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Natural Products in Cancer Prevention and Treatment

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Bioactives and Nutraceuticals".

Deadline for manuscript submissions: closed (20 July 2025) | Viewed by 12520

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Dr. Simona Serini

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Department of Translational Medicine and Surgery, Section of General Pathology, School of Medicine and Surgery, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Rome, Italy
Interests: cancer; nutrition; omega-3 fatty acids; antioxidants; phenolic compounds; inflammation; neurodegenerative diseases; metabolic diseases
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Dr. Gabriella Calviello

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Dear Colleagues,

Cancer is a noncommunicable disease characterized by the uncontrolled proliferation of cells. It is a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020. Even though innovative strategies such as targeted therapy and immunotherapy are being largely used, in most cases, chemotherapy and radiation therapy are still the most predominantly used forms of therapy. However, since they mainly act by damaging the DNA of rapidly dividing cancer cells, they also affect other normal cells with high rates of proliferation, and thus can be associated with deleterious side effects. Moreover, drug resistance very frequently arises in treated patients. Targeted therapy and immunotherapy have also been associated with undesired side effects. As a result, there is growing interest in exploring new therapeutic approaches able to exert an efficacious antineoplastic effect, while being safe to normal cells. In recent years, natural compounds extracted from vegetables, fruits, and other dietary constituents, such as marine polyunsaturated fatty acids and minerals, have been widely studied for their potential to prevent cancer or for their use in combination with conventional or innovative anti-neoplastic therapies to improve their beneficial effects against cancer cells and reduce the concentration of drugs used.

This Special Issue will highlight results of preclinical and clinical studies currently focused on cancer and that are related to anti-neoplastic therapeutic strategies involving natural products. In particular, it will provide an overview of novel molecular pathways targeted by natural products that are crucial for cancer treatments. Hence, for this Special Issue, we are inviting researchers to contribute original articles and reviews on these topics.

Dr. Simona Serini
Dr. Gabriella Calviello
Guest Editors

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Keywords

natural products
cancer
therapeutic strategies
novel molecular pathways

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Related Special Issue

Natural Products in Cancer Prevention and Treatment—Second Edition in International Journal of Molecular Sciences

Published Papers (11 papers)

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Research

Jump to: Review

13 pages, 4035 KB

Open AccessArticle

Chemopreventive Potential of Artemisinin and Rubus occidentalis in the Progression of Oral Leukoplakia to Oral Cancer: A Preclinical Murine Study

by Maria Leticia de Almeida Lança, Nathan Steven Cezar da Conceição, Isabella Souza Malta, Daniela Oliveira Meneses, Luciana Yamamoto Almeida and Estela Kaminagakura

Int. J. Mol. Sci. 2025, 26(17), 8120; https://doi.org/10.3390/ijms26178120 - 22 Aug 2025

Viewed by 109

Abstract

Oral leukoplakia (OL) is the most common potentially malignant oral disorder, with variable risk of progression to oral squamous cell carcinoma (OSCC). This study evaluated the chemopreventive and immunomodulatory potential of Artemisinin (ART) and Rubus occidentalis (RO), alone or combined (ARO), in a 4NQO-induced murine model. Mice received 4NQO (100 µg/mL) in drinking water, and treatments began at week 8. Animals were euthanized at weeks 12 and 16 for histological, apoptotic (caspases-3, -8, -9; calreticulin), inflammatory (IL-1β, IL-10, HMGB1), and immune (CD8, CD68, CD56, IFN-γ, GM-CSF) marker analyses. RO-treated animals showed delayed malignant transformation, with no carcinomas at week 16 and increased expression of caspase-9, calreticulin, HMGB1, IFN-γ, and GM-CSF, indicating transient activation of antitumor immune responses. ART-treated mice showed increased CD68 and reduced CD56 expression, suggesting an immunosuppressive profile and higher carcinoma incidence. The ARO combination did not improve outcomes beyond ART alone. These findings support the immunomodulatory and pro-apoptotic effects of RO in delaying OL progression, highlighting its chemopreventive potential. ART showed limited benefit under current conditions, warranting further investigation into dose optimization and synergistic strategies. Full article

(This article belongs to the Special Issue Natural Products in Cancer Prevention and Treatment)

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21 pages, 3094 KB

Open AccessArticle

Anticancer Activity of Ethanolic Extract of Tabernaemontana catharinensis in Breast Cancer Lines MCF-7 and MDA-MB-231

by Diana del Carmen Martínez-Méndez, María de la Luz Sánchez-Mundo, María del Rocío Thompson-Bonilla, Luis Marat Álvarez-Salas, Víctor Hugo Rosales-García, Jacobo Rodríguez-Campos and María Eugenia Jaramillo-Flores

Int. J. Mol. Sci. 2025, 26(16), 8111; https://doi.org/10.3390/ijms26168111 - 21 Aug 2025

Viewed by 391

Abstract

Breast cancer is a serious public health problem worldwide. Although current treatments with drugs such as cisplatin and paclitaxel are effective, they are associated with severe adverse effects and the development of drug resistance, which has prompted the search for new therapeutic strategies. In this context, the present study evaluated the anticancer activity of the ethanolic extract of Tabernaemontana catharinensis (EET) on the breast cancer cell lines MCF-7 (hormone-sensitive) and MDA-MB-231 (triple-negative) using 2D and 3D models. The results showed that EET significantly reduced cell viability in both lines, with IC₅₀ values of 83.06 µg/mL (MCF-7) and 8.3 µg/mL (MDA-MB-231) in 2D and 499.3 µg/mL and 280 µg/mL, respectively, in 3D. In addition, treatment with EET caused cell cycle arrest in the G1 phase, reduced CDK4 activity by 58% and ALDH3A1 activity by 32%, and increased levels of the tumor suppressor protein p53. Significant induction of apoptosis was also observed, evidenced by the activation of caspases -3/7, -8, and -9, along with a decrease in intracellular ATP levels (37% in MCF-7 and 90% in MDA-MB-231), suggesting mitochondrial dysfunction. Finally, EET showed the ability to inhibit cell invasion. Taken together, these results indicate that the ethanolic extract of Tabernaemontana catharinensis has potent antiproliferative, proapoptotic, and antimetastatic activity in breast cancer cells, in both two-dimensional and three-dimensional models. Its effect on various key molecular pathways and its ability to enhance the action of conventional chemotherapeutic agents position it as a promising adjuvant agent in the treatment of breast cancer. Full article

(This article belongs to the Special Issue Natural Products in Cancer Prevention and Treatment)

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18 pages, 2432 KB

Open AccessArticle

Alkali Lignin-Based Biopolymer Formulations for Electro-Assisted Drug Delivery of Natural Antioxidants in Breast Cancer Cells—A Preliminary Study

by Severina Semkova, Radina Deneva, Georgi Antov, Donika Ivanova and Biliana Nikolova

Int. J. Mol. Sci. 2025, 26(15), 7481; https://doi.org/10.3390/ijms26157481 - 2 Aug 2025

Viewed by 448

Abstract

Recently, a number of natural biologically active substances have been proven to be attractive alternatives to conventional anticancer medicine or as adjuvants in contemporary combination therapies. Although lignin-based materials were previously accepted as waste materials with limited usefulness, recent studies increasingly report the possibility of their use for novel applications in various industrial branches, including biomedicine. In this regard, the safety, efficiency, advantages and limitations of lignin compounds for in vitro/in vivo applications remain poorly studied and described. This study was carried out to investigate the possibility of using newly synthesized, alkali lignin-based micro-/nano-biopolymer formulations (Lignin@Formulations/L@F) as carriers for substances with antioxidant and/or anticancer effectiveness. Moreover, we tried to assess the opportunity for using an electro-assisted approach for achieving improved intracellular internalization. An investigation was conducted on an in vitro panel of breast cell lines, namely two breast cancer lines with different metastatic potentials and one non-tumorigenic line as a control. The characterization of all tested formulations was performed via DLS (dynamic light scattering) analysis. We developed an improved separation procedure via size/charge unification for all types of Lignin@Formulations. Moreover, in vitro applications were investigated. The results demonstrate that compared to healthy breast cells, both tested cancer lines exhibited slight sensitivity after treatment with different formulations (empty or loaded with antioxidant substances). This effect was also enhanced after applying electric pulses. L@F loaded with Quercetin was also explored only on the highly metastatic cancer cell line as a model for the breast cancer type most aggressive and non-responsive to traditional treatments. All obtained data suggest that the tested formulations have potential as carriers for the electro-assisted delivery of natural antioxidants such as Quercetin. Full article

(This article belongs to the Special Issue Natural Products in Cancer Prevention and Treatment)

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22 pages, 8293 KB

Open AccessArticle

Time-Dependent Impact of Betulin and Its Derivatives on IL-8 Expression in Colorectal Cancer Cells with Molecular Docking Studies

by Marcel Madej, Adrianna Halama, Elwira Chrobak and Joanna Magdalena Gola

Int. J. Mol. Sci. 2025, 26(13), 6186; https://doi.org/10.3390/ijms26136186 - 27 Jun 2025

Viewed by 459

Abstract

Colorectal cancer (CRC) remains one of the most prevalent malignancies of the gastrointestinal tract worldwide, with chronic inflammation recognized as a key factor in its progression. Among pro-inflammatory cytokines, interleukin 8 (IL-8) plays a pivotal role in promoting angiogenesis, tumor cell migration, and metastasis. Elevated IL-8 expression is frequently associated with advanced CRC stages. This study investigated the effects of betulin and its semi-synthetic derivatives, EB5 and ECH147, on IL-8 expression in CRC cell lines characterized by differing malignancy grades. IL-8 transcript and protein levels were quantified using real-time RT-qPCR and a proximity ligation assay, respectively, following compound exposure at 2, 8, and 24 h. Basal IL-8 levels were significantly higher in low-grade CRC cell lines. Among the compounds tested, ECH147 exerted the most pronounced, time-dependent inhibitory effect on CXCL8 expression. Furthermore, molecular docking analyses revealed that ECH147 exhibits stronger binding affinity toward the IL-8 protein compared to conventional chemotherapeutics. These findings suggest that the modification of the betulin structure via the incorporation of a propynoyl moiety enhances both its molecular interaction with CXCL8 and its anti-inflammatory potential. ECH147 and EB5 thus emerge as promising candidates for further development as immunomodulatory agents targeting the IL-8-associated pathway in CRC. Full article

(This article belongs to the Special Issue Natural Products in Cancer Prevention and Treatment)

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24 pages, 5537 KB

Open AccessArticle

Gratiola officinalis Alcoholic Extract Targets Warburg Effect, Apoptosis and Cell Cycle Progression in Colorectal Cancer Cell Lines

by Stefano Bianchini, Federica Bovio, Stefano Negri, Flavia Guzzo, Matilde Forcella and Paola Fusi

Int. J. Mol. Sci. 2025, 26(5), 2220; https://doi.org/10.3390/ijms26052220 - 28 Feb 2025

Cited by 1 | Viewed by 862

Abstract

Colorectal cancer (CRC) is the second deadliest cancer in the Western world. Increased body weight, a diet rich in red meat and alcohol, as well as a sedentary lifestyle, are all involved in sporadic CRC pathogenesis. Since current CRC therapies show several side effects, there is a need to find new and more effective therapeutic approaches, allowing conventional drug dosages and toxicity to be reduced. Gratiola officinalis alcoholic extract was characterized by LC-MS and its effect investigated on a healthy colon mucosa cell line and on different colorectal cancer cell lines. Cell viability, apoptosis and cell cycle progression were evaluated through flow cytometry; energy production and glycolysis were investigated using Seahorse technology, while cancer markers were analyzed through Western blotting. The untargeted metabolomics analysis of G. officinalis alcoholic extract revealed glycosides of different polyphenols and glycosides of cucurbitane-type triterpenes. This extract showed a stronger impact on CRC cell line viability compared to healthy colon cells. In the E705 CRC cell line, it induced cell apoptosis and caused the downregulation of glycolysis, inhibiting cell proliferation. On the other hand, SW480 CRC cells treated with G. officinalis extract showed G₂/M cell cycle arrest. This work shows that G. officinalis extract can reduce glycolysis and promote cell cycle arrest in CRC cells, suggesting that G. officinalis could represent a novel player in the prevention and treatment of CRC. Full article

(This article belongs to the Special Issue Natural Products in Cancer Prevention and Treatment)

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17 pages, 3084 KB

Open AccessArticle

Tepary Bean (Phaseolus acutifolius) Lectins as Modulators of Intracellular Calcium Mobilization in Breast Cancer and Normal Breast Cells

by Andrea Díaz-Betancourt, María Elizabeth Galicia-Castillo, Verónica Morales-Tlalpan, Jorge Luis Chávez-Servín, Alejandro Blanco-Labra, Teresa García-Gasca and Carlos Saldaña

Int. J. Mol. Sci. 2025, 26(3), 1064; https://doi.org/10.3390/ijms26031064 - 26 Jan 2025

Viewed by 1028

Abstract

Lectins are proteins that specifically recognize carbohydrates on cell membranes, triggering several cellular events such as apoptosis of cancer-transformed cells; however, the mechanisms of action remain incompletely understood. Our research group has reported that a concentrated fraction of Tepary bean lectins (Phaseolus acutifolius; TBLF) exhibits the concentration-dependent induction of apoptosis in colon cancer cells by caspase activation. It is well established that an increase in cytoplasmic calcium ([Ca²⁺]_i) initiates intracellular signals involved in processes such as exocytosis, gene transcription, apoptosis, cell cycle regulation, and muscle contraction, among others. Furthermore, dysregulated calcium signaling has been implicated in various diseases, including certain neurological disorders and cancer. In this study, we aim to demonstrate the effects of native TBLF lectins and a recombinant lectin (rTBL-1) on calcium mobility in breast cancer cells (MCF-7) and non-cancerous cells (MCF-12F). Both TBLF and rTBL-1 increased intracellular calcium concentrations and mobilized calcium from intracellular stores in a concentration-dependent manner; however, the two cell lines exhibited differential responses. While MCF-12F cells restored cytoplasmic calcium concentration, MCF-7 cells maintained a high intracellular calcium concentration. This strongly suggests that lectins can elicit differential cellular responses in cancer and non-cancer cells due to variations in their intrinsic mechanisms of calcium homeostasis. Finally, we demonstrated that TBLF and rTBL-1 can differentially alter Metabolic Cellular Activity (MCA) as a direct measure of cell viability (CVi) in both cell lines. These findings strengthen the evidence of the therapeutic potential of Tepary bean lectins. Undoubtedly, further studies will be necessary to elucidate the mechanisms underlying their applications. Full article

(This article belongs to the Special Issue Natural Products in Cancer Prevention and Treatment)

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14 pages, 1639 KB

Open AccessCommunication

The Effects of a Grape Seed Procyanidin Extract on Cytochrome P450 3A4 Activity and Inflammatory Mediators in the Lungs of Heavy Active and Former Smokers

by Bingye Xue, Clifford Qualls, Alexander Lanthiez, Qing-Yi Lu, Jieping Yang, Ru-Po Lee, Patricia Neis and Jenny T. Mao

Int. J. Mol. Sci. 2024, 25(23), 13105; https://doi.org/10.3390/ijms252313105 - 6 Dec 2024

Cited by 1 | Viewed by 1578

Abstract

Grape seed procyanidin extract (GSE) is widely used to promote cardiovascular health and has purported anti-inflammatory properties. Chronic inflammation in the lungs caused by environmental toxins such as tobacco smoking plays a pivotal role in lung cancer development. In a modified phase I lung cancer chemoprevention study conducted in heavy active and former smokers using leucoselect phytosome (LP), a standardized grape seed procyanidin extract complexed with soy phospholipids to enhance bioavailability, three months of LP treatment favorably modulated a variety of surrogate endpoint biomarkers, including markers of cell proliferation. In this correlative study, we further analyzed the effects of LP on cytochrome P450 3A4 (CYP3A4) activities by comparing the endogenous conversions of cortisol and cortisone to 6-beta-hydroxycortisol and 6-beta-hydroxycortisone, respectively, before and after LP treatment and the anti-inflammatory effects of LP in the lung microenvironment of these participants by comparing a profile of inflammatory cytokines and chemokines in matched pre- and post-treatment bronchoalveolar lavage (BAL) fluids. LP treatment did not significantly alter CYP3A4 activity, and three months of LP treatment significantly decreased tumor necrosis factor (TNF), C-C Motif Chemokine Ligand 3 (CCL3) and granzyme B in BAL fluids. Furthermore, post-LP-treatment BAL fluids significantly reduced migration/invasion of various human lung neoplastic cells in vitro. Our findings support the anti-inflammatory effects of GSE/LP in the lung microenvironment and its potential utility for reducing cancerizing forces, as well as driving forces for other common respiratory diseases such as chronic obstructive pulmonary disease and asthma, in the lungs of heavy former and active smokers. Full article

(This article belongs to the Special Issue Natural Products in Cancer Prevention and Treatment)

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14 pages, 3520 KB

Open AccessArticle

Stilbene Treatment Reduces Stemness Features in Human Lung Adenocarcinoma Model

by Vittoria Livraghi, Alice Grossi, Anna Scopelliti, Giorgia Senise, Luciano Augusto Gamboa, Samantha Solito, Lucia Anna Stivala, Virginie Sottile and Monica Savio

Int. J. Mol. Sci. 2024, 25(19), 10390; https://doi.org/10.3390/ijms251910390 - 27 Sep 2024

Viewed by 1623

Abstract

Lung cancer is among the most clinically challenging tumors because of its aggressive proliferation, metastasis, and the presence of cancer stem cells (CSCs). Natural bioactive substances have been used for cancer prevention, and, in particular, resveratrol (RSV), a stilbene-based compound with wide biological properties, has been proposed for chemoprevention. Its lesser-known analogue 4,4’-dihydroxy-trans-stilbene (DHS) has demonstrated superior activity both in cell-based assays and in mouse and zebrafish in vivo models. The present study analyzed the effects of DHS and RSV on A549 lung cancer cells, with a particular focus on stemness features and CSCs, isolated by sorting of the side population (SP). The results show that both stilbenes, especially DHS, strongly inhibited cell cycle progression. A reduction in the S phase was induced by DHS, whereas an increase in this phase was obtained with RSV. In addition, 50% reductions in the clonogenicity and soft agar colony formation were observed with the DHS treatment only. Finally, both stilbenes, especially DHS, reduced stemness marker expression in A549 cells and their sorted SP fraction. Spheroid formation, higher in SP cells than in the main population (MP), was significantly reduced after pretreatment with DHS, which was found to decrease SOX2 levels more than RSV. These findings indicate that stilbenes, and particularly DHS, affect stemness features of A549 cells and the SP fraction, suggesting their potential utility as anticancer agents, either alone or combined with chemotherapeutic drugs. Full article

(This article belongs to the Special Issue Natural Products in Cancer Prevention and Treatment)

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Review

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26 pages, 2602 KB

Open AccessReview

Nutrients Lowering Obesity-Linked Chemokines Blamable for Metastasis

by Gabriela Ion, Marinela Bostan, Wanda Elaine Hardman, Margaret Putt McFarland, Coralia Bleotu, Nicoleta Radu, Carmen Cristina Diaconu, Mirela Mihaila, Mihai Dan Caramihai and Camelia Mia Hotnog

Int. J. Mol. Sci. 2025, 26(5), 2275; https://doi.org/10.3390/ijms26052275 - 4 Mar 2025

Viewed by 1650

Abstract

Food intake is an essential contributor to both health and disease. Nutrients contribute to a beneficial metabolic equilibrium at the cellular level, preventing or delaying disease onset. Dietary intake contributes to obesity, and obesity supports further cancer and metastasis. Metastasis, a multifactorial and multistep process, is supported by the systemic inflammation of obesity. Spreading of the cancer cells requires the presence of a plethora of recruiter and regulator molecules. Molecules such as chemokines are provided at high levels by obesity-associated fat depots. Chemokine up-regulation in adipose tissue of obese individuals has been associated with different types of cancers such as breast, prostate, colon, liver, and stomach. Chemokines support all metastasis steps from invasion/migration to intravasation, circulation, extravasation, and ending with colonization. The obesity pool of chemokines supporting these processes includes CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11, CCL18, CCL19, CCL20, CXCL1, CXCL5, CXCL 8, CXCL10, and CXCL12. Keeping obesity under control can be beneficial in reducing the levels of pro-inflammatory chemokines and the risk of poor cancer outcome. Nutrients can help, support, and boost cancer treatment effects or jeopardize the treatment. Constituents with anti-inflammatory and anti-obesity properties such as polyphenols, organosulfur components, fatty acids, curcumin, and vitamin E have a proven beneficial effect in lowering obesity and its contribution to metastasis. Full article

(This article belongs to the Special Issue Natural Products in Cancer Prevention and Treatment)

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15 pages, 2217 KB

Open AccessReview

Potential Anticancer Effects of Isoflavone Prunetin and Prunetin Glycoside on Apoptosis Mechanisms

by Se Hyo Jeong, Hun Hwan Kim, Min Yeong Park, Pritam Bhangwan Bhosale, Abuyaseer Abusaliya, Kwang Hyun Hwang, Yeon Gyu Moon, Jeong Doo Heo, Je Kyung Seong, Meejung Ahn, Kwang Il Park, Chung Kil Won and Gon Sup Kim

Int. J. Mol. Sci. 2024, 25(21), 11713; https://doi.org/10.3390/ijms252111713 - 31 Oct 2024

Cited by 4 | Viewed by 1510

Abstract

Cancer is a deadly disease caused by cells that deviate from the normal differentiation and proliferation behaviors and continue to multiply. There is still no definitive cure, and many side effects occur even after treatment. However, apoptosis, one of the programs imprinted on cells, is becoming an important concept in controlling cancer. Flavonoids are polyphenolic compounds found in plants, are naturally bioactive compounds, have been studied for their anticancer effects, and have fewer side effects than chemical treatments. Isoflavones are phytoestrogens belonging to the flavonoid family, and this review discusses in depth the potential anticancer effects of prunetin, one of the many flavonoid families, via the apoptotic mechanism. In addition, a glycoside called prunetin glucoside has been investigated for its anticancer effects through apoptotic mechanisms. The primary intention of this review is to identify the effects of prunetin and its glycoside, prunetin glucoside, on cell death signaling pathways in various cancers to enhance the potential anticancer effects of these natural compounds. Full article

(This article belongs to the Special Issue Natural Products in Cancer Prevention and Treatment)

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22 pages, 3994 KB

Open AccessReview

NRF2 Modulators of Plant Origin and Their Ability to Overcome Multidrug Resistance in Cancers

by Piotr Wadowski, Michał Juszczak and Katarzyna Woźniak

Int. J. Mol. Sci. 2024, 25(21), 11500; https://doi.org/10.3390/ijms252111500 - 26 Oct 2024

Cited by 5 | Viewed by 1723

Abstract

Cancer is one of the most common causes of death in the world. Despite the fact that there are many types of therapies available, cancer treatment remains a major challenge. The main reason for the ineffectiveness of chemotherapy is the acquisition of multidrug resistance (MDR) by cancer cells. One of the factors responsible for the acquisition of MDR is the NRF2 transcription factor, which regulates the expression of proteins such as HO-1, NQO1, MRP1, MRP2, and GST. In normal cells, NRF2 is the first line of defense against oxidative stress, thereby preventing carcinogenesis. Still, its hyperactivation in cancer cells causes them to acquire MDR, which significantly reduces or eliminates the effectiveness of chemotherapy. Considering the important role NRF2 plays in the acquisition of MDR, its modulators and, above all, inhibitors are being sought after, including among compounds of plant origin. NRF2 inhibition may prove to be a key element of anticancer therapy. This review summarizes the current state of knowledge about plant NRF2 inhibitors and presents the effects of their use in overcoming MDR in cancer. Full article

(This article belongs to the Special Issue Natural Products in Cancer Prevention and Treatment)

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