Pharmacological role of Herba Patriniae and Coix seed in colorectal cancer

Abstract

Colorectal cancer (CRC) is the most prevalent cancer globally, and its traditional treatment modalities commonly encompass radiation therapy, chemotherapy, surgery and the administration of cytotoxic drugs. Currently, novel chemotherapy drugs that combine traditional Chinese medicine (TCM) with herbal extracts exhibit superior comprehensive benefits. Herein, we delved into an article authored by Wang et al, focusing specifically on the pharmacological effects of "Herba Patriniae and Coix seed (HC)" and their targeted mechanisms in combating CRC. From the perspective of TCM philosophy, damp-heat stagnation and toxicity are the cardinal pathogenic factors underlying CRC. HC, renowned for their abilities to antipyretic and enhance diuresis, have demonstrated promising efficacy in preliminary studies for the treatment of CRC. These findings offer potential insights in favor of fostering anti-cancer medications.

Key Words: Colorectal cancer; Herba Patriniae; Coix seed; Antitumor; Chinese medicine

Core Tip: Colorectal cancer (CRC) can be treated with novel chemotherapeutic agents combining traditional Chinese medicine (TCM) and herbal extracts in addition to traditional treatments including radiotherapy, chemotherapy, surgery and cytotoxic drugs. The TCMs Herba Patriniae and Coix seed can act on the signaling pathways of CRC, such as phosphoinositide 3 kinase/Akt/mammalian target of rapamycin, p53, transforming growth factor-β/SMAD, NFkappaB and Wnt/β-catenin, to show better therapeutic effect, and their future treatments and applications in CRC are very valuable and promising.

INTRODUCTION

Colorectal cancer (CRC) is the third most common cancer globally, with an incidence rate of 9.6%, and it ranks second in terms of mortality, affecting 9.3% of cancer-related deaths worldwide[1]. Among the conventional treatments, including surgery, radiotherapy, chemotherapy, immunotherapy and targeted therapies, there are still many significant impediments to the side effects of these methods[2].

In recent years, traditional Chinese medicine (TCM) has shown significant promise in the treatment of CRC. TCM not only helps alleviate clinical symptoms and boosts the immune response in patients but also plays a crucial role in preventing tumor recurrence and metastasis. A notable example is the combination of Herba Patriniae and Coix seed (HC), which are valued in TCM for their heat-clearing and phlegm-reducing properties. Research suggests that the active components in these herbs can inhibit the apoptosis of CRC cells by modulating the phosphoinositide 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), P53, NFkappaB (NF-κB), mitogen activated protein kinase, and transforming growth factor-β (TGF-β)/SMAD pathways[3,4]. Additionally, they have been shown to reverse epithelial-mesenchymal transition (EMT) by inhibiting the Wnt/β-catenin signaling pathway, thus reducing the spread and migration of CRC cells. The objective of this article is to investigate the pharmacological effects of HC and their targeted mechanisms in CRC, drawing on an article by Wang et al[5] in the World Journal of Gastrointestinal Oncology. This study comprehensively reviews the scientific literature on the pathogenesis of CRC and the medicinal value of HC as well as its application in the treatment of colorectal cancer. Additionally, it elaborates on the major molecular mechanisms implicated in these processes. Finally, it discusses the future development directions and prospects of HC in the treatment of CRC.

PATHOGENESIS OF CRC

CRC arises from a complex interplay of genetic and environmental factors[6]. Genetically, the majority of CRC cases are sporadic, with approximately 80% lacking a clear familial predisposition[7]. Early detection and screening programs have been shown to be effective in preventing more than 90% of CRC cases[8]. In Western countries, it is suggested that up to 71% of CRC cases could be attributed to modifiable lifestyle factors[9]. While the incidence and mortality rates of CRC are showing signs of stabilization and decline in highly developed countries, this is largely attributed to extensive colonoscopy practices, national screening initiatives, and dietary changes[10]. Conversely, in many developing countries, the incidence of CRC is on the rise, reflecting the need for improved prevention strategies and healthcare infrastructure[11].

Environmental factors significantly contribute to the development of CRC, encompassing a range of elements such as obesity, height, diet, alcohol consumption, physical activity, and smoking[12]. Notably, dietary factors, including red meat, processed meat, animal-derived saturated fats and alcohol have been identified as influential in CRC development[13]. International Agency for Research on Cancer classifies processed meat consumption as a group 1 carcinogen[14]. Studies in rodent models have shown that heme iron in red meat can trigger lipid oxidation and the formation of 4-hydroxynonenal, which is associated with precancerous conditions[15]. In vitro, components such as animal fats, proteins from red meat, N-nitroso compounds, heterocyclic amines, and heme iron are implicated in CRC induction, with heme iron specifically enhancing cellular inflammation and permeability, leading to genetic damage[16,17]. Adherence to healthy dietary patterns, such as the Mediterranean, vegetarian, and semi-vegetarian diets, which include whole grains, full-fat dairy products, and calcium, has been shown to decrease CRC morbidity[18]. Ethanol, when consumed, is metabolized into acetaldehyde and subsequently oxidized into acetate, a known carcinogen that increases the risk of cancer. Moreover, ethanol's impact on the DNA methylation of the COLCA1 and COLCA2 genes is associated with an elevated risk of CRC[19]. Regular and sufficient physical activity has been demonstrated to reduce the incidence of CRC and improve survival rates among those diagnosed. Chen et al[20] utilized a polygenic risk score to analyze the relationship between physical activity and CRC risk, finding a consistent inverse association with CRC risk, regardless of genetic predisposition. Smoking is a primary factor in the etiology of early-stage CRC, and its long-term use is linked to the progression of advanced CRC[21]. Cigarette contains over 7000 harmful chemicals, including at least 70 known carcinogens that can affect nearly every biological system in the human body[22]. Toxic chemicals in cigarettes, such as nitrosamines, heterocyclic amines, benzene, and polycyclic aromatic hydrocarbons, have the potential to induce cancer in the colon and rectum, either through direct exposure or systemic circulation to the colorectal mucosa[23].

In terms of deeper pathogenesis, cancer stem cells (CSCs) constitute a small subset of cells within the tumor that share characteristics with embryonic stem cells (ESCs)[24]. The majority of CRCs are believed to arise from CSCs within the colonic epithelium, which accumulate genetic and epigenetic alterations over time. These cells possess the ability for self-renewal and differentiation, and they can suppress tumor suppressor genes while activating oncogenes. This leads to abnormal growth patterns and a slow rate of cellular turnover, making them resistant to therapies that target rapidly dividing cells[25]. The genesis of CSCs is attributed to two primary mechanisms: (1) First, the accumulation of oncogenic mutations in normal adult stem cells or ESCs can lead to a deregulation of cell proliferation, resulting in uncontrolled growth[26,27]; and (2) Second, differentiated cancer cells may revert to a stem-cell-like state through a process known as dedifferentiation. Biomarkers such as c-Myc, STAT3, aldehyde dehydrogenase, ABCG2, and CD133 are strongly associated with the presence of cancer. Furthermore, specific markers including CD44, LGR5, and EpCAM have been identified as particularly relevant in the context of CRC[28].

CRC can be classified into four distinct consensus molecular subtypes (CMS), which are delineated by their gene expression profiles. CMS1 is characterized by microsatellite instability (MSI) and immune system activation, CMS2 is considered the typical subtype, CMS3 is defined by its metabolic dysregulation, and CMS4 is distinguished by its mesenchymal features. The genetic and molecular pathways associated with each subtype are interrelated[29].

Tumors with MSI and those that are metabolic in nature are predominantly found in the right-sided colon. Specifically, CMS1 is associated with MSI, BRAF mutations, an increase in immune cell infiltration, and the upregulation of checkpoint inhibitors. In contrast, CMS2 is defined by chromosomal instability, the activation of the Wnt/MYC signaling pathway, and a decrease in immune cell presence. The CMS3 subtype is frequently associated with KRAS mutations, while CMS4 is marked by a mesenchymal phenotype, activation of the TGF-β pathway, and increased matrix deposition along with heightened immune cell infiltration[30].

NEW CRC TREATMENT DRUGS: "HERBA PATRINIAE AND COIX SEED"

Currently, the main approaches to treating CRC include surgery, radiotherapy, chemotherapy, immunotherapy and targeted therapy. Despite these methods, challenges such as persistent proliferation signaling, resistance to chemotherapy, postoperative complications, drug side effects, and high rates of metastasis and recurrence pose significant obstacles to effective CRC treatment[2]. These factors contribute to the high mortality rate associated with CRC.

Recent advancements in interdisciplinary treatment strategies have achieved notable breakthroughs over traditional methods. Specifically, molecular targeting and immunotherapy, which focus on tumor-associated proteins and the regulation of signaling pathways involved in tumor growth and progression, have shown promise in enhancing treatment efficacy and revolutionizing conventional treatment approaches[31].

TCM with its extensive history, has increasingly become a vital resource in the development of anti-CRC drugs[32]. TCM employs a multi-component approach, targeting multiple protein and signaling pathways, which can significantly mitigate the adverse effects of radiation and chemotherapy. This approach not only enhances immune function but also improves patients' overall quality of life, life expectancy, and reduces the incidence of tumor recurrence and metastasis[33]. Sijunzi Decoction, has been shown to effectively alleviate clinical symptoms, improve patients' quality of life, extend survival, and reduce the risk of tumor recurrence and metastasis[34].

The "Compendium of Materia Medica" recognizes Coicis Semen as a traditional Chinese medicinal material with both pharmacological value and culinary uses[3,35]. Historically esteemed in TCM, Coicis Semen is frequently combined with other herbs to treat various conditions. For instance, the 'Qian Jin Yao Fang' describes the Phragmites Stem Soup, a formulation that pairs Coicis Semen with Phragmites Stem and Winter Melon Seeds to address respiratory issues such as lung abscess, lobar pneumonia, and bronchitis. This blend aims to enhance urine excretion and regulate spleen function, thereby alleviating diarrhea. Furthermore, the 'Wen Bing Diao Bian' by Wu JT details the Sanzi Decoction, which includes Coicis Semen, Amomum Villosum Lour, and Almond among other ingredients, specifically formulated for damp-heat syndrome treatment[36].

Herba Patriniae, another traditional Chinese medicinal herb, is celebrated for its purifying and antioxidant properties and is used in treatments for diarrhea, acute hepatitis, ulcerative colitis, cancer, and other diseases[37]. First documented in the 'Shennong Herbal Classic', Herba Patriniae has been valued for its medicinal properties and applied to treat a range of conditions. Modern pharmacological studies have identified the plant's chemical constituents as having antioxidant, anti-inflammatory, and sedative effects[38].

In terms of modern clinical treatment, HC known for their diuretic, purgative, hemostatic, and anti-inflammatory properties[4,39]. This combination has demonstrated efficacy in improving experimental enteritis in mice by reducing the secretion of inflammatory cytokines and oxidative stress[40]. The Coicis Semen Polysaccharide component of HC is notable for its ability to activate the PI3K/Akt signaling pathway, which enhances the population of bacteria that produce short-chain fatty acids. This mechanism contributes to the lowering of blood sugar levels in mouse models of type 2 diabetes[41]. Coicis Semen has established itself as an anti-cancer agent, particularly effective against CRC[42]. It possesses the capacity to reduce the proliferation, invasion, and migration of various cancer cells. Furthermore, Coix has been shown to disrupt NF-κB signaling, which enhances the anti-tumor effects of gemcitabine in pancreatic cancer treatment[43]. Coicis Semen Oil (CSO) has also emerged as an agent with potential anti-cancer activity against triple-negative breast cancer by modulating the miR-205/S1PR1 axis[44]. The compound Kanglaite, extracted from Coicis Semen, has demonstrated clinical utility as a broad-spectrum anti-tumor agent[45].

Herba Patriniae, on its own, has shown promise in inducing apoptosis in CRC cells and suppressing tumor growth and angiogenesis, presenting itself as an innovative therapeutic option for CRC treatment[46].

MODE OF ACTION OF HERBA PATRINIAE AND COIX SEED IN CRC

The signal pathway related to CRC is a major direction of CRC treatment, and exploring the mechanism of the CRC-related signal pathway also helps to further clarify the drug targets for anti-CRC. EMT process is widely acknowledged to be involved in cancer invasion and metastasis, and is regulated by numerous transcription factors[47]. The process of EMT in cancer cells can be triggered by multiple intrinsic signaling pathways. These pathways include the PI3K/Akt/mTOR, TGF-β/SMAD and Wnt/β-catenin. We are mainly interested in HC in regulating the signaling pathways driven by PI3K/Akt/mTOR, p53, TGF-β/SMAD, NF-κB and Wnt/β-catenin (Figure 1).

Figure 1 A graphical illustration showcasing the immunomodulatory mechanisms of Herba Patriniae and Coix seed on signaling pathways implicated in the onset and progression of cancer. APC: Anaphase-promoting-complex; BAX: B cell lymphoma/leukemia-2-associated X protein; BCL-2: B cell lymphoma/leukemia-2; CK1: Casein kinase; DR5: Death receptor 5; DVL: Dishevelled; EGFR: Epidermal growth factor receptor; ERK: Extracellular signal-regulated protein kinases; IL: Interleukin; IKB: IkappaB; IKK: KappaB kinase; LRP: Lung resistance protein; MDM2: Murine double minute 2; MEK: Mitogen-activated protein kinase; MMPs: Matrix metalloproteinases; MTORC1: Mammalian target of rapamycin complex 1; MyD88: Myeloid differentiation factor 88; NF-κB: NFkappaB; PDK1: Phosphoinositide-dependent kinase 1; PI3K: Phosphoinositide 3 kinase; RAS: Rat sarcoma; RTKs: Receptor tyrosine kinases; TBK1: TANK-binding kinase 1; TGF: Transforming growth factor; TGFBR2: Transforming growth factor-beta1 receptor 2; TLR: Toll like receptor; TNF-α: Tumour necrosis factor-alpha; TRAF2: Tumour necrosis factor receptor associated factor 2; TRAIL: Tumor necrosis factor-related apoptosis-inducing ligand; TRADD: Tumour necrosis factor receptor-associated death domain; TSC1/2: Tuberous sclerosis complex 1/2.

The PI3K/Akt/mTOR signaling pathway is a crucial intracellular signaling mechanism, primarily functioning as a downstream effector of receptor tyrosine kinases and G protein-coupled receptors. It has been implicated in various cancer types, including CRC[48,49]. Research by Ni et al[50] has demonstrated that CSO can target the PI3K/Akt signaling pathway, leading to the arrest of HT-29 cells in the G2 phase and the induction of apoptosis. Similarly, Yang et al[51] reported that Coix lacryma oil influences mitochondrial function by modulating the PTEN/PI3K/Akt pathway, thereby promoting apoptosis in human pancreatic cancer cells. The aqueous extract of Herba Patriniae exert anticancer effects by activating kinase signals including p38, extracellular signal-regulated protein kinases 1 and 2, c-Jun N-terminal kinase, mitogen extracellular kinase 1 and 2, and mitogen-and stress-activated protein kinase 1 and 2[52]. An extract from Patrinia heterophylla, a species categorized under Herba Patriniae, has exhibited significant anti-CRC potential by markedly reducing the mRNA and protein expression levels of epidermal growth factor receptor, PI3K, and Akt in HCT116 cells[53].

The p53 protein plays a pivotal role in various cellular processes, including the regulation of cell cycle arrest, apoptosis, DNA repair, and senescence by binding to specific DNA response elements[54]. It is widely recognized as a crucial gene that protects against cancer. However, in the context of cancer, the p53 function is often compromised due to inactivation or mutation[55]. Coicis Semen Extract has been shown to induce apoptosis through multiple mechanisms, such as the inhibition of Bcl-2, upregulation of p53, and modulation of cleaved poly (adenosine diphosphate-ribose) polymerase, as well as cleaved caspase-3 and caspase-8[56]. Kang Lai Te (KLT) injection, an antitumor drug derived from Coix, primarily exerts its effects by inhibiting tumor cell proliferation. It achieves this by reducing cell mitosis through the blockade of the G2/M phase of the cell cycle and by activating pro-apoptotic factors, thereby promoting cell apoptosis[57]. Similarly, Herba Patriniae and its constituent isovitexin have demonstrated the ability to effectively combat CRC by inducing apoptosis and arresting the cell cycle through the activation of p53[52].

NF-κB family is a prevalent class of transcription factors that play a significant role in cellular processes. Activation of NF-κB is known to promote cell growth, decelerate cell death, and is implicated in disease progression, including genetic instability and the potential activation of resistance genes, which may contribute to the development of rectal cancer[58]. A substantial body of research has indicated that HC possess the ability to inhibit NF-κB function. For instance, Hu et al[59] discovered that Coixol, a component of Coix seed, can suppress the activation of the mitogen-activated protein kinase, NF-κB pathway, and the NOD-like receptor thermal protein domain associated protein 3 inflammasome. Similarly, Chen et al[60] reported that KLT, an active extract derived from Coix lacryma-jobi seeds, enhances the effectiveness of cisplatin in hepatocellular carcinoma treatment by inhibiting chemokine-like factor 1-mediated NF-κB signaling and modulating transporter-associated drug efflux. Furthermore, ginsenosides present in Herba Patriniae have been shown to exert anti-invasive effects on CRC by dampening the NF-κB signaling pathway and regulating the expression of EMT markers, such as E-cadherin and N-cadherin[61].

The TGF-β/SMAD signaling cascade is a critical regulatory mechanism for EMT in colon cancer. It impacts a broad spectrum of human diseases by modulating cellular processes such as proliferation, apoptosis, differentiation, lineage commitment, motility, and the maintenance of stem cell homeostasis[62]. The aqueous extract of Herba Patriniae mediates its therapeutic effects through the regulation of key signaling pathways, specifically the TGF-βR1-SMAD2/3-E-cadherin and FAK-RhoA-cofilin axes. This modulation influences the immune cell composition and cytokine levels within the tumor microenvironment, as well as the gut microbiota, which are essential factors in cancer progression[63].

The Wnt/β-catenin signaling pathway is a critical mediator in the progression of human CRC and is considered a significant target for therapeutic intervention[64]. This pathway involves a complex network of proteins, including glycogen synthase kinase 3β (GSK3β), casein kinase 1 (CK1), the tumor suppressor Axin, and adenomatous polyposis coli (APC), which together form a destruction complex. Axin acts as the structural framework of this complex, enabling the interaction of β-catenin with APC, CK1, and GSK3β[65]. Upon activation, β-catenin translocates to the nucleus, where it interacts with transcription factors to drive the transcription of essential target genes such as c-Myc, Cyclin D1, and matrix metalloproteinases[66]. Plant-derived medicinal foods, with Coix seed as a primary component, have shown a robust ability to inhibit tumor growth. This is achieved by disrupting the Wnt/β-catenin signaling cascade and reversing EMT process[67].

CONCLUSION

HC, widely recognized as plant-based medicines across many Asian countries, have attracted considerable interest due to their notable anticancer properties. A plethora of studies has attested to the efficacious tumor suppressive and immune regulatory capabilities of these botanical agents, which can counteract numerous oncogenic signal molecules and pathways. To date, the inhibitory impact of HC on signaling pathways associated with CRC has been highly encouraging, with the targeting of the PI3K/Akt/mTOR pathway showing particular promise and value. Despite these advances, research into their application in CRC cell lines and the disease's clinical context remains relatively limited.

Further investigation is warranted to delineate the precise mechanisms of action and the specific signaling pathways modulated by these compounds. Utilizing CRC cell lines as a screening platform can facilitate this evaluation. Based on these findings, HC along with their isolated compounds, opens up promising directions and offers valuable insights for the development of innovative anticancer therapeutics. This exploration can deepen our understanding of the pharmacological value and therapeutic potential of these natural agents in treating CRC. In summary, HC present themselves as candidates for novel combination chemotherapy agents in the management of CRC.