | Limited drug loading for some cargos; stability and burst release issues | Useful for EGCG/quercetin delivery in xenografts; heat/bone microenvironment may alter release | EGCG-SLNs, quercetin-SLNs showing improved efficacy in TRAMP/xenograft models. | Mostly preclinical; limited clinical translation to date in prostate cancer. | [119, 120] |
| 4 | Dendrimers | Precisely defined structure; multivalent surface for ligand conjugation; high payload density | Potential toxicity (cationic dendrimers); complex synthesis; regulatory hurdles | Multivalency supports PCSC marker targeting (CD44/CD133); toxicity needs addressing before clinical use | EGCG + cisplatin dendrimer (dual pH/ROS responsive) showed selective PCSC targeting in vitro. | Mostly preclinical; translational path requires toxicity mitigation. | [121] |
| 5 | Micelles | Excellent solubilization of hydrophobic phytochemicals; small size for tumour penetration | Less stable in circulation; premature drug release risk | Useful for small hydrophobic phytochemicals that need deep tumour penetration; circulation stability must be engineered | Berberine-docetaxel micelles showed enhanced antitumor effect in PCa models. | Preclinical examples dominate; engineered micelles in clinical oncology exist but limited PCa data. | [122, 123] |
| 6 | Exosomes/ biomimetic (cell-membrane coated) | Natural biodistribution; immune evasion; intrinsic targeting signals | Cargo loading control, batch variability, regulatory/manufacturing challenges | Potential to target metastatic niches and immune-suppressive microenvironment; promising for theranostics but translational complexity is high | Ursolic acid delivered via exosomes in orthotopic PCa models; engineered exosomes targeted NEPC in recent preclinical work. | Diagnostic exosome tests (ExoDx) are clinically used for PCa detection/triage; therapeutic exosomes are in early translational/first-in-human studies. | [124, 125] |
| 7 | Mesoporous silica nanoparticles (MSNs) | High surface area and loading; tunable pore release; easy surface modification | Potential long-term bioaccumulation; biocompatibility concerns | Good for co-delivery (curcumin + paclitaxel) with triggered glutathione release to target PCSCs in hypoxic niches | Curcumin + paclitaxel MSN (glutathione-responsive) depleted ALDH1+ cells in preclinical models. | Preclinical stage; translational concerns about silica clearance remain. | [126, 127] |
| 8 | Lipid-polymer hybrid NPs | Combine advantages of lipids + polymers (stability + biocompatibility); tunable release | More complex manufacture; regulatory pathway less established than simple liposomes | Suitable for co-delivery and surface targeting to PSMA/CD44; can be engineered for bone homing ligands | Resveratrol + temozolomide lipid-polymer NP (pH-sensitive) showed apoptosis and migration inhibition in PCSC models. | Mostly preclinical; strong potential for translation. | [128, 129] |
| 9 | Magnetic/ theranostic NPs | Allow imaging + therapy (magnetothermal ablation); multimodal theranostics | Need external triggers; safety and off-target heating risk | Potential to ablate PCSC-rich lesions and track biodistribution; requires image guidance for bones/CNS | Quercetin + doxorubicin magnetic NP (magnetothermal + pH responsive) targeted CD44/CD133 in preclinical models. | A few early translational theranostic studies exist; not yet standard in PCa. | [130] |
| 10 | Nanogels/ hydrogel nanoparticles | High water content, excellent biocompatibility, allow enzyme/pH responsiveness | Potentially large size if not optimized; manufacturing complexity | Enzyme/pH dual responsive nanogels showed spheroid inhibition and improved drug sensitivity in PCSC models promising for intratumour/local delivery to bone lesions | EGCG + cisplatin nanogel inhibited spheroid formation and enhanced drug sensitivity (preclinical). | Preclinical; potential for loco-regional therapy strategies. | [124, 131] |
| SLN, Solid Lipid Nanoparticle; PLGA, Poly(lactic-co-glycolic) acid; PEG/PEGylation, Polyethylene Glycol/PEG-surface modification (improves stability & circulation time); EPR, Enhanced Permeability and Retention (passive tumor targeting effect); PSMA, Prostate-Specific Membrane Antigen; CD44/CD133, Cluster of Differentiation markers (prostate cancer stem cell markers); EpCAM, Epithelial Cell Adhesion Molecule; ALDH1, Aldehyde Dehydrogenase 1 (CSC marker enzyme); NEPC, Neuroendocrine Prostate Cancer; MSNs, Mesoporous Silica Nanoparticles; NPs, Nanoparticles; ROS, Reactive Oxygen Species; SPIONs, Superparamagnetic Iron Oxide Nanoparticles (used in imaging/theranostics); TEADs, TEA Domain transcription factors (partners of YAP/TAZ signaling); AR, Androgen Receptor; HIF-1α, Hypoxia-Inducible Factor 1-alpha (angiogenesis regulator); VEGF, Vascular Endothelial Growth Factor. |
The natural products delivery systems based on the use of nanotechnology has greatly improved the use of natural products in treating prostate cancer. Also, because of a combination of mitigation of pharmacokinetic constraints and targeted delivery, nanocarriers boost the efficacy and safety of bioactive compounds. The further study of the optimization of those nanocarriers, as well as their clinical implementation, has great potential in making the therapy of prostate cancer more successful. Table 3 (Ref. [80, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150]) summarizes the key details on the progress in Nanotechnology-Enabled Delivery of Natural Products in Prostate Cancer Therapy.
| Serial number | Natural Product | Nanocarrier Type | Class of Compound | Target/Mechanism in PCa | Advantages of Nanoformulation | Preclinical Models | Preclinical Animal Models | Clinical Trials | References |
| 1 | Curcumin | Liposome | Polyphenol | Induces apoptosis; inhibits NF-κB | Improved stability and cellular uptake | PC-3, DU145 cells | Nude mouse xenografts | Multiple clinical trials in PCa prevention and therapy | [132] |
| 2 | Resveratrol | Polymeric Nanoparticles | Stilbene | Anti-proliferative; inhibits PI3K/AKT | Controlled release and enhanced bioavailability | LNCaP xenograft mice | Athymic mouse model | Clinical trials in PCa prevention and metabolic health | [132] |
| 3 | EGCG | Solid Lipid Nanoparticles | Catechin | Downregulates androgen receptor signaling | Prolonged circulation and tumor targeting | TRAMP mouse model | TRAMP mice | Clinical trials in PCa chemoprevention | [80] |
| 4 | Quercetin | Dendrimers | Flavonoid | Suppresses PSA and AR signaling | Enhanced solubility and bio-distribution | PC-3 cells | Mouse xenografts | Limited human studies; not PCa-specific | [133] |
| 5 | Berberine | Micelles | Isoquinoline alkaloid | Inhibits telomerase and induces apoptosis | Improved water solubility and cellular uptake | DU145 cells | Rat xenografts | Clinical trials in metabolic disorders; not PCa | [134] |
| 6 | Honokiol | Liposome | Lignan | Targets cancer stem-like cells | Enhanced delivery across membranes | PC-3 xenografts | Nude mice | No clinical trial in PCa | [135] |
| 7 | Genistein | Polymeric Nanoparticles | Isoflavone | Inhibits cell cycle via AKT/mTOR | Controlled and sustained release | LNCaP and PC-3 cells | Mouse xenografts | Clinical trials in PCa prevention and therapy | [136] |
| 8 | Silibinin | Solid Lipid Nanoparticles | Flavonolignan | Inhibits migration, angiogenesis | Enhanced tumor accumulation via EPR effect | Orthotopic PCa model | TRAMP and xenografts | Clinical trials in PCa chemoprevention | [137] |
| 9 | Apigenin | Dendrimers | Flavone | Inhibits HIF-1α and VEGF pathways | Site-specific targeting with surface modification | DU145 and LNCaP cells | Nude mouse models | No PCa-specific trials | [138] |
| 10 | Thymoquinone | Micelles | Quinone | Induces ROS-mediated apoptosis | Increased plasma half-life and tumor specificity | PC-3 cell line | Xenograft mice | Trials in metabolic and inflammatory disorders; not PCa | [139] |
| 11 | Luteolin | Liposome | Flavone | Suppresses Notch and AR pathways | Improves solubility and endocytosis | LNCaP cells | Nude mouse xenograft | No PCa-specific trials | [140] |
| 12 | Betulinic acid | Polymeric Nanoparticles | Triterpenoid | Triggers mitochondrial apoptosis | Enhanced permeability and retention | DU145 xenografts | Nude mice | Early cancer trials (non-PCa) | [141] |
| 13 | Diosgenin | Solid Lipid Nanoparticles | Steroidal saponin | Anti-proliferative, suppresses invasion | Stable and high drug-loading | TRAMP mouse model | TRAMP mice | No PCa-specific trials | [142] |
| 14 | Ursolic acid | Exosomes | Pentacyclic triterpenoid | Targets PI3K/AKT and NF-κB | Natural targeting and immune evasion | PCa orthotopic model | Mouse orthotopic models | Phase I/II in solid tumors, not PCa | [143] |
| 15 | Baicalein | Biomimetic Carriers | Flavone | Inhibits EMT and CSCs | Improved bioavailability and biocompatibility | PC-3 and DU145 | Mouse xenografts | No PCa-specific trials | [144] |
| 16 | Withaferin A | Polymeric Nanoparticles | Steroidal lactone | Suppresses vimentin and AKT/mTOR signaling | Enhanced cellular uptake and tumor suppression | PC-3 and LNCaP | Xenograft mice | No PCa trials; studied in other cancers | [145] |
| 17 | Ginsenoside Rg3 | Liposome | Triterpenoid saponin | Induces apoptosis, anti-angiogenesis | Improved systemic delivery and tumor accumulation | LNCaP xenograft | Nude mice | Clinical trials in lung and gastric cancers; not PCa | [146] |
| 18 | Piperine | Solid Lipid Nanoparticles | Alkaloid | Enhances curcumin uptake and apoptosis | Increased synergism and bioavailability | PC-3 and DU145 | Mouse xenograft | Human trials in drug metabolism enhancers; not PCa | [147, 148] |
| 19 | β-Caryophyllene | Micelles | Sesquiterpene | Inhibits cell growth via p53 activation | Increased solubility and drug retention | DU145 cells | Rat xenografts | No clinical trials | [149] |
| 20 | Gambogic acid | Dendrimers | Xanthonoid | Inhibits NF-κB and induces cell cycle arrest | Enhanced cytotoxicity and tumor targeting | Prostate cancer mouse model | BALB/c nude mice | Phase II trials in solid tumors (China); not PCa | [150] |
| NP, Nanoparticle; SLN, Solid Lipid Nanoparticle; EMT, Epithelial-to-Mesenchymal Transition; AR, Androgen Receptor; PSA, Prostate-Specific Antigen; PI3K, Phosphoinositide 3-Kinase; AKT, Protein Kinase B; mTOR, Mechanistic Target of Rapamycin; NF-κB, Nuclear Factor kappa-light-chain-enhancer of activated B cells; HIF-1α, Hypoxia-Inducible Factor 1-alpha; VEGF, Vascular Endothelial Growth Factor; CSC, Cancer Stem Cells; PCa, Prostate Cancer; TRAMP, Transgenic Adenocarcinoma of Mouse Prostate (mouse model); BALB/c nude mice, Immunodeficient laboratory mice (BALB/c strain) lacking T cells. |
5. Synergistic nanomedicine approaches for targeting prostate cancer stem cells
Reoccurrence and resistance to the conventional therapies of prostate cancer has been an ongoing problem, therefore, much scientific effort has been concentrated on PCSCs, a unique subpopulation of tumor-initiating cells with self-renewing, pluripotent, and extraordinary tumor propagating ability [151]. The cells that make up PCSCs are highly resistant to conventional chemotherapeutic drugs because of their quiescence, amplified DNA repair processes, and drug efflux transporters expression [27, 151]. This causes them to survive during the initial therapy, hence causing relapse and metastasis of the disease. To resolve this hurdle, scientists have created synergistic nanomedicine strategies that concentrate on comodulation of natural products and conventional chemotherapeutics. Natural compounds, like curcumin, resveratrol, quercetin, and epigallocatechin gallate, target multiple signaling pathways implicated in stemness, proliferation and chemoresistance, such as Wnt/β-catenin, Notch, Hedgehog, and PI3K/AKT [18, 152]. In a nanocarrier system in which traditional cytotoxic drugs like docetaxel or paclitaxel are co-delivered with natural compounds, these natural compounds have a sensitization effect upon PCSCs to chemotherapy, diminish drug resistance, and lead to an increase in therapeutic response. This bilateral approach has shown more apoptosis and tumor shrinkage in preclinical models, the added advantage being that the use of a controlled drug release and selective biodistribution greatly reduces systemic toxicity [153].
In this respect, another significant breakthrough in the field is the development of multifunctional and stimuli-responsive nanocarriers, which provide a much greater precision of drug delivery to PCSCs [154]. These nanocarriers are designed to have intelligent properties which enable them to respond to a select stimulus that is available in the tumor microenvironment, such as low pH, high glutathione level or overexpressed enzyme. As an example, redox-responsive or pH-sensitive liposomes or polymeric nanoprobes can resist the environment of the systemic circulation, but they should disintegrate or swell at the tumor location and hence discharge their drug content specifically in the cancerous tissue [154]. This specific release is less of a waste of the drugs and does not cause impact at the wrong place, ensuring that a maximum effect of the therapeutic agents is created at the right location. On the other hand, multifunctionality in the nanocarrier systems involves, besides using imaging agents to monitor the real-time activity, introduction of stealth coatings to avoid immune clearance, and also loading dual/triple-drugs to carry out combinatorial therapies [155]. A good example is a pH- and redox-responsive nanoplatform, which has a delivery of both a chemotherapeutic drug and phytochemical, which increases its intracellular uptake and induces synergistic killing of PCSCs. In addition, there are highly developed platforms that have photothermal or photodynamic therapy and the delivery of drugs, thus providing multi-modal therapy approach. These new generation nanocarriers mark a major leap to the development of a strategy in eliminating PCSCs and drug resistance in prostate cancer [156].
The ability to deliver nanomedicine to PCSCs via molecular ligands is a key factor of effective nanomedicine-based approach. Various surface markers, including CD44, CD133, ALDH1, and EpCAM, are strongly expressed in PCSCs and therefore useful targets in ligand-based delivery system [157]. Conjugation of ligands (such as monoclonal antibodies, aptamers, peptides or small-molecules) to the surface of nanocarriers have enabled researchers to selectively target and bind to PCSCs to increase drug accumulation and retention in the tumor stem cell niche [158]. An example is aptamer-coated nanoparticles with specificity to CD133 which have shown a high binding affinity, successful cellular internalization and enhanced apoptosis induction on PCSC populations [157, 159]. Compared to this, CD44-linked liposomes proved to be able to inhibit PCSCs proliferation, movement, and self-renewal potential. Such ligand-directed approaches do not only enhance the therapeutic index of nanomedicine constructs, but also enable the downstream of pluripotent-related pathways and metastasis inhibition [160]. Notably, such methods preserve normal cells and have minimal systemic side effects, which complies with precise oncology tenets. Taken together with the co-delivery of natural products and the smart characteristics of stimuli-responsive carriers, targeted nanomedicine platforms integrate a potent and wide-ranging approach to the clinical problem of PCSC-mediated resistance. A combination of such synergistic measures collectively heralds a paradigm shift in the treatment of prostate cancer, and provides cause of optimism that we will see more lasting responses, less likely recurrence, and an increase in patient survival.
Table 4 (Ref. [157, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176]) puts the spotlight on some typical examples of synergetic nanotherapeutic approaches that act to target PCSCs successfully. These strategies are based on the combination of the natural bioactive compounds with the common chemotherapeutic agents; they are co-encapsulated with the advanced carriers. The table serves to demonstrate the heterogeneity of nanocarrier platforms, such as liposomes, polymeric nanoparticles, dendrimers, and mesoporous silica nanoparticles, with a multi-functional, or stimuli responsive character to improve therapeutic specificity and precise drug release. In addition, such nanocarriers are conjugated to targeting agents (antibodies, aptamers, peptides) and/or bind to PCSC-surfaced markers (e.g., CD44, CD133, ALDH1, EpCAM) on cells. The combination of co-delivery, responsive release, and molecular targeting demonstrates considerable enhancement of drug uptake, apoptosis programming, self-renewal detainment, and tumor recreating in the preclinical trials. This table provides an overall overview of the current developments and provides breakthroughs into how nanotechnology-based combinatorial treatments of prostate cancer will pan out translator-wise.
| Serial number | Nanocarrier Type | Co-Delivered Agents | Stimuli-Responsive Feature | Targeting Ligand | PCSC Marker Targeted | Therapeutic Outcome | References |
| 1 | Liposome | Curcumin + Docetaxel | pH-sensitive | Anti-CD44 antibody | CD44 | Enhanced apoptosis and reduced PCSC self-renewal | [157] |
| 2 | Polymeric nanoparticle | Resveratrol + Paclitaxel | Redox-sensitive | CD133 aptamer | CD133 | Improved drug uptake and stem cell inhibition | [161, 162] |
| 3 | Solid lipid nanoparticle | Quercetin + Doxorubicin | Enzyme-sensitive | EpCAM peptide | EpCAM | Synergistic cytotoxicity and tumor growth suppression | [163, 164] |
| 4 | Dendrimer | EGCG + Cisplatin | Dual pH/ROS-responsive | CD44 aptamer | CD44 | Selective PCSC targeting and minimal systemic toxicity | [165, 166] |
| 5 | Mesoporous silica nanoparticle | Curcumin + Paclitaxel | Glutathione-sensitive | Anti-ALDH1 antibody | ALDH1 | Depletion of PCSCs and sensitization to chemotherapy | [167, 168] |
| 6 | Micelle | Berberine + Docetaxel | Thermo-sensitive | CD133 antibody | CD133 | Enhanced antitumor effect and reduced recurrence | [162, 169] |
| 7 | Lipid-polymer hybrid NP | Resveratrol + Temozolomide | pH-sensitive | Anti-CD44 antibody | CD44 | Induced apoptosis and inhibited migration of PCSCs | [157, 170] |
| 8 | Magnetic nanoparticle | Quercetin + Doxorubicin | Magnetothermal + pH-responsive | CD44/CD133 dual aptamers | CD44 & CD133 | Targeted ablation of PCSCs and bulk tumor reduction | [171, 172] |
| 9 | Nanogel | EGCG + Cisplatin | Enzyme/pH dual-responsive | CD133 aptamer | CD133 | Inhibited spheroid formation and enhanced drug sensitivity | [173, 174] |
| 10 | Polymer-lipid nanoplatform | Silibinin + Paclitaxel | Acid-sensitive | Anti-EpCAM antibody | EpCAM | Reduced PCSC viability and metastatic potential | [175, 176] |
| NP, Nanoparticle; CD44, Cluster of Differentiation 44 (CSC surface glycoprotein); CD133, Cluster of Differentiation 133 (Prominin-1; CSC marker); ALDH1, Aldehyde Dehydrogenase 1 (enzyme; CSC marker); EpCAM, Epithelial Cell Adhesion Molecule; PCSCs, Prostate Cancer Stem Cells; CSC, Cancer Stem Cells. |
6. Clinical translation and challenges
Although, natural product based nanomedicines have demonstrated good preclinical performance in targeting PCSCs, little clinical translation has been achieved [177]. Clinical trials have been conducted to establish the effectiveness of natural products, including resveratrol, curcumin, and granting, on prostate cancer, although their effectiveness has been impeded due to low bioavailability and high rate of metabolism, among a few [157, 178]. In order to resolve those shortcomings, nanocarrier-based delivery platforms have been proposed and tested in the early-stage clinical trials [179]. Chemotherapeutic agents (Liposomal versions of them) and compounds derived naturally in plants have enhanced the pharmacokinetics and limited the drug toxicities in patients, but trials were limited to examine nanomedicine and specifically attack PCSCs [180]. The investigations that are currently conducted regarding nanoparticle-based delivery into prostate cancer are at early phases, and there is no detailed information concerning their safety and efficiency in the long term. As a result, available studies on the combination of natural products with nanocarriers of clinical nature are still poorly developed [181, 182].
The most urgent questions that are faced by clinical translation, the safety, and biocompatibility of nanomedicine preparations deserve to be mentioned. Although natural products are believed to be non-hazardous, their interaction with synthetic carriers provides some concerns in the form of immunogenicity, off-target effects, and cumulative toxicities [183]. Regulatory agencies such as the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) demand full toxicological profiling, biodistribution experiments, and pharmacodynamic testing, prior to approval. Moreover, there are no uniform procedures to assess the conduct of nanoparticles in biological systems, making the regulatory acceptance even more difficult [184]. The next level of complexity is associated with different cell compositions of PCSC populations, which could be heterogeneous in their responsiveness to any causal or therapeutic interventions, so stratification of the patient population and personalized treatment is essential [185]. The evaluation of the treatment response and the optimization of the dosing regimen are hard to do effectively without reliable PCSCs-related biomarkers in the clinical practice.
Scalability of manufacturing and knowledge gaps are two related challenges to clinical translation, in addition to safety and regulatory obstacles. Commercial-scale production of nanocarriers with homogeneous size, surface characteristics, and drug loading capacity is also technically challenging and expensive [186, 187]. Industrial-scale production is complicated by batch-to-batch variability, storage stability problems, and the demand of sterile production facilities [187]. Furthermore, biological complexity of PCSCs and tumor microenvironment is not fully elucidated, as it produces a gap in optimal target identification and delivery [188]. Improved knowledge of the interaction between nanocarriers and human physiology, more concrete regulatory systems, and additional clinical evidence will be necessary in closing the bench-to-bedside gap in the context of prostate cancer nanomedicine.
7. Future perspectives and conclusions
The development in nanotechnology has produced auspicious horizons towards the precision therapy of prostate cancer and especially the PCSCs, which are key in the therapeutic resistant, recurrence, and metastasis. Into the future, personalized nanomedicine holds out the prospect of a revolutionary approach to treatments that are more specific, with less toxicity that by-passes a target. Based on patient-specific biomarkers as well as genetic profiling and the tumor microenvironment signature, the next generation of nanomedicines may be tailored to the patient to showcase natural targeting of PCSCs with increased specificity in a more accurate manner. These individualized methods would allow specific ablation of PCSCs to spare unaffected tissues, which may lead to efficacious treatment and an overall minimization of side-effects. Further, personalization can also be improved by introducing the concept of omics-based tools and artificial intelligence (AI) in the design of nanoparticle systems, to provide adaptive changes in response to dynamic changes in tumors at real-time.
There is also another promising trend of diagnostic therapeutics integration in terms of creating theranostic nanoplatforms. These multi-purpose nanosystems are able to detect, monitor, and treat PCSCs in the tumor microenvironment simultaneously. Theranostic nanoparticles usually contain imaging elements, most commonly quantum dots, superparamagnetic iron oxide nanoparticles (SPIONs) or near infrared dyes, in conjunction with a therapeutic compound so that drug delivery and therapeutic success can be tracked in real-time. In addition, clinicians can use such platforms to determine PCSC burden and treatment response, thus helping to make the necessary changes in treatment in time. Combination of those systems with non-invasive imaging systems like Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET), or optical imaging may be a revolution point in individual cancer management of prostate cancer patients. Moreover, on-target drug delivery that could be achieved using stimuli-responsive nanocarriers releasing therapeutic payloads upon exposure to tumor-specific stimuli, e.g., pH, redox gradients, and enzyme activity, could additionally lower off-target toxicity.
Hence, the future of prostate cancer treatment is in the capacity to adequately eliminate PCSCs and block the recurrence and metastasis of the disease. With the current nanoplatforms, there is a chance that emerging nanomedicine approaches, especially those that utilize immunotherapy or gene-editing systems such as Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein 9 (CRISPR/Cas9), can break inherent and acquired PCSCs resistance. Considering that research on nanoparticle engineering, their scale-up manufacturing, and clinical translation is advancing, regulatory issues and safety information on the long-term should be studied to guarantee safety in use of nanoparticles on the patients. The oncologists, nanotechnologists, regulatory organizations, and industry stakeholders will also need to work across disciplines to move these innovations to bedside. The next-generation nanotherapeutics would have a critical role in enhancing survival and the quality of life of advanced prostate cancer patients in case these problems are overcome.
8. Conclusions
The continuous struggle on the recurrence of prostate cancer, treatment resistance, and metastases highlights the importance of prostate cancer stem cells (PCSCs) in the progression of the cancer. The attack on PCSCs has come as a strategic way of neutralizing these barriers. Medicinal compounds found in plants are naturally produced, and have considerable promise in interfering with central pathways of the signaling related to PCSC persistence and survival. Nonetheless, they have not yet entered clinical use because of low solubility, poor bioavailability, and fast clearance of these compounds in the system. The nanotechnology field provides a new platform to get out of the challenge, and increases the delivery of these natural compounds to the tumor and stem cell niches, in addition to increasing their stability and specificity. These phytochemicals may then be accurately targeted to PCSCs via smart nanocarriers: liposomes, dendrimers, polymeric nano-particles and biomimetic systems that reduce off-target effects and maximize therapeutic benefit. Combination approaches using synergistic nanomedicine strategies, that can lead to the co-delivery of natural products and traditional chemotherapeutics, have demonstrated synergy in preclinical models, sensitizing PCSCs and chemosensitizing drug-resistant cells.
Although encouraging, the successful use of the strategies in clinical practice is dependent on several issues surrounding the long-term safety, regulatory clearance, scale-up production, and patient stratification. It is also important that interdisciplinary cooperation, the development of personalized therapies, artificial intelligence, and theranostic nanoplatforms allow improving and accelerating the clinical practice of these therapies. Altogether, a combination of natural products and nanotechnology has the revolutionary potential to eliminate PCSCs, lower the recurrence of prostate cancer, and provide better survival rates in patients across the world.
Availability of data and materials
All used data is fully presented in the manuscript.
Author contributions
DEU and EUA—conceived and designed the review. DEU, IB and SIE—conducted literature search. DEU, WAO and OPCU—performed figures generation. DEU and WAO—drafted the manuscript. All authors critically reviewed, edited, and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Acknowledgment
Not applicable.
Funding
This research received no external funding.
Conflict of interest
The authors declare no conflict of interest.
