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Exploring the Anticancer and Immunomodulatory Mechanisms of Phytochemicals and Natural...
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Exploring the Anticancer and Immunomodulatory Mechanisms of Phytochemicals and Natural Bioactive Compounds

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: 15 July 2025 | Viewed by 6123

Special Issue Editor

Prof. Dr. Suyun Lyu

E-Mail Website
Guest Editor
College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Suncheon 57922, Republic of Korea
Interests: Natural products; anticancer; immunomodulation

Special Issue Information

Dear Colleagues,

Natural products have long been valuable for drug discovery and development, especially in oncology and immunology. This Special Issue focuses on the anticancer and immunomodulatory mechanisms of phytochemicals and other bioactive compounds derived from natural sources. Recent advancements have highlighted the potential of these compounds to modulate various cellular pathways, enhance immune responses, and inhibit cancer cell proliferation and metastasis.

Phytochemicals exhibit diverse mechanisms of action, including the induction of apoptosis, cell cycle arrest, and inhibition of angiogenesis. These natural compounds often target multiple signaling pathways, making them effective against various cancer types and reducing the likelihood of drug resistance. Furthermore, many natural products possess immunomodulatory properties, enhancing the body’s immune system to recognize and eliminate cancer cells. They can stimulate the activity of immune cells, such as T cells and natural killer cells, and modulate the production of cytokines and other immune mediators.

This issue invites submissions that explore the molecular mechanisms, bioavailability, and therapeutic potential of natural compounds in cancer treatment and immune regulation. Studies on novel natural products, combination therapies, and clinical trials are welcome. By understanding and harnessing the power of natural compounds, we can develop more effective and less toxic therapies for cancer and immune-related diseases.

Prof. Dr. Suyun Lyu
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • natural products
  • phytochemicals
  • anticancer
  • immunomodulation
  • bioactive compounds

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Published Papers (6 papers)

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Research

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15 pages, 4800 KiB  
Article
Evaluation and DFT Analysis of In Vitro Anticancer Activity of Consolida orientalis, Smyrnium rotundifolium, and Euphorbia virgata Plant Extracts in Colorectal Cancer
by Eda Sönmez Gürer, Zuhal Tunçbilek, Cemile Zontul, Ahu Kutlay, Amrendra Kumar and Gaurav Jhaa
Pharmaceuticals 2025, 18(7), 943; https://doi.org/10.3390/ph18070943 (registering DOI) - 22 Jun 2025
Abstract
Background: Colon cancer is one of the leading causes of cancer-related deaths today. Crucial research continues for the ideal chemotherapy. In this context, natural compounds of plant origin play an important role in the development of new anticancer drugs. Methods: In [...] Read more.
Background: Colon cancer is one of the leading causes of cancer-related deaths today. Crucial research continues for the ideal chemotherapy. In this context, natural compounds of plant origin play an important role in the development of new anticancer drugs. Methods: In this study, the effects of Consolida orientalis ethanol extract (flower parts), Smyrnium rotundifolium ethanol extract (aerial parts), and Euphorbia virgata ethanol extract (aerial parts) samples on HT-29 (human colorectal adenocarcinoma cell line) and healthy CCD-18Co (human normal colon fibroblast cell line) were investigated for the first time in the literature by applying 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) test within the scope of in vitro cytotoxicity analysis. Results: As a result of the study, it was observed that all plant extracts were most effective at 72 h. S. rotundifolium ethanol extract (aerial parts) was found to be the most effective on the HT-29 cell line. Both the higher cell viability of C. orientalis in healthy cells applied to it compared to S. rotundifolium and its effectiveness on colon cancer cell lines make C. orientalis more advantageous. Conclusions: When evaluating the efficacy of extracts on cancer cells, the load on healthy cells should be taken into account. Therefore, C. orientalis ethanol extract (flower parts) was found to have the potential to be a chemotherapeutic agent against colon cancer. Chemical reactivities of the dominant components of bioactive components were analyzed via Conceptual Density Functional Theory-based calculations. The power of the interactions with EGFR kinase of these compounds is checked via Molecular Docking Calculations. It was noted that Chlorogenic acid, which is the most reactive bioactive component, has a stronger binding to the mentioned enzyme. Full article
(This article belongs to the Special Issue Exploring the Anticancer and Immunomodulatory Mechanisms of Phytochemicals and Natural Bioactive Compounds)
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20 pages, 12613 KiB  
Article
Skimmianine Modulates Tumor Proliferation and Immune Dynamics in Breast Cancer by Targeting PCNA and TNF-α
by Tuğcan Korak, Hayat Ayaz and Fırat Aşır
Pharmaceuticals 2025, 18(5), 756; https://doi.org/10.3390/ph18050756 - 20 May 2025
Viewed by 433
Abstract
Background/Objectives: Breast cancer continues to be a major global health challenge, driving the urgent need for innovative therapeutic strategies. This study evaluates the anticancer and immunomodulatory potential of skimmianine in breast cancer through a comprehensive approach, integrating biochemical, histopathological, immunohistochemical, and bioinformatics [...] Read more.
Background/Objectives: Breast cancer continues to be a major global health challenge, driving the urgent need for innovative therapeutic strategies. This study evaluates the anticancer and immunomodulatory potential of skimmianine in breast cancer through a comprehensive approach, integrating biochemical, histopathological, immunohistochemical, and bioinformatics analyses. Methods: Thirty-six female Wistar albino rats were divided into three groups: control, 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast cancer, and DMBA + skimmianine (n = 12/group). Breast cancer was induced with a single oral dose of 50 mg/kg DMBA in sesame oil. After 16 weeks, skimmianine (40 mg/kg) was administered intraperitoneally for four weeks. Serum CA15-3 levels were measured via enzyme-linked immunosorbent assay (ELISA). Histopathological assessment was performed using hematoxylin and eosin (H&E) staining, and proliferating cell nuclear antigen (PCNA) and tumor necrosis factor-alpha (TNF-α) were evaluated immunohistochemically. Pathway and hub gene analyses were performed using Cytoscape, functional annotation with Enrichr, and immune analyses via the Tumor and Immune System Interaction Database (TISIDB) and Sangerbox. Results: The tumor burden in the animals increased after DMBA induction compared to the control groups (0.00 ± 0.00% vs. 89.00 ± 6.60%, respectively, p < 0.001), while skimmianine treatment significantly reduced the tumor burden in the animals (49.00 ± 9.40%, vs. DMBA group, p = 0.191). Histopathological analysis showed DMBA-induced structural disorganization and malignant clustering, whereas skimmianine preserved ductal structures and mitigated the damage. Compared to the control group, DMBA administration markedly elevated serum CA15-3 levels (0.23 ± 0.06 ng/mL vs. 8.57 ± 1.01 ng/mL, respectively), along with PCNA (13.0 ± 3.0% vs. 25.0 ± 4.0%, respectively) and TNF-α (8.4 ± 1.7% vs. 34.0 ± 5.3%, respectively) expression, indicating active tumor progression. Skimmianine treatment significantly reduced CA15-3 (3.72 ± 0.58 ng/mL), PCNA (20.0 ± 4.1%), and TNF-α (25.0 ± 3.9%) levels (p < 0.001). In silico analyses indicated skimmianine’s effects on PCNA influence cell cycle pathways, while TNF-α suppression impacts toll-like receptor (TLR) signaling (adjusted p < 0.05). PCNA- and TNF-α-related anticancer effects were especially notable in basal molecular and C2 immune subtypes (p < 0.05). Related hub proteins may regulate immune dynamics by reducing immunosuppression and tumor-promoting inflammation (p < 0.05). Conclusions: Skimmianine shows promise as a breast cancer therapy by simultaneously targeting tumor growth and immune regulation, with PCNA and TNF-α identified as potential key players. Full article
(This article belongs to the Special Issue Exploring the Anticancer and Immunomodulatory Mechanisms of Phytochemicals and Natural Bioactive Compounds)
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24 pages, 3945 KiB  
Article
Medicinal Phytocompounds as Potential Inhibitors of p300-HIF1α Interaction: A Structure-Based Screening and Molecular Dynamics Simulation Study
by Muhammad Suleman, Abrar Mohammad Sayaf, Sohail Aftab, Mohammed Alissa, Abdullah Alghamdi, Suad A. Alghamdi, Mohammed A. Alshehri, Kar Kheng Yeoh, Sergio Crovella and Abdullah A. Shaito
Pharmaceuticals 2025, 18(4), 602; https://doi.org/10.3390/ph18040602 - 21 Apr 2025
Cited by 1 | Viewed by 630
Abstract
Background: Hypoxia plays a key role in cancer progression, mainly by stabilizing and activating hypoxia-inducible factor-1 (HIF-1). For HIF-1 to function under low oxygen conditions, it must interact with the transcriptional coactivator p300, a critical step for promoting cancer cell survival and adaptation [...] Read more.
Background: Hypoxia plays a key role in cancer progression, mainly by stabilizing and activating hypoxia-inducible factor-1 (HIF-1). For HIF-1 to function under low oxygen conditions, it must interact with the transcriptional coactivator p300, a critical step for promoting cancer cell survival and adaptation in hypoxic environments. Methods: Consequently, we used drug design and molecular simulation techniques to screen phytochemical databases, including traditional Chinese and African medicine sources, for compounds that could disrupt the p300/HIF-1 interaction. Results: In this study, we identified potential compounds with high docking scores such as EA-176920 (−8.719), EA-46881231 (−8.642), SA-31161 (−9.580), SA-5280863 (−8.179), NE-5280362 (−10.287), NE-72276 (−9.017), NA-11210533 (−10.366), NA-11336960 (−7.818), TCM-5281792 (−12.648), and TCM-6441280 (−9.470 kcal/mol) as lead compounds. Furthermore, the compound with the highest docking score from each database (EA-176920, SA-31161, NE-5280362, NA-11210533, and TCM-5281792) was subjected to further analysis. The stable binding affinity of these compounds with p300 was confirmed by Post-simulation binding free energy (−22.0020 kcal/mol, −25.4499 kcal/mol, −32.4530 kcal/mol, −33.9918 kcal/mol, and −57.7755 kcal/mol, respectively) and KD analysis. Moreover, the selected compounds followed the Lipinski rules with favorable ADMET properties like efficient intestinal absorption, high water solubility, and no toxicity. Conclusions: Our findings highlight the potential of natural compounds to target key protein–protein interactions in cancer and lay the groundwork for future in vitro and in vivo studies to explore their therapeutic potential. Specifically, disrupting the p300/HIF-1 interaction could interfere with hypoxia-driven pathways that promote tumor growth, angiogenesis, and metastasis, offering a promising strategy to suppress cancer progression at the molecular level. Full article
(This article belongs to the Special Issue Exploring the Anticancer and Immunomodulatory Mechanisms of Phytochemicals and Natural Bioactive Compounds)
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22 pages, 1772 KiB  
Article
Phaseolus acutifolius Recombinant Lectin Exerts Differential Proapoptotic Activity on EGFR+ and EGFR− Colon Cancer Cells and Provokes T Cell-Assisted Antitumor Responses in Mice
by Francisco Luján-Méndez, Patricia García-López, Laura C. Berumen, Guadalupe García-Alcocer, Roberto Ferriz-Martínez, Anette Ramírez-Carrera, Jaqueline González-Barrón and Teresa García-Gasca
Pharmaceuticals 2025, 18(2), 213; https://doi.org/10.3390/ph18020213 - 5 Feb 2025
Viewed by 1101
Abstract
Background: rTBL-1, a recombinant lectin from Phaseolus acutifolius, exhibit proapoptotic activity on colon cancer cells and inhibitory properties on colon tumorigenesis in vivo. Apoptosis has been associated with a phospho-EGFR/phospho-p38/phospho-p53 mechanistic axis. Immunogenicity data have been observed in treated animals, [...] Read more.
Background: rTBL-1, a recombinant lectin from Phaseolus acutifolius, exhibit proapoptotic activity on colon cancer cells and inhibitory properties on colon tumorigenesis in vivo. Apoptosis has been associated with a phospho-EGFR/phospho-p38/phospho-p53 mechanistic axis. Immunogenicity data have been observed in treated animals, but its possible involvement in the antitumor response remained unexplored. Objective: We investigated whether the cytotoxic activity of rTBL-1 depends on EGFR and its capacity to produce antitumor responses on syngeneic colon cancer in mice, with and without T cells, in order to explore its possible involvement in the process. Results:rTBL-1 exhibited cytotoxic effects in a concentration-dependent manner in both EGFR+ (MC-38) and EGFR− (CT-26) colon cancer cells with LC50 values of 23.50 and 30.01 µg/mL, respectively (p = 0.063). Apoptotic effects were slower and longer-lasting in MC-38 than in CT-26 cells. Significant increases in caspase-3 proteolytic activation and PARP1 cleavage were detected in both cell types, despite PARP1 rheostasis in CT-26 cells. Intralesional treatment with rTBL-1 inhibited the growth of established tumors in immunocompetent BALB/c mice in 27.81% (p = 0.0008) with a benefit in survival (p = 0.022), but not in immunodeficient BALB/c nude mice. Conclusions:rTBL-1 induces apoptosis in colon cancer cells by EGFR independent mechanisms, although its presence could be related to deeper responses. Unresponsiveness in nude mice indicated that rTBL-1 antitumor effect is the synergistic result of apoptosis induction and T cell-mediated cytotoxicity in the tumor. Future studies will focus on the immunogenic effects triggered by the antitumor activity of rTBL-1 in colon cancer. Full article
(This article belongs to the Special Issue Exploring the Anticancer and Immunomodulatory Mechanisms of Phytochemicals and Natural Bioactive Compounds)
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18 pages, 2595 KiB  
Article
Phytochemical Profile and Anticancer Potential of Helichrysum arenarium Extracts on Glioblastoma, Bladder Cancer, and Breast Cancer Cells
by Ihsan Nalkiran and Hatice Sevim Nalkiran
Pharmaceuticals 2025, 18(2), 144; https://doi.org/10.3390/ph18020144 - 22 Jan 2025
Viewed by 1404
Abstract
Background/Objectives: Cancer is the second leading cause of death globally. Medicinal plants have emerged as fundamental sources of bioactive compounds with anticancer potential, largely attributed to their diverse secondary metabolites. This study aimed to investigate the cytotoxic effects of Helichrysum arenarium extracts from [...] Read more.
Background/Objectives: Cancer is the second leading cause of death globally. Medicinal plants have emerged as fundamental sources of bioactive compounds with anticancer potential, largely attributed to their diverse secondary metabolites. This study aimed to investigate the cytotoxic effects of Helichrysum arenarium extracts from two distinct regions of Turkiye, Mersin, and Artvin, on cancerous (MDA-MB-231, RT4, T98G) and non-cancerous (ARPE-19, hGF) cell lines and to identify bioactive compounds responsible for these effects. Methods: H. arenarium plant extracts were prepared using ethanol and methanol as solvents, followed by lyophilization and dissolution in DMSO. The cytotoxic effects of the extracts were evaluated using Hoechst staining and MTS assays to assess cell viability. IC50 values and selectivity indices were calculated. Phytochemical composition was analyzed using Quadrupole Time-of-Flight mass spectrometry. Results: The ethanol extract from Mersin (HAE-M) demonstrated superior cytotoxicity, particularly against breast and bladder cancer cells, while showing minimal impact on non-cancerous cells. HAM-M, HAE-A, and HAM-A exhibited comparatively less potent effects. Phytochemical analysis of HAE-M identified 16 bioactive compounds, including Naringenin, Luteolin, and Quercitrin, known for their antioxidant and anticancer properties. Conclusions: These findings highlight the potential of H. arenarium extracts, particularly HAE-M, as a source of potent anticancer agents. This study is novel in its comprehensive analysis of different extraction methods and regional plant sources, combined with phytochemical profiling, to identify selective anticancer effects. Further investigations into the mechanisms of action of these extracts could contribute to the development of plant-derived anticancer therapies. Full article
(This article belongs to the Special Issue Exploring the Anticancer and Immunomodulatory Mechanisms of Phytochemicals and Natural Bioactive Compounds)
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Review

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35 pages, 2569 KiB  
Review
Seaweed in the Diet as a Source of Bioactive Metabolites and a Potential Natural Immunity Booster: A Comprehensive Review
by Amiya Kumar Mandal, Sudhamayee Parida, Akshaya Kumar Behera, Siba Prasad Adhikary, Andrey A. Lukatkin, Alexander S. Lukatkin and Mrutyunjay Jena
Pharmaceuticals 2025, 18(3), 367; https://doi.org/10.3390/ph18030367 - 4 Mar 2025
Viewed by 1740
Abstract
Seaweed plays an essential role in the survival of marine life, provides habitats and helps in nutrient recycling. It is rich in valuable nutritious compounds such as pigments, proteins, polysaccharides, minerals, vitamins, omega-rich oils, secondary metabolites, fibers and sterols. Pigments like fucoxanthin and [...] Read more.
Seaweed plays an essential role in the survival of marine life, provides habitats and helps in nutrient recycling. It is rich in valuable nutritious compounds such as pigments, proteins, polysaccharides, minerals, vitamins, omega-rich oils, secondary metabolites, fibers and sterols. Pigments like fucoxanthin and astaxanthin and polysaccharides like laminarin, fucoidan, galactan and ulvan possess immune-modulatory and immune-enhancing properties. Moreover, they show antioxidative, antidiabetic, anticancer, anti-inflammatory, antiproliferative, anti-obesity, antimicrobial, anticoagulation and anti-aging properties and can prevent diseases such as Alzheimer’s and Parkinson’s and cardiovascular diseases. Though seaweed is frequently consumed by Eastern Asian countries like China, Japan, and Korea and has gained the attention of Western countries in recent years due to its nutritional properties, its consumption on a global scale is very limited because of a lack of awareness. Thus, to incorporate seaweed into the global diet and to make it familiar as a functional food, issues such as large-scale cultivation, processing, consumer acceptance and the development of seaweed-based food products need to be addressed. This review is intended to give a brief overview of the present status of seaweed, its nutritional value and its bioactive metabolites as functional foods for human health and diseases owing to its immunity-boosting potential. Further, seaweed as a source of sustainable food and its prospects along with its issues are discussed in this review. Full article
(This article belongs to the Special Issue Exploring the Anticancer and Immunomodulatory Mechanisms of Phytochemicals and Natural Bioactive Compounds)
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