Therapeutic potentials of plant‑based antioxidants on colorectal cancer: Challenges and perspectives (Review)

Introduction

Colorectal cancer (CRC) represents one of the most prevalent malignancies of the digestive tract. In 2020, CRC emerged as the third most diagnosed cancer worldwide and ranked second among global cancer mortality factors (1). Due to its insidious onset, most CRC patients present with advanced-stage disease at initial diagnosis, which limits opportunities for curative interventions such as surgical resection and local ablation (2). Consequently, the development and establishment of efficient multimodal therapeutic strategies have emerged as a research hotspot globally.

Current therapeutic modalities for CRC primarily encompass surgical resection, radiotherapy, chemotherapy and targeted therapy, which have demonstrably provided symptomatic relief, prolonged survival and improved the life quality of patients. However, adjuvant pharmacological treatment regimens for CRC, using chemotherapeutic agents such as irinotecan hydrochloride, 5-fluorouracil (5-FU), oxaliplatin and cetuximab, frequently induce irreversible damage to normal tissues and organs, accompanied by severe adverse reactions and toxic side effects (3). For instance, 5-FU administration may precipitate severe gastrointestinal reactions that exacerbate mucosal damage and related symptomatology (4). In addition, the emergence of drug resistance to cetuximab has progressively become a major clinical challenge requiring urgent attention (5). Therefore, developing effective yet low-toxicity therapeutic agents for CRC may constitute a pivotal strategy to enhance overall treatment efficacy.

Recent researches have elucidated that the pathogenesis of CRC involves the dysregulation of a number of cascading signaling pathways, including signal transducer and activator of transcription 3 (STAT3), transforming growth factor-β (TGF-β), phosphoinositide 3-kinase/protein kinase (PI3K/Akt) and Wnt/β-catenin, characterized by aberrant silencing or activation of specific targets (6). However, current pharmacological interventions for CRC predominantly focus on single-target therapies. While acknowledging the clinical efficacy of specific single-target agents in CRC management (such as immune checkpoint inhibitors), monotherapy targeting individual signaling cascades or biological markers generally fail to achieve optimal therapeutic outcomes. Naturally derived phytochemicals exhibit marked advantages in modulating signal transduction cascades through multi-target, multi-pathway and multi-effect mechanisms, thereby enhancing treatment efficacy and quality of life in CRC patients while effectively preventing recurrence and potentiating targeted drug performance (7). Notable examples include paclitaxel, the first plant-derived chemotherapeutic agent and camptothecin, another plant-based antineoplastic alkaloid, have shown promising clinical applications. These instances underscore the growing significance of natural product-derived chemicals in anticancer drug discovery and research.

Chronic inflammation and oxidative stress-induced damage are closely implicated in the initiation and progression of CRC. Under physiological conditions, the balanced production of reactive oxygen species (ROS) and their elimination by endogenous antioxidants maintains the body's oxidative-antioxidant equilibrium. However, during pathological states, various environmental and endogenous stressors stimulate excessive ROS generation, disrupting this equilibrium and triggering oxidative stress. The resultant oxidative stress induces macromolecular oxidation of proteins, lipids and DNA/RNA, leading to lipid peroxidation of biomembranes, denaturation of intracellular proteins and enzymes and DNA damage. These alterations compromise intestinal mucosal barrier integrity, ultimately promoting mucosal injury, colitis and colorectal carcinogenesis (8,9).

Over the past decade, numerous plant-based antioxidants (PBAs) with anticancer properties have been identified, such as curcumin and epigallocatechin gallate (EGCG) (10). Chemically, PBAs under investigation for CRC therapy comprise diverse structural classes including phenolics, polysaccharides, alkaloids and terpenoids (Fig. 1). While these monomer compounds have demonstrated promising antitumor activities in epidemiological, in vitro and preclinical studies across various malignancies, their combinatorial application in CRC chemotherapy remains underexplored and the precise synergistic antitumor mechanisms remain incompletely elucidated (11). As oncology enters the era of precision medicine, effective integration of research on PBAs against CRC to maximize their therapeutic potential represents an urgent priority in fundamental research.

Figure 1 Representative plant-based antioxidants with anti-CRC effects. Polyphenols: Curcumin, EGCG, resveratrol, oleuropein, quercetin, baicalin, hesperetin, luteolin; Vitamins: Vitamin E; Polysaccharides: Astragalus polysaccharides; Saponins: Ginsenoside Rg1, polyphyllin II; Alkaloids: Berberine; Quinones: Shikonin, emodin.

The present review elucidated the preventive and therapeutic effects of PBAs on the occurrence and progression of CRC from the foundational cellular mechanisms and clinical research. Various types of PBAs play roles by regulating the signaling pathways related to CRC and modulating the expression of target genes involved in these pathways. Rather than focusing solely on a class of plant compounds or herbal medicines that modulate the gut microbiota of CRC (12,13), the present review comprehensively detailed the classification and therapeutic effects of various plant-derived antioxidant monomer components with anti-CRC properties. The present review also provided a more comprehensive theoretical basis for further understanding of the molecular mechanism of PBAs in the treatment of CRC. Additionally, there are few clinical studies on the prevention and treatment of CRC using PBAs and they are still facing bioavailability and safety problems. Different drug delivery strategies and individualized treatment concepts have been developed and the present review highlighted and emphasized the limitations and challenges of current progress. It requires further investigation to explore and promote the efficacy of PBAs in CRC.

Foundational mechanisms of plant-based antioxidants

Antioxidant and redox homeostasis

The mutation and transformation of normal tissue cells into cancerous cells can be triggered by the accumulation of free radicals during early stages, with oxygen-derived free radicals subsequently participating in cancer progression. Free radicals produced by Enterococcus bacteria in the colon may directly induce colonic DNA mutations, thereby contributing to CRC development (14). Oxidative stress is widely thought to promote intestinal epithelial cell damage by inducing genetic instability, specific gene alterations and aberrant methylation, creating opportunities for colorectal carcinogenesis. Excessive ROS generation triggers tissue or intracellular oxidative stress, further inducing oxidative DNA damage. Increased DNA damage stimulates the uptake of ω-polyunsaturated fatty acids as a compensatory response (15). Concurrently, ROS activates both intrinsic mitochondrial-mediated and extrinsic death receptor-mediated apoptosis pathways, thereby promoting CRC initiation and progression (16).

Gingerol (6-Shogaol, 20 mg/kg/day, orally), compared with the control group [a mouse colorectal adenoma model induced by Azoxymethane (AOM) and dextran sulfate sodium (DSS)], reportedly demonstrates significant antioxidant stress effects by reducing levels of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), lipid peroxidation, myeloperoxidase (MPO) and nitric oxide (NO), while markedly enhancing activities of superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) (17). These effects collectively promote redox homeostasis restoration in colonic tissues. Curcumin activates intracellular redox reactions to induce ROS generation, which upregulates apoptotic receptors on tumor cell membranes. In addition, curcumin enhances the expression and activity of p53, a tumor suppressor that inhibits proliferation and promotes apoptosis. This compound also potently inhibits NF-κB and COX-2 activities, both linked to overexpression of anti-apoptotic genes such as Bcl-2. Curcumin further attenuates pro-survival PI3K signaling while increasing mitogen-activated protein kinase (MAPK) expression, stimulating endogenous ROS production, which may activate a ROS/KEAP1/NRF2/miR-34a/b/c cascade to suppress colorectal cancer metastasis (18).

Anti-inflammatory and immunomodulatory effects

Colitis-associated CRC (CAC) is now understood to develop from chronic inflammatory bowel disease (IBD) (19). During early intestinal inflammation and mucosal barrier disruption, luminal microbial antigens trigger immune cell chemotaxis to the colonic mucosa. These infiltrating cells secrete pro-inflammatory cytokines including IL-6, IL-1β, TNF-α and interferon-γ (IFN-γ), establishing a chronic inflammatory microenvironment. Concurrently, immune-derived reactive oxygen/nitrogen species, such as inducible nitric oxide synthase (iNOS), induce colonic epithelial DNA damage (20). Nuclear factor-κB (NF-κB) serves as a master regulator of inflammatory mediator production, with its hyperactivation critical for maintaining colonic inflammation and promoting epithelial dysplasia (21). Upon activation, inhibitors of NF-κB (IκBs) undergo phosphorylation and degradation, releasing the p65 subunit for nuclear translocation and pro-inflammatory gene transcription (22). To investigate the effect of Berberine (BBR) on intestinal inflammatory response in AOM/DSS-induced CAC mice, BBR (daily gavage of 100 mg/kg) markedly decreased the colonic levels of TNF α, IL-6 and IL-1β compared with the CAC group (daily gavage of 100 μl PBS). Furthermore, compared with the CAC group, the zonula occludens-1 (ZO-1), occludin and mucin-2 (MUC-2) mRNAs were markedly upregulated in response to BBR (23). These results indicated that BBR could improve colitis symptoms and epithelial injury in inflamed mucosa, inhibiting CAC development. Toll-like receptor 4 (TLR4), a pathogen recognition receptor expressed in colonic epithelia and lamina propria immune cells, activates downstream inflammatory pathways that exacerbate IBD-associated inflammation and tumorigenesis (24). Compared with the control group (constituting AOM/DSS-induced CAC mouse model), Rosmarinic acid (30 mg/kg/day; orally) markedly decreased 83.3% of the polypoid tumor number and inhibited COX-2 and iNOS protein levels in vivo. Furthermore, Rosmarinic acid (25 μM) competitively antagonizes TLR4, blocking NF-κB and STAT3 activation in HCT116 cells and HT29 cells exposed to the inflammatory microenvironment (25). This suppression reduces inflammatory mediator levels and confers chemo-preventive effects against CAC.

The intestine constitutes the most significant component of the human immune system, making the modulation of intestinal immune status to restore homeostasis a promising therapeutic approach for treating IBD and preventing CAC development. During intestinal inflammation, myeloid-derived suppressor cells (MDSCs) are recruited and activated in gut tissues, where they suppress dendritic cell antigen uptake/processing and subsequent CD4+ T cell proliferation/activation. This impairment compromises pathogen clearance at bacterial penetration sites, perpetuating chronic inflammatory stimuli (26). The resultant shift from acute to chronic inflammation creates a permissive microenvironment for tumor initiation.

Madecassic acid (MA), a triterpenoid compound isolated from Centella asiatica, blocks MDSC migration by inhibiting γδT17 cell activation and related chemokine expression. Compared with the control group (AOM/DSS mouse model) and the positive control group (5-amino-o-hydroxybenzoic acid, 5-ASA; 75 mg/kg/day, orally), orally administrated of MA (25 mg/kg/day) can markedly weaken the severity of CAC and reduce the incidence of tumors and 5-ASA only delays the progression of tumors (27). This intervention enhances antitumor immunity and suppresses CAC progression. Curcumin (20 μM) exerts dual actions by inducing CT26 tumor cell apoptosis and heat shock protein 70 expression while recruiting CD3+ T cells and F4/80+ macrophages to inhibit CRC growth (28). In addition, tumors from curcumin-treated rats (750 μg/kg, i.p. on days 21 and 26) were infiltrated with numerous activated lymphocytes, compared with the control group (untreated). The proteome alterations showed that curcumin suppresses Foxp3 expression while enhancing type II interferon production, skewing T cell differentiation toward Th1 phenotype and counteracting tumor immune evasion (29).

Cell cycle and apoptosis regulation

Dysregulation of cell cycle progression represents a critical mechanism underlying uncontrolled proliferation and malignant transformation of tumor cells, with aberrant activation of cell cycle checkpoints playing a pivotal role in this process. Overexpression of Cyclin D1 and Cyclin B1, key rate-limiting regulators for G1/S and G2/M phase transitions, respectively, disrupts cellular proliferation control, impairs differentiation and facilitates oncogenic progression (30). Consequently, targeted cell cycle arrest has emerged as a promising therapeutic avenue for cancer cell elimination. EGCG has been shown to downregulate mRNA expression of several cell cycle-related genes while enhancing expression of the cyclin-dependent kinase inhibitor p21 and apoptosis-associated death receptor 5 (31). Disrupted apoptotic processes compromise the equilibrium between apoptosis and proliferation in colonic epithelial cells, ultimately contributing to CRC development. It demonstrates that various PBAs exert anti-apoptotic effects via mitochondria-dependent apoptotic pathways, primarily by modulating the expression of cysteine-aspartic acid protease (caspase) family members and Bcl-2 family proteins (Fig. 2).

Figure 2 Signaling pathway diagram illustrating the mechanisms of plant-based antioxidants against CRC. Plant-based antioxidants exhibit significant efficacy in the prevention and treatment of CRC. Its molecular mechanisms of action encompass multi-targets, including NF-κB, TLR4, Wnt/β-catenin, PI3K/Akt and MAPK/ERK signaling pathways, which suppress chronic inflammation, alleviate oxidative stress, inhibit cell proliferation and angiogenesis, induce cell apoptosis and cell cycle arrest and regulate gut microbiota composition. CRC, colorectal cancer; NF-κB, nuclear factor kappa-B; TLR4, toll-like receptor 4; PI3K/Akt, phosphoinositide 3-kinase/protein kinase; MAPK/ERK, mitogen-activated protein kinase/extracellular signal-regulated kinase; LPS, lipopolysaccharide; IKBs, inhibitors of NF-κB; STAT3, signal transducer and activator of transcription 3; mTOR, mammalian target of rapamycin; ROS, reactive oxygen species; SCFAs, short chain fatty acids; iNOS, inducible nitric oxide synthase; COX2, cyclooxygenase-2; SOD, superoxide dismutase; CAT, catalase; HO-1, heme oxygenase 1; GSH, glutathione; GST, glutathione S-transferase; VEGF, vascular endothelial growth factor; FGF, fibroblast growth factor.

The cell viability assay showed that curcumin analogue, MS13 (1,5-Bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadien e-3-one) has a greater cytotoxicity effect on SW480 (EC50: 7.5±2.8 μM) and SW620 (EC50: 5.7±2.4 μM), compared with curcumin (SW480, EC50: 30.6±1.4 μM) and SW620, EC50: 26.8±2.1 μM). Subsequent analysis indicated that MS13 induced apoptosis by enhancing caspase-3 activity while reducing Bcl-2 protein levels, thereby suppressing CRC cell growth (32). Furthermore, a significant proportion of these phytochemicals activate mitochondrial apoptosis by targeting aberrant signaling cascades within cancer cells, including the PI3K/Akt, MAPK/extracellular signal-regulated kinase (ERK) and p38 MAPK pathways (Fig. 2). In addition, it has been established that EGCG inhibits tumor cell growth and apoptosis through the PI3K-Akt-Cyclin D1 and p53 signaling axes. Its pro-apoptotic mechanism also involves suppression of fasciclin-like arabinogalactan protein-mediated Jun N-terminal kinase (JNK) signaling, leading to increased BAX/Bcl-2 ratio (31). These findings collectively underscore the multi-targeted therapeutic potential of PBAs in CRC management through coordinated regulation of apoptosis-related proteins and oncogenic signaling networks.

Epigenetic modifications and miRNA regulation

Recent investigations have elucidated the biological activities of EGCG in inhibiting DNA methyltransferase (DNMT) and microRNA expression, which play pivotal roles in cancer therapeutics (31). EGCG reportedly suppresses DNMT activity via radical scavenging and antioxidant mechanisms, leading to demethylation and upregulated expression of tumor suppressor genes P16 and P21, ultimately inducing apoptosis and inhibiting tumorigenesis. Notably, treatment of EGCG (20 μg/ml) to head and neck cancer cell lines markedly reduced DNMT activity to 60% in SCC-1 and 80% in FaDu cells. An in vivo study demonstrated that administration of EGCG (0.5%, w/w) inhibited tumor growth in xenografts in nude mice (80%) compared with non-EGCG-treated controls (33).

During the progression of IBD, numerous miRNAs exhibit altered expression patterns and regulate the expression of related tumor suppressor genes and proto-oncogenes, exerting pro-carcinogenic effects by disrupting intestinal homeostasis. Substantial evidence supports the association between CAC and inflammation-induced aberrant miRNA expression. Pristimerin, a natural triterpenoid compound isolated from Celastraceae plants, alleviates intestinal inflammation symptoms in DSS-induced colitis models through intraperitoneal injection of 0.4 mg/kg daily for 5 days compared with the untreated model mice (34). This effect is mediated by inhibiting intestinal miRNA-155 expression and suppressing the NF-κB signaling pathway. Resveratrol, a naturally occurring stilbene compound, has been reported to markedly inhibit LoVo and SW480 cell viability by 50% at the concentration of 50 μM. Compared with control groups, Resveratrol treatment led to increased miR-769-5p expression and decreased MSI1 expression in CRC cells (35). This indicates that Resveratrol inhibits CRC cell proliferation and migration by activating the miR-769-5p/MSI1 pathway. The aforementioned studies overlap in their assertion that PBAs can attenuate intestinal inflammation and suppress CRC by targeting miRNAs, highlighting the need for developing more miRNA-targeted small molecule therapeutics to expand clinical treatment options.

Gut microbiota regulation

CRC patients exhibit marked alterations in gut microbiota composition and distribution, characterized by reduced beneficial bacteria and increased pathogenic species. Pathogens such as Escherichia coli, Fusobacterium, Streptococcus and Enterococcus promote colorectal carcinogenesis by secretion of oncogenic metabolites that induce DNA damage, amplify inflammation and activate proliferative signaling pathways (36). Conversely, probiotics and their metabolites (such as short-chain fatty acids, SCFAs) exert chemopreventive effects via anti-mutagenesis, proliferation suppression, apoptosis induction, mucosal barrier enhancement, inflammatory microenvironment modulation and immune activation (37,38). Gut microbiota can produce ROS or stimulate intestinal epithelial cells to produce ROS, thereby promoting tumorigenesis and development (39).

PBAs have shown promise in alleviating gut dysbiosis in CRC animal models. Compared with the NC group, an AOM/DSS induced CRC model group (PBS, 150 mg/kg/day) exhibited a marked reduction in colon length and an obvious increase in tumor count, while the curcumin treatment groups (CRC-Cur, 150 mg/kg/day) increased the length of the colon and markedly reduced the number of tumors. The intestinal flora and intestinal metabolites analysis showed that curcumin educed harmful bacteria (such as Ileibacterium, Monoglobus and Desulfovibrio) and increased the abundance of Clostridia_UCG-014, Bifidobacterium and Lactobacillus in AOM/DSS-induced CRC model mice (40). Patchouli essential oil (40 mg/kg/day) markedly reduced the number of polyps (47.14±15.66) compared with the control group (vehicle 0.5% carboxymethyl cellulose + 1% DMSO, 81.86±12.36) in ApcMin/+ mice while enhancing intestinal barrier integrity and alleviating the inflammatory microenvironment. This effect was associated with decreased abundance of pathogenic bacteria (Desulfovibrio, Mycoplasma genitalium and Clostridium difficile) and elevated fecal SCFAs, which upregulated SCFA receptors (GPR41, GPR43 and GPR109a) and peroxisome proliferator-activated receptor γ expression (41). Compared with a dextran sulfate sodium (DSS)-induced colitis group (daily gavage of PBS for 3 weeks with 2.5% DSS in drinking water for the last 6 days), an EGCG group (50 mg/kg) altered the gut microbiome of DSS-treated mice by increasing Akkermansia abundance and butyrate production. The alteration of gut microbiome further promotes anti-inflammatory effects and colonic barrier integrity (42). Current research on plant-based CRC prevention has mainly focused on microbiota modulation and metabolite production, with little emphasis on host-microbiota crosstalk mechanisms involving antitumor immunity and epithelial cell signaling. Accordingly, further investigations are warranted to elucidate these interactive pathways.

Unique anti-tumor effects of key plant-based antioxidants in CRC

Polyphenols

Curcumin

Curcumin, derived from the rhizome of Curcuma longa (turmeric), exhibits diverse biological activities including anti-cancer, antimicrobial, anti-inflammatory, antiviral, antioxidant, anti-aging, anti-diabetic and cardiovascular protective properties (43). Systematic meta-analyses show that curcumin has therapeutic potential for CRC, improves survival rates and enhances quality of life (44-46). Curcumin targets proliferating cancer stem-like cells (CSCs) within CRC premalignant adenoma and early-stage cancer tissues. Curcumin decreases the proportion of proliferating CSCs by direct binding to NANOG, thereby inhibiting tumor development (47). Moreover, Curcumin can inhibit CRC growth by inducing ferroptosis via regulation of p53 and SLC7A11/glutathione/GPX4 axis (48). Combining curcumin (50 μM) and metformin (40 μM) markedly suppresses the migration ability of HCT116 cells and promote ROS-induced cell death (49), which provides a potential option for CRC treatment. Overall, these findings indicate that curcumin plays an effective adjunct therapy for CRC on a number of molecular targets. However, its low bioavailability and rapid metabolism limit its clinical translation (46). Addressing these challenges through more studies, determining effective doses and improving formulations to enhance absorption is essential.

EGCG

The anti-cancer mechanisms of EGCG encompass angiogenesis inhibition, induction of tumor cell death and suppression of tumor growth.

EGCG downregulates the expression of HIF-1α, HIF-1β and VEGF in CRC cells, reducing tumor vascular density and effectively controlling tumor cell metastasis while inhibiting the PI3K/Akt signaling pathway (31). Furthermore, EGCG inhibits CRC cell proliferation and induces apoptosis by blocking the activation of the receptor tyrosine kinases family members EGFR, IGF-1R and VEGFR2 (50). In the Caco-2 cell line, EGCG (15 μM) downregulates the expression of MMP-2 and MMP-9 through a NOX1/EGFR signaling pathway-dependent mechanism, while directly inhibiting the enzymatic activity of MMPs, thereby effectively suppressing tumor cell invasion and metastasis (51). A fibril composed of EGCG and lysozyme (EGCG-LYS) demonstrated excellent siRNA delivery efficiency in in vitro experiments. It could effectively silence the expression of circMAP2K2 (hsa_circRNA_102415), thereby inhibiting the epithelial-mesenchymal transition (EMT)-like phenotype generated by circMAP2K2 through the protease-mediated PCBP1/GPX1 axis, inhibiting the activated AKT/GSK3β signaling pathway and achieving the goal of inhibiting the proliferation and metastasis of gastric cancer cells, which provides a new tool for the treatment of gastric cancer (52). Collectively, these findings demonstrate that EGCG effectively alleviates tumor angiogenesis and metastasis.

Apoptosis, a programmed cellular protective mechanism, represents the primary pathway for eliminating tumor cells through the induction of their programmed death. EGCG induces apoptosis in gastrointestinal tumor cells in a dose-dependent manner without affecting normal cell growth and it triggers cancer cell death through a number of pathways (31). Specifically, EGCG enhances the translocation of cytochrome c from the mitochondrial inner membrane to the cytoplasm, inhibits ATP synthesis, disrupts mitochondrial membrane potential, activates caspase cascades and promotes tumor cell apoptosis (53). Moreover, treatment with 10 μg/ml EGCG for 24 h induced apoptosis and markedly suppressed the proliferation in CACO-2 and CW-2 cells. The miRNA analysis showed that the expression of hsa-miR-187-5p in CW-2 cells was markedly downregulated following EGCG treatment (54). An in vitro dosage of 6 μM EGCG has an initial antagonistic effect on oxaliplatin cytotoxicity and increases the sensitivity of HCT116 and HT29 cells to subsequent oxaliplatin administration, which provides an adjunctive treatment for CRC with lower and safer doses of EGCG (55). EGCG also inhibits gastric cancer cell proliferation by targeting STAT3 to inhibit M2 macrophages polarization induced by PLXNC1-mediated exosomes (56). In an in vivo study, mice received intraperitoneal injections of EGCG at a dose of 50 μg/kg (0.1 ml) developed markedly smaller tumors than the control group treated with 0.1 ml PBS alone (54). While EGCG primarily antagonizes gastrointestinal tumors by inducing tumor cell apoptosis, the methods of triggering such apoptosis are complex and diverse, with a number of underlying mechanisms remaining unclear. Elucidating the molecular mechanisms of tumor apoptosis represents one of the significant future directions in cancer research to more effectively induce this process. Furthermore, EGCG can be administered orally or injected with an acceptable safety profile and its safe dose of antitumor effects still needs more reports.

Resveratrol

Resveratrol exerts multi-faceted effects on CRC through various mechanisms, including suppression of cell proliferation, inhibition of metastasis, induction of apoptosis, stimulation of autophagy, modulation of immune responses, alleviation of inflammation, regulation of gut microbiota and enhancement of other anticancer drug efficacy (57). The expression of pro-inflammatory cytokine tumor necrosis factor-β and its receptor activates nuclear transcription factor NF-κB, which participates in CRC cell growth and proliferation. Compared with HCT116 and SW480 cells in the control groups, resveratrol (5 μM) suppressed the cancer cell proliferation with the regulation of β1-integrin/FAK/p65-NF-kB pathway and cyclin D1-signaling. CRC cells treated with resveratrol markedly inhibited β1-integrin expression and reduced the distribution of β1-integrin receptors on the cell surface (58). In addition, high concentration (>10 μM) of resveratrol disrupted interactions between CRC cells and stromal cells within the multicellular tumor microenvironment, triggering apoptosis through promoting hyperacetylation of p53 and FOXO3a as post-translational substrates of Sirt-1 in the CRC tumor microenvironment (59). Furthermore, resveratrol markedly reduced serine/threonine kinase 1/2/3 (Akt1/2/3) phosphorylation, downregulated bone morphogenetic protein expression via PI3K/Akt signaling inhibition, upregulated STATB2 to promote Bax-Caspase 3/9 apoptotic pathway protein expression in HCT116 cells and induced CRC cell apoptosis (60).

Oxidative stress has been established as a pro-carcinogenic factor and resveratrol alleviates oxidative stress by up-regulating antioxidant enzymes. Reports suggest that resveratrol achieves therapeutic efficacy by inhibiting SOD activity or activating Nrf2-mediated antioxidant signaling pathways, thereby suppressing oxidative stress in CRC. Resveratrol (10 μmol/l) was found to activate Nrf2 and Sirt-1 to regulate cellular oxidation, reducing 5-FU-induced oxidative stress damage in normal cells at a 5 μg/ml concentration, demonstrating a dose-response relationship (61). Furthermore, in a murine cardiotoxicity model established via intraperitoneal injection of 5-FU at 15, 30 and 60 mg/kg, resveratrol was found to attenuate myocardial cell toxicity induced by 5-FU, showing potential in mitigating cardiac damage associated with long-term high-dose 5-FU treatment for CRC (62). Sprague-Dawley rats that received oxaliplatin (2 mg/kg/day, cumulative dose: 6 mg/kg, i.p.) and oral resveratrol (7.14 mg/kg/day) was found not to develop mechanical allodynia or hypersensitivity, which inhibited upregulation of NF-κB, TNF-α, AIF3 and excitatory neuronal promoter c-fos, while increasing expression of Nrf2, NQO-1, HO-1 and Sirt1. This combination restored the GSH/GSSG ratio, preventing and antagonizing chemotherapy-induced peripheral neuropathic pain (63).

Oleuropein

Oleuropein represents one of the primary phenolic compounds in olive leaf extracts. It has demonstrated that oleuropein exerts protective effects in acetic acid-induced ulcerative colitis in rats by inhibiting the production of intestinal inflammatory factors (64). There were three groups: Normal control, positive control (ulcerative colitis and untreated) and oleuropein group (treated with intrarectal oleuropein at a dose of 350 mg/kg). Compared with the positive control group, oleuropein resulted in a significant reduction of MPO and NO levels and increased SOD, CAT and GPX levels in colon tissues. Moreover, the expression levels of pro-inflammatory cytokines (IL-1β, TNF-α, IL-10, COX-2, iNOS and NF-κB) were also decreased in the oleuropein group. In the intestinal tissues of rats treated with oleuropein, expression of the pro-apoptotic gene Bcl-2-associated X protein was reduced, while the anti-apoptotic gene Bcl-2 was upregulated. These findings indicate that oleuropein alleviates inflammation by suppressing aberrant apoptosis of intestinal cells.

Flavonoids

Flavonoids represent a class of plant secondary metabolites characterized by a basic structure comprising two benzene rings interconnected via a three-carbon bridge, establishing a C6-C3-C6 configuration (65). Baicalin, a natural flavonoid, has been found to possess remarkable anti-CRC properties. Studies have revealed its capacity (at 100 μg/ml) to induce cell cycle G1 phase arrest in CRC cells, promote p53-independent apoptosis and suppress both endogenous and exogenous TGF-β1-induced EMT via inhibition of the TGF-β/Smad pathway (66). In an in vivo test, orthotopic transplanted colon tumor model mice were randomly divided into negative control, positive control (25 mg/kg of 5-FU), low dose group (100 mg/kg of baicalin) and high dose group (200 mg/kg baicalin), respectively. The low-dose baicalin group exhibited markedly tumor inhibition rates (ratios of average tumor size of treated groups and negative control group) compared with those in both positive control and high-dose baicalin groups. Hesperetin, a flavonoid primarily derived from citrus fruits, has been reported to prevent DSS-induced colitis. The mice were randomly divided into four groups: control group, DSS group, hesperetin treated group (20 mg/kg, injected daily intraperitoneally) and DSS with hesperetin treated group (20 mg/kg, injected daily intraperitoneally). The DSS group showed a lower weight and colon length compared with the control group, while these changes were rescued by hesperetin treatment. Hesperetin enhances intestinal expression of ZO-1, occludin and MUC-2, while reducing TNF-α, IL-6, IL-18, HMGB1 and IL-1β levels to exert intestinal protective effects (67). Further investigation revealed hesperetin's ability to decrease expression of receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL), two critical mediators of necroptosis pathways, suggesting its capacity to ameliorate DSS-induced intestinal inflammation through suppression of the RIPK3/MLKL necroptosis signaling cascade (67). This anti-inflammatory action preserves intestinal barrier homeostasis and inhibits intestinal tissue carcinogenesis driven by persistent inflammatory stimuli. Moreover, 50 or 100 mg/kg of luteolin has been found to markedly attenuate DSS-induced murine colitis symptoms compared with a DSS group, primarily by inhibiting JNK1/2, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling, NF-κB and STAT3 pathways to exert anti-inflammatory, anti-apoptotic and anti-autophagic effects for colonic homeostasis restoration (68).

Vitamins

Defects in intestinal mucosal antioxidant defense constitute the initiating factor in the pathogenesis of IBD, with oxidative imbalance in the intestinal mucosa further associated with disease activity and progression. Reduced plasma levels of vitamins A, E and β-carotene, coupled with decreased antioxidant enzyme activity in the intestinal mucosa, correlate with IBD severity and may serve as indicators of disease activity (69). Notably, vitamin E (δ-tocotrienol), a natural antioxidant, protects phagocytes and surrounding tissues from oxidative assault by free radicals generated from neutrophils and macrophages (70). This compound inhibits the elevation of free radicals produced during lipid and lipoprotein oxidative damage in IBD.

Polysaccharides

Polysaccharides, complex carbohydrate macromolecules formed through condensation and dehydration of a number of monosaccharide units, have recently attracted significant interest in their anti-CRC effects. Tao et al (71) investigated the anti-tumor activities of Dendrobium officinale polysaccharides, Astragalus polysaccharides and Lentinus edodes polysaccharides with varying molecular weights using a zebrafish xenograft model. Compared with the model group (inhibition 0±5.09%), the results indicated that all three polysaccharides inhibited the growth of HT29 cells in the xenograft model, with Dendrobium officinale polysaccharides (250 μg/ml) exhibiting the most significant inhibitory effect on CRC (67.91±1.69%). Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis suggested that their primary mechanisms may involve immunomodulation and induction of apoptosis. Astragalus polysaccharides, a major bioactive component in Astragalus membranaceus, primarily consist of arabinose, galactose, glucose, xylose and mannose (72). Compared with the AOM/DSS control group, in vivo studies revealed that middle doses (200 mg/kg) of Astragalus polysaccharides effectively improved CD8+ T cell function through modulation of the STAT3/Gal-3/LAG3 pathway to inhibit CRC development (73). These findings suggest that Astragalus polysaccharides may exert anti-CRC effects as a novel strategy for future clinical development of natural anti-tumor drugs.

Saponins

Ginsenoside Rg1, a bioactive component derived from the traditional Chinese medicine Panax ginseng, exerts therapeutic effects via modulation of various metabolic pathways of the gut microbiota, primarily by enhancing tryptophan metabolite levels to influence microbial tryptophan metabolism, thereby alleviating intestinal inflammation (74). Polyphyllin, a natural steroidal saponin derived from the traditional Chinese medicine Paris polyphylla, encompasses compounds such as Polyphyllin I, II, VI and VII, demonstrating significant anti-tumor, antimicrobial, antioxidant, sedative, analgesic, hemostatic, immunomodulatory and organ-protective effects, with particularly notable anti-tumor activities (75). Li et al (76) found that the percentages of the apoptotic cells for HCT116 cells increased from 4.7-35.2% in the control group and the Polyphyllin II treated group (4 μM) and for SW620 cells from 4.6-27.3% in the control group and the Polyphyllin II treated group. In vivo study showed Polyphyllin II (0.5 or 1 mg/kg, i.p. once every 3 days) suppressed HCT116 tumor growth in nude mice. Further mechanism study revealed that Polyphyllin II markedly induced G2/M-phase cell cycle arrest and apoptosis and reduced the expression levels of phosphorylated (p-)PI3K, p-Akt and p-mTOR in HCT116 and SW620 cells, promoting the expression of autophagy-related protein LC3B-II. Further increases in LC3B-II expression were observed upon treatment with the mTOR inhibitor rapamycin, indicating that Polyphyllin II induces tumor cell autophagy by inhibiting the PI3K/Akt/mTOR signaling pathway. Moreover, Polyphyllin II was found to induce tumor cell apoptosis by suppressing the Janus kinase 2/signal transducer and activator of STAT3 signaling pathway, exerting anti-CRC effects (76).

Alkaloids

Alkaloids are organic compounds containing one or more basic nitrogen atoms arranged in cyclic structures. Berberine, also known as berberrubine, is a quaternary ammonium isoquinoline alkaloid isolated from the traditional Chinese medicine Coptischinensis, demonstrating diverse biological activities including anti-tumor, anti-oxidant, anti-inflammatory, cholesterol-lowering, anti-diabetic, anti-obesity and anti-microbial properties (77). Its anti-cancer effects and mechanisms have been extensively studied, establishing it as a potential anti-cancer drug candidate. It has been reported that berberine alleviates AOM/DSS-induced intestinal barrier damage in mice, thereby reducing microbial invasion (78). In the AOM/DSS mice model, berberine was daily administered with a dose of 50 and 100 mg/kg and aspirin was the positive control. Compared with the AOM/DSS model group, berberine markedly reduced the number and load of tumors in mice. Furthermore, berberine suppressed inflammation and CRC development by increasing the abundance of short-chain fatty acid-producing bacteria and decreasing pathogenic bacterial populations (78). By reshaping the gut microbiota composition, berberine increased the expression of occludin and ZO-1, inhibited the activation of the p-NF-κB/p-STAT3 pathway, consequently impeding colorectal adenocarcinoma progression. Berberine's restorative mechanisms against oxidative stress-induced DNA damage have been demonstrated across murine models. In adenovirus-infected AOM/DSS mice administered with 28 mg/kg berberine for 5 weeks, berberine enhanced Dicer expression and reduced IL-6 expression, mitigating intestinal injury (79). Collectively, these findings indicate that berberine suppresses CRC progression by reducing inflammation-related chemotactic factors, enhancing antioxidant radical scavenging capacity and repairing DNA damage.

Terpenoids

Terpenoids represent a class of compounds composed of five-carbon isoprene units (C5H8), categorized based on the number of isoprene units into monoterpenes, sesquiterpenes, diterpenes, sesterterpenes, triterpenes, tetraterpenes and polyterpenes (80). Zingiberene, a sesquiterpene compound and the primary constituent of ginger essential oil, exhibits anti-cancer, antioxidant, antibacterial, anti-inflammatory and anti-angiogenic activities. In the aberrant crypt focus (ACF) rat model induced with 1.2 Dimethylhydrazine (DMH) at a 20 mg/kg dose, the experimental treatment group (DMH + Zingiberene at a 300 mg/kg concentration) showed decreased amount of AC in the distal region compared with the positive induction control group (81). It also has shown that zingiberene demonstrates specific activity against HT-29 cells with minimal effects on non-cancerous cells. It promotes the formation of autophagosomes in tumor cells, increasing LC3-II expression and decreasing p62 expression to induce autophagy (82).

Quinones

There has been burgeoning research interest in the potential of various plant-based quinone bioactive compounds for CRC drug development due to their promising therapeutic efficacy. Shikonin, a naphthoquinone component primarily sourced from the traditional Chinese medicinal herb Lithospermumerythrorhizon, activates ROS-mediated endoplasmic reticulum stress to notably inhibit HCT116 cell proliferation. In addition, 1.5 μM shikonin markedly inhibited the HCT116 cell colonies compared with the control group. In the HCT116 xenograft mouse model, a dose of 3 mg/kg (i.p.) shikonin effectively inhibited tumor growth by 52.3% in vivo. Moreover, shikonin downregulates Bcl-2 expression and activates cleavage of caspase3/9 and PARP to induce apoptosis (83). Emodin is a natural anthraquinone compound with antioxidant, anti-inflammatory and anti-tumor properties. In AOM/DSS-induced models, emodin (50 mg/kg) reduced recruitment of inflammatory cells, expression of cytokines and pro-inflammatory enzymes in the tumor microenvironment while enhancing CD3+ T lymphocyte levels. In addition, emodin decreased viability, migration and fibroblast-induced invasion capacity of SW-620 and HCT116 cells in vitro (84).

Current challenges and progress in clinical research

PBAs have shown promising therapeutic effects in CRC cell lines and animal models. Several clinical trials investigating the prevention and treatment of CRC with PBAs have been conducted (Table I). Carroll et al (85) assessed the effects of oral curcumin (2 g/day or 4 g/day for 30 days) on PGE2 within ACF in a nonrandomized, open-label clinical trial. Colonoscopy revealed no significant ACF reduction in the 2 g/day group, whereas the 4 g/day group showed a 40% reduction. Cruz-Correa et al (86) evaluated the regress adenomas effects of curcumin (480 mg/day) and quercetin (20 mg/day) in 5 post-colectomy familial adenomatous polyposis (FAP) patients. Colonoscopy demonstrated a 60.4% reduction in polyp number and a 50.9% decrease in size compared with baseline. While this study showed prominent therapeutic effects, a subsequent larger trial involving 44 FAP patients found no significant differences in polyp number or size (87). Panahi et al (88) assessed the effects of curcumin in 67 stage III CRC patients with chemotherapy after the surgery. The results demonstrated that 8-week curcuminoids capsules (500 mg daily) improved erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP) levels, while also enhancing the quality of life in stage III CRC patients Compared with the control group taking placebo capsules. The effect of curcumin on the prognosis of CRC patients remains unclear. Several completed clinical trials (NCT02439385, NCT01490996 and NCT01948661) are expected to provide further elucidation upon publication of their results.

Table I Clinical researches of PBAs.

Table I

Clinical researches of PBAs.

First author/s, year	Type of PBA	Type of study	Patients	Group	Outcomes	(Refs.)
Carroll et al, 2011	Curcumin	Open-label trial	44 eligible smokers with 8 or more ACF on screening colonoscopy	2 g/day or 4 g/day for 30 days	No significant ACF reduction in the 2 g/day group, 40% reduction in ACF number in the 4 g/day group	(85)
Cruz-Correa et al, 2006	Curcumin	Single-arm trial	5 post-colectomy FAP patients	Curcumin (480 mg/day) and quercetin (20 mg/day)	60.4% reduction in polyp number and 50.9% decrease in size compared with baseline	(86)
Cruz-Correa et al, 2018	Curcumin	Randomized controlled trial	44 FAP patients who had not undergone colectomy	Curcumin (1,500 mg orally, twice per day) or identical-appearing placebo capsules for 12 months	No significant difference in mean polyp size between the curcumin group and the placebo group	(87)
Panahi et al, 2021	Curcumin	Randomized controlled trial	67 stage III CRC patients with chemotherapy after the surgery	Treatment group receiving curcuminoids capsules (500 mg/day) (n=36), or the control group taking placebo capsules (n=36) for 8 weeks	A significant change in CRP and ESR in treatment group. A significant improvement in functional and global quality of life in treatment group	(88)
Patel et al, 2010	Resveratrol	Single-arm trial	20 CRC patients before surgical resection	0.5 or 1g daily for 8 days	5% reduction in tumor cell proliferation	(89)
Seufferlein et al, 2022	EGCG	Randomized controlled trial	1,001 patients with colon adenomas	EGCG (150 mg/day) or placebo groups over 3 years	No significant difference in adenoma rate between the EGCG group and the placebo group	(90)
Sinicrope et al, 2021	EGCG	Randomized controlled trial	39 patients with at least 5 rectal ACF	EGCG (780 mg/day) or placebo groups over 6 months	No significant differences in ACF number, total ACF burden and adenoma recurrence	(91)
Bonelli et al, 2013	Vitamin	Randomized controlled trial	411 post-polypectomy patients	Active compound (200 μg selenium, 30 mg zinc, 2 mg vitamin A, 180 mg vitamin C, 30 mg vitamin E) or a placebo daily for 5 years	39% reduction of the risk of recurrence in the intervention group Compared with the placebo group	(92)
Oliai Araghi et al, 2019	Vitamin	Randomized controlled trial	2,524 Participants aged 65 years and over with an elevated homocysteine Level	Folic acid (400 μg/day) and vitamin B12 (500 μg/day) vs. placebo over 2 to 3 years	Vitamin B12 were markedly associated with a higher risk of CRC	(93)
Greenberg et al, 1994	Vitamin	Randomized controlled trial	864 patients who had at least one histologically confirmed adenoma removed from the large bowel	Beta carotene (25 mg daily); vitamin C (1 g daily) and vitamin E (400 mg daily); or the beta carotene plus vitamins C and E; placebo	There was no evidence that either beta carotene or vitamins C and E reduced the incidence of adenomas	(94)
Gaziano et al, 2009	Vitamin	Randomized controlled trial	14,641 male physicians aged 50 years or older	400 IU of vitamin E every other day and 500 mg of vitamin C daily; placebo	Neither vitamin E nor vitamin C had a significant effect on CRC incidence	(95)
Wang et al, 2012	Vitamin	Randomized controlled trial	816 CRC patients and 815 controls	Dietary intakes of vitamin C and vitamin E were assessed by a PC-assisted interview regarding 148 food items	Intake of vitamin C and vitamin E were not related to CRC risk in either men or women	(96)
Ng et al, 2019	Vitamin	Randomized controlled trial	139 patients with advanced or metastatic CRC	mFOLFOX6 plus bevacizumab chemotherapy every 2 weeks and either high-dose vitamin D3 (n=69) or standard-dose vitamin D3 (n=70) daily	No significant improvement in progression-free survival between high-dose and standard-dose groups	(97)
Chen et al, 2020	Berberine	Randomized controlled trial	553 participants who had colorectal adenomas that had undergone complete polypectomy	Berberine (0.3 g twice daily) or placebo	Lower adenoma recurrence in the berberine group vs. the placebo group	(98)

[i] PBAs, plant-based antioxidants; ACF, aberrant crypt focus; FAP, familial adenomatous polyposis; CRC, colorectal cancer; ESR, erythrocyte sedimentation rate; EGCG, epigallocatechin gallate.

Patel et al (89) enrolled 20 CRC patients who received 0.5 g or 1.0 g/day resveratrol for 8 days before surgery intervention. Post-intervention tissue analysis revealed a 5% reduction in tumor cell proliferation. Further clinical trials (NCT00256334 and NCT00433576) have been conducted, with the results eagerly expected.

Seufferlein et al (90) investigated EGCG's preventive effects on CRC, with 1,001 colon adenoma patients randomized to EGCG (150 mg/day) or placebo groups. At 3 years, colonoscopy showed adenoma recurrence rates of 55.7% (placebo) vs. 51.1% (EGCG), with no statistical significance. Sinicrope et al (91) also studied EGCG's effects on 39 patients with 35 rectal ACFs, with no significant differences in ACF number, total ACF burden and adenoma recurrence observed. Several clinical trials (NCT02891538 and NCT01360320) investigating the preventive effects of EGCG have been completed, though their results remain unpublished.

The clinical evidence regarding vitamin supplementation for CRC prevention remains contradictory. Bonelli et al (92) demonstrated in a double-blind randomized trial that vitamins A, C and E could markedly reduce intestinal adenoma recurrence in patients with prior polypectomy. However, Oliai et al (93) reported that vitamin B12 could potentially increase risk of CRC. A number of relevant clinical trials have demonstrated no significant effects of vitamins on CRC outcomes. In Greenberg et al's study (94) of 864 adenoma patients, vitamin C and E supplementation showed no difference in adenoma incidence compared with placebo groups. Gaziano et al's large-scale trial (95) involving 14,641 male physicians found no effect of vitamin E and C on CRC incidence. Similarly, Wang et al (96) analyzed antioxidant vitamin C and E intake in 816 CRC patients vs. 815 controls, showing no association with cancer risk. Ng et al (97) evaluated vitamin D3 supplementation in advanced/metastatic CRC, revealing no significant improvement in progression-free survival (PFS) between high-dose and standard-dose groups. Ongoing clinical trials (NCT02969681, NCT01574027, NCT00905918 and NCT02603757) are currently underway, whose findings are expected to further clarify the role of vitamins in CRC.

A multicenter, double-blind, randomized controlled trial has demonstrated berberine's efficacy in CRC prevention. In this study, Chen et al (98) enrolled 1,108 patients with colorectal adenomas, which were randomly allocated to the berberine group (n=553, 0.3 g twice daily) and placebo group (n=555). Colonoscopy evaluation after a 2-year's follow-up revealed lower adenoma recurrence in the berberine group (n=155, 36%) compared with the placebo group (n=216, 47%). These results warrant validation through ongoing clinical trials (NCT03281096, NCT02226185 and NCT03333265).

Despite the potential anticancer effects demonstrated in preclinical studies, PBAs have not shown clear clinical benefits in CRC and their clinical translation faces a number of challenges. Indeed, low bioavailability is a critical limiting factor. For example, bioavailability of oral curcumin is <1% (99), with resulting concentrations in plasma much lower than the doses in vitro. Second, the core roles of PBAs in CRC remain unclear. While current research reveals a number of anti-tumor mechanisms (gene expression, signaling pathways and epigenetics) of PBAs in CRC, the heterogeneity across models (cell lines, animal species) and differences between models and human obscure the core mechanisms. Third, clinical trial design requires optimization. Dose selection lacks standardization: Carroll et al (85) found efficacy with 4 g/day curcumin, whereas a larger trial by Cruz-Correa et al (87) showed no benefit at 480 mg/day, highlighting the need for pharmacokinetic-guided individualized dosing. Moreover, the influence of patient heterogeneity on the anticancer effects of PBAs warrants further confirmation. For example, genetic backgrounds of FAP patients may affect curcumin response (86,87).

Directions for future research

Improving bioavailability represents the central goal for clinical translation of PBAs. Nano-drug delivery system has become a research focus in the context of PBAs given its ability to improve drug solubility, prolong circulation time and enhance tumor targeting (100,101). Currently, nanoparticles, nano micelles and liposomes are relatively reliable nano-drug delivery systems to improve the bioavailability of PBAs (Fig. 3).

Figure 3 Nano-drug delivery systems for plant-based antioxidants. (A) Drugs are encapsulated in nanoparticles. Surface modification of nanoparticles with PEG and ligands enhances their water solubility and targeting capability. (B) Liposomes have hydrophobic phospholipid bilayer and encapsulate drugs in central cavity. (C) Nano-micelles have hydrophilic shell and hydrophobic core, with drugs encapsulated in central cavity (101). PEG, polyethylene glycol.

Nanoparticles are generally classified into three classes: Inorganic, organic and carbon-based. Various strategies such as surface modification of nanoparticles with synthetic polymer polyethylene glycol (PEG) can improve the water solubility of nanoparticles (101). Zhang et al (102) developed erythrocyte membrane-coated resveratrol nanoparticles modified with PCL-PEG, markedly prolonging half-life of resveratrol. Sun et al (103) designed PEG-modified amphiphilic cyclodextrin nanoparticles for co-delivery of ginsenoside and quercetin, enhancing duration of drug in CRC models. In addition, designing nanoparticles according to the characteristics of PBAs represents an effective way to improve bioavailability.

Nanomicelles, self-assembled amphiphilic polymer structures, feature a hydrophilic shell to enhance pharmacokinetics and a hydrophobic core to encapsulate the drug and control release (104). Ran et al (105) encapsulated ginsenoside compound K in nanomicelles fabricated via ultrasonic self-assembly of O-carboxymethyl chitosan, N-isopropylacrylamide and thermoresponsive IR820. The nanomicelles markedly improved water solubility and bioavailability of ginsenoside. Zhu et al (106) incorporated silybin into Soluplus-PVPVA nanomicelles, enhancing the pharmacokinetics of silybin.

Liposomes are biocompatible and biodegradable spherical vesicles with hydrophilic cores and lipid bilayers (107). These structures serve as effective carriers for the delivery of PBAs. Notably, curcumin liposomes exhibit improved solubility and anticancer activity against CRC cell lines (82,108), with clinical studies confirming safety and tolerability in CRC patients (109).

Developing nano-drug delivery systems combining PBAs with chemotherapeutics is another direction of further research. Curcumin can reportedly reverse the resistance of CRC cell lines to 5-FU, irinotecan and oxaliplatin through a number of mechanisms (110,111). Quercetin can synergistically enhance the killing effect of doxorubicin, 5-FU and oxaliplatin on CRC cells (112-114). Rutin can alleviate ensartinib-induced hepatotoxicity (115). Howells et al (116) conducted a study of 28 patients with metastatic CRC receiving either FOLFOX alone or FOLFOX combined with curcumin. The results showed that the curcumin-FOLFOX combination exhibited favorable safety and superior clinical outcomes compared with FOLFOX. Therefore, the combination of PBAs and chemotherapeutic drugs may enhance the therapeutic effect of chemotherapeutic drugs and appropriate nano-drug delivery systems can further improve the utilization and targeting of drugs. Sen et al (117) developed a liposome containing both apigenin and 5-FU, which demonstrated improved anti-tumor effects than 5-FU. Liu et al (118) designed a nanoparticle loaded with irinotecan and quercetin with Conatumumab modified to target CRC cells, with the nanoparticle yielding improved anti-tumor effects without systemic toxicity.

Personalized treatment involving PBAs in CRC will contribute to its clinical translation. First, the mechanism underlying the efficacy of different PBAs in treating CRC needs to be elucidated. Integrating single-cell sequencing or spatial transcriptome technology will help to identify the core targets of specific cell subsets (119). The core targets can subsequently be harnessed to identify populations that benefit from PBAs or those for whom they are unsuitable. For instance, microsatellite-stable CRC cell lines are more sensitive to curcumin (120), while EGCG may restore TCF4-chromatin interactions and activate the Wnt pathway in p53-mutant models, paradoxically promoting tumorigenesis (121). Thus, microsatellite-stable CRC patients could be potential beneficiaries of curcumin, while EGCG should be avoided in patients with p53 mutations. Future efforts should focus on integrating molecular subtyping and biomarkers to identify the potential population, thereby advancing the clinical application of PBAs in CRC treatment.

Conclusion

CRC remains a formidable global health challenge, with conventional therapies often limited by toxicity, drug resistance and poor patient compliance. PBAs, characterized by their multi-target, multi-pathway mechanisms, have emerged as promising candidates for CRC prevention and treatment. Preclinical studies highlight their ability to modulate oxidative stress, inflammation, apoptosis, epigenetic dysregulation and gut microbiota imbalance; key drivers of CRC pathogenesis. Compounds such as curcumin, EGCG, resveratrol and berberine demonstrate pleiotropic effects, including chemo-sensitization, immune modulation and synergy with conventional therapies. Notably, these natural agents mitigate chemotherapy-induced toxicity while enhancing therapeutic efficacy, underscoring their potential as adjunctive or alternative treatments.

However, clinical translation faces significant hurdles and clinical efficacy from limited phase I/II trials. Low bioavailability, inconsistent clinical outcomes and heterogeneous patient responses remain critical barriers. In this regard, while curcumin exhibits dose-dependent adenoma reduction in trials, its poor absorption limits clinical utility. Similarly, EGCG and vitamin supplementation trials revealed mixed results, emphasizing the need for optimized trial designs, standardized dosing and biomarker-driven patient stratification. Advances in nano-drug delivery systems, such as nanoparticles, liposomes and nanomicelles, offer promising solutions to enhance solubility, stability and tumor targeting. Combinatorial strategies integrating PBAs with chemotherapeutics (such as FOLFOX-curcumin) further demonstrate improved safety and efficacy, warranting expanded clinical exploration.

Future research should prioritize elucidating core mechanisms through advanced technologies such as single-cell sequencing and spatial transcriptomics, enabling precise identification of molecular targets and responsive patient subgroups. Personalized approaches, informed by CRC molecular subtypes (such as microsatellite stability, p53 status), will refine therapeutic applications. In addition, deeper investigations into gut microbiota-PBAs crosstalk and host-microbe interactions may unlock novel preventive and therapeutic avenues.

In conclusion, PBAs represent a versatile and sustainable frontier in CRC management. While challenges persist, interdisciplinary innovations in drug delivery, mechanism elucidation and precision medicine are key to unlocking their full clinical potential, ultimately bridging the gap between traditional phytotherapy and modern oncology.

Availability of data and materials

Not applicable.

Authors' contributions

Conceptualization, investigation and writing the original draft was by DF, HF, KY, YW, BN and XL. DF, HF, KY, YW, BN and XL were responsible for writing, review and editing. DF, HF, KY, YW, BN and XL were responsible for visualization. DF, HF and XL were responsible for supervision. HF, XL and DF were responsible for project administration. Data authentication is not applicable. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Acknowledgements

Not applicable.

Funding

The present study was supported by the National Natural Science Foundation of China (grant no. 82303765) and the Beien funding from the Bethune Charitable Foundation (grant no. bnmr-2023-004).

References