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Cytotoxicity, Antioxidant and Anticancer Activity of Natural Products, 2nd Edition

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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: 20 January 2026 | Viewed by 7895

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Prof. Dr. Balik Dzhambazov

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Faculty of Biology, Plovdiv University “Paisii Hilendarski”, 24 Tsar Assen Str., 4000 Plovdiv, Bulgaria
Interests: cell biology; immunology; immunomodulation; biomarkers; autoimmune diseases; allergy; cytotoxicity; anticancer activity; natural products; probiotics; prebiotics; nanoparticles
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Dear Colleagues,

The main reason for the high economic and social burden of cancer is the lack of effective drug agents and therapies. Therefore, the efforts of a large part of the scientific community are directed at identifying new anticancer compounds from natural sources (plants, algae or other organisms) as well as developing new formulations in order to increase the healing potential and minimize the side effects of currently used therapeutic agents. Thus, the search for new biologically active compounds is important for the discovery of new drugs relative to the treatment of cancer.

Evaluation of the anticancer activity is performing by detection of specific cytotoxicity of the test agent, affecting fundamental cellular functions of cancer cells causing their death. Changes in metabolic processes (e.g., mitochondrial activity) and the level of ATP or free radicals are early indicators of cell damage. Disruption of the plasma membrane integrity increases the concentration of enzymes in the extracellular environment, which together with the DNA fragmentation are key parameters for assessing the cell damage. Therefore, anticancer activity is assessed on the basis of specific cytotoxicity observed by examining the basic parameters of cell damage.

This Special Issue aims to publish original research studies related to the isolation and characterization of natural products with anticancer activity as well as their molecular mechanisms of action or effects on a particular metabolic or signalling pathway. Authors are invited to submit their high-quality articles, reviews or short communications concerning this topic. Multidisciplinary studies involving in vitro and/or in vivo experiments that address specific delivery of anticancer drugs by using different novel technologies based on natural products are also welcome.

Importantly, the exact active ingredient of plant extract must be reported in the submitted research manuscript, since papers describing effects of mixed extraction from plants will not be accepted. More published papers could be found in the closed Special Issue: Cytotoxicity, Antioxidant and Anticancer Activity of Natural Products.

Prof. Dr. Balik Dzhambazov
Guest Editor

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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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

natural products
anticancer activity
apoptosis
immunomodulation
free radicals
proliferation
phytomolecules
nanoparticles
drug delivery

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Published Papers (7 papers)

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Research

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23 pages, 8387 KiB

Open AccessArticle

Solvent Fractionation of Polygonum cuspidatum Sieb. et Zucc. for Antioxidant, Biological Activity, and Chromatographic Characterization

by Yuchen Cheng, Yuri Kang and Woonjung Kim

Int. J. Mol. Sci. 2025, 26(14), 7011; https://doi.org/10.3390/ijms26147011 - 21 Jul 2025

Viewed by 229

Abstract

This study investigated the natural bioactive compounds in Polygonum cuspidatum Sieb. et Zucc. (P. cuspidatum) by fractionating a 70% ethanol extract using n-hexane, chloroform, ethyl acetate, n-butanol, and water. The total polyphenol and flavonoid contents of each fraction were determined, and their antioxidant activities were evaluated using DPPH, ABTS, and FRAP assays. Additionally, the anti-diabetic potential was assessed via α-glucosidase inhibitory activity, while anti-obesity activity was evaluated using lipase inhibitory activity. The fractions were also tested for tyrosinase and elastase inhibitory activities to assess their skin-whitening and anti-wrinkle potential, and their antibacterial activity against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa was determined using the agar diffusion method. Finally, bioactive compounds were identified and quantified using HPLC and GC–MSD. The results showed that the ethyl acetate fraction possessed the highest total polyphenol content (0.53 ± 0.01 g GAE/g) and total flavonoid content (0.19 ± 0.02 g QE/g). It also exhibited strong antioxidant activity, with the lowest DPPH radical scavenging IC₅₀ (0.01 ± 0.00 mg/mL), ABTS radical scavenging IC₅₀ (0.06 ± 0.00 mg/mL), and the highest FRAP value (6.02 ± 0.30 mM Fe²⁺/mg). Moreover, it demonstrated potent enzyme inhibitory activities, including tyrosinase inhibitory activity (67.78 ± 2.50%), elastase inhibitory activity (83.84 ± 1.64%), α-glucosidase inhibitory activity (65.14 ± 10.29%), and lipase inhibitory activity (85.79 ± 1.04%). In the antibacterial activity, the ethyl acetate fraction produced a clear inhibitory zone of 19.50 mm against Staphylococcus aureus, indicating notable antibacterial activity. HPLC-PDA and GC–MSD analyses identified tannic acid and emodin as the major bioactive constituents. These findings suggest that the ethyl acetate fraction of P. cuspidatum extract, rich in polyphenol and flavonoid compounds, is a promising natural source of bioactive ingredients for applications in the food, pharmaceutical, and cosmetic industries. Further research is needed to explore its mechanisms and therapeutic applications. Full article

(This article belongs to the Special Issue Cytotoxicity, Antioxidant and Anticancer Activity of Natural Products, 2nd Edition)

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19 pages, 4003 KiB

Open AccessArticle

Anti-lymphoma Activity of Acyclic Terpenoids and Its Structure–Activity Relationship: In Vivo, In Vitro, and In Silico Studies

by Fernando Calzada, Jesica Ramírez-Santos, Rosa María Ordoñez-Razo, Miguel Valdes, Claudia Velázquez and Elizabeth Barbosa

Int. J. Mol. Sci. 2025, 26(12), 5683; https://doi.org/10.3390/ijms26125683 - 13 Jun 2025

Viewed by 451

Abstract

Terpenoids are a large group of molecules present in several plant species and in many essential oils reported with cytotoxic and anticancer properties. The aim of this study was to evaluate the anticancer activity of eleven acyclic terpenes; seven monoterpenoids: geranyl acetate (C1), geranic acid (C2), citral (C3, mixture of neral and geranial), geraniol (C4), methyl geranate (C5), nerol (C6) and citronellic acid (C7); two sesquiterpenes: farnesal (C8) and farnesol (C9); and one triterpene: squalene (C10), using in vivo, in vitro, and in silico models. Anti-lymphoma activity was evaluated using male Balb/c mice inoculated with U-937 cells. Cytotoxic activity was evaluated using the WST-1 method. Computer tools were used to obtain a molecular docking study, measuring pharmacokinetic and toxicological properties of the acyclic terpenoids with greater antitumor activity. The results showed that the terpenoids with the highest cytotoxic and nodal growth inhibitory activity were C3, C4, C6, and C9, and their effects were better compared to MTX. The data obtained suggest that the anti-lymphoma activity could be due to the presence of the aldehyde, hydroxyl, and acetate groups in the C1 of the monoterpenes and sesquiterpenes evaluated. The theoretical results obtained from molecular docking showed that geranial (C3A), neral (C3B), C9, and C6 terpenoids obtained a higher affinity for the HMG-CoA reductase enzyme and suggest that it could be a target to induce anti-lymphoma activity of bioactive terpenoids. Our study provides evidence that C3, C6, and C9 could be potential anticancer agents for the treatment of histiocytic lymphoma. Full article

(This article belongs to the Special Issue Cytotoxicity, Antioxidant and Anticancer Activity of Natural Products, 2nd Edition)

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18 pages, 1331 KiB

Open AccessArticle

Dihydroquercetin and Related Flavonoids in Antioxidant Formulations with α-Tocopherol

by Vera Olicheva, Vladimir Beloborodov, Shamimeh Sharifi, Anna Dubrovskaya, Anastasiya Zhevlakova, Irina Selivanova and Igor Ilyasov

Int. J. Mol. Sci. 2025, 26(12), 5659; https://doi.org/10.3390/ijms26125659 - 13 Jun 2025

Viewed by 729

Abstract

The concomitant utilization of flavonoids and α-tocopherol has the potential to establish a comprehensive antioxidant system that operates in both hydrophilic and lipophilic environments. The objective of this study was to examine the antioxidant interactions between dihydroquercetin, a flavonoid that has shown promise in various studies, as well as structurally related flavonoids, and α-tocopherol in various ratios. The antioxidant capacity was assessed using two ABTS^•+ radical-cation inhibition assays: a decolorization assay and a lag-time assay. The results of this study indicated that formulations of dihydroquercetin, quercetin, rutin, or morin with α-tocopherol exhibited additive or mildly subadditive interactions, independent of their ratios. A two-phase pattern was exhibited by the lag-time data, which, in comparison with individual components, allowed us to suggest that α-tocopherol appeared to dominate the initial phase of radical scavenging, while flavonoids became active in the later phase. This finding indicates that α-tocopherol may play a role in protecting flavonoids from premature oxidation in alcoholic media. The findings could prove valuable for the rational design of antioxidant formulations in the nutraceutical, cosmeceutical, and pharmaceutical industries. Additionally, the two-stage antioxidant behavior offers prospects for the formulation of straightforward, cost-effective analytical approaches to measure components in binary antioxidant formulations. Full article

(This article belongs to the Special Issue Cytotoxicity, Antioxidant and Anticancer Activity of Natural Products, 2nd Edition)

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25 pages, 6518 KiB

Open AccessArticle

Tolypothrix Strains (Cyanobacteria) as a Source of Bioactive Compounds with Anticancer, Antioxidant and Anti-Inflammatory Activity

by Ivanka Teneva, Tsvetelina Batsalova, Dzhemal Moten, Zhana Petkova, Olga Teneva, Maria Angelova-Romova, Ginka Antova and Balik Dzhambazov

Int. J. Mol. Sci. 2025, 26(11), 5086; https://doi.org/10.3390/ijms26115086 - 26 May 2025

Viewed by 560

Abstract

Cyanobacterial extracts offer significant potential for the development of new natural antioxidants and biologically active compounds with applications in various industries. Data on the genus Tolypothrix are limited; therefore, the aim of the present study was to investigate the anticancer, antioxidant and anti-inflammatory activity of extracts prepared from strains of this genus. Cytotoxicity and anticancer activity were evaluated by in vitro tests with four cell lines using the MTT assay. The assessment of antioxidant activity was performed by the DPPH and ABTS methods in combination with the calculation of the total phenolic content. Anti-inflammatory activity was investigated using the LPS-stimulated macrophage model (RAW264.7) and subsequent measurement of the levels of secreted cytokines IL-6 and TNF-α. The lipid content and fatty acid composition of the non-polar extracts were determined by gas chromatography (GC). To elucidate the mechanism of cytotoxicity/anticancer action of the non-polar extracts, the effects of stearidonic acid, which was detected in four of the studied cyanobacterial strains, were additionally tested on the same cell lines. A molecular docking analysis was performed simulating the interaction between stearidonic acid and its target molecules and receptors (ALOX5, COX-2, NF-kB and PPAR-γ). In all cancer cell lines (but not in the normal one), dose-dependent cytotoxic effects were observed after exposure to different concentrations of non-polar Tolypothrix extracts. The most pronounced inhibitory effect was observed on the HT-29 cell line, with an IC₅₀ value of 106.27 µg/mL. A dose-dependent antioxidant effect was established for all tested extracts, measured by both DPPH and ABTS methods. All non-polar extracts reduced the production of pro-inflammatory cytokines IL-6 and TNF-α in LPS-stimulated macrophages RAW264.7, and the effects were dose-dependent. Analysis of the fatty acid composition revealed 26 different fatty acids. Our conclusion is that the Tolypothrix strains exhibit anticancer, antioxidant, and anti-inflammatory activity and could be a promising source for the production of natural products. Full article

(This article belongs to the Special Issue Cytotoxicity, Antioxidant and Anticancer Activity of Natural Products, 2nd Edition)

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24 pages, 4706 KiB

Open AccessArticle

New Dimethoxyaryl-Sesquiterpene Derivatives with Cytotoxic Activity Against MCF-7 Breast Cancer Cells: From Synthesis to Topoisomerase I/II Inhibition and Cell Death Mechanism Studies

by Ileana Araque, Rut Vergara, Jaime Mella, Pablo Aránguiz, Luis Espinoza-Catalán, Cristian O. Salas, Alejandro F. Barrero, José Quílez del Moral, Joan Villena and Mauricio A. Cuellar

Int. J. Mol. Sci. 2025, 26(10), 4539; https://doi.org/10.3390/ijms26104539 - 9 May 2025

Viewed by 874

Abstract

Breast cancer is a prevalent type of cancer worldwide, leading to both high incidence and mortality, and hence, effective and safe drugs are needed. Because of this, the use of natural products and their derivatives has become a popular strategy for developing new chemotherapeutic agents. In this study, 17 new sesquiterpene-aryl derivatives were synthesized using (−)-drimenol as the starting material. The cytotoxicity of these semi-synthetic derivatives was determined in MCF-7 cells, a breast cancer model, and in a non-tumor cell line, MCF-10, to evaluate selectivity. The results show that five of these sesquiterpene derivatives had IC₅₀ values between 9.0 and 25 µM. Of these, compound 14c stands out for its higher cytotoxicity in MCF-7 cells but lower cytotoxicity in MCF-10 cells, being more selective than daunorubicin (selective index values of 44 and 28, respectively). In addition, compound 14c induced oxidative stress in MCF-7 cells, activated caspases-3/7, and selectively inhibited topoisomerase II (TOP2) versus topoisomerase I (TOP1) in MCF-7 cells. In silico studies allowed us to propose a binding mode for 14c to the TOP2 DNA complex to validate the experimental results. Therefore, this study demonstrated the importance of aryl-sesquiterpene structures and their promising profiles in the search for new bioinspired antitumor drugs in natural products. Full article

(This article belongs to the Special Issue Cytotoxicity, Antioxidant and Anticancer Activity of Natural Products, 2nd Edition)

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19 pages, 7566 KiB

Open AccessArticle

Cytotoxicity, Proapoptotic Activity and Drug-like Potential of Quercetin and Kaempferol in Glioblastoma Cells: Preclinical Insights

by Magdalena Kusaczuk, Elena Tovar-Ambel, Paola Martín-Cabrera, Mar Lorente, Nélida Salvador-Tormo, Agnieszka Mikłosz, Adrian Chabowski, Guillermo Velasco and Monika Naumowicz

Int. J. Mol. Sci. 2024, 25(19), 10740; https://doi.org/10.3390/ijms251910740 - 5 Oct 2024

Cited by 5 | Viewed by 2537

Abstract

Despite the increasing understanding of the pathogenesis of glioblastoma (GBM), treatment options for this tumor remain limited. Recently, the therapeutic potential of natural compounds has attracted great interest. Thus, dietary flavonoids quercetin (QCT) and kaempferol (KMF) were investigated as potential cytostatic agents in GBM. Moreover, the physicochemical properties of QCT and KMF, determining their bioavailability and therapeutic efficiency, were evaluated. We proved that both polyphenols significantly reduced the viability of GBM cells. We also demonstrated that both QCT and KMF evoked the cytotoxic effect in T98G cells via induction of apoptotic cell death as shown by increased activity of caspase 3/7 and caspase 9 together with an overexpression of the cleaved form of PARP. Apoptosis was additionally accompanied by the activation of stress responses in QCT- and KMF-treated cells. Both polyphenols caused oxidative stress and endoplasmic reticulum (ER) stress, as demonstrated by the increased generation of reactive oxygen species (ROS), deregulated expressions of superoxide dismutases (SOD2 and Sod1 on protein and transcriptomic levels, respectively), as well as an overexpression of ERO1α, GRP78, p-JNK, and an up-regulation of Chop, Atf4 and Atf6α genes. The antitumor effect of QCT and KMF was also confirmed in vivo, showing reduced growth of tumor xenografts in the chick chorioallantoic membrane (CAM) experiment. Moreover, electrophoretic light scattering (ELS) was used to measure the zeta potential of cell membranes upon exposition to QCT and KMF. Additionally, on the basis of existing physicochemical data, the drug-likeness score of QCT and KMF was evaluated. Analyses showed that both compounds accomplish Lipinski’s Rule of 5, and they both fit into the criteria of good central nervous system (CNS) drugs. Altogether, our data support the idea that QCT and KMF might be plausible candidates for evaluation as therapeutic agents in preclinical models of glioblastoma. Full article

(This article belongs to the Special Issue Cytotoxicity, Antioxidant and Anticancer Activity of Natural Products, 2nd Edition)

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Review

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14 pages, 1598 KiB

Open AccessReview

Research on the Action and Mechanism of Pharmacological Components of Omphalia lapidescens

by Keyang Xu, Li Wang and Dan He

Int. J. Mol. Sci. 2024, 25(20), 11016; https://doi.org/10.3390/ijms252011016 - 13 Oct 2024

Viewed by 1607

Abstract

Omphalia lapidescens is a macrofungus that is used in traditional Chinese medicine for its insecticidal and stagnation-relieving properties. The active ingredients of this fungus including proteins, polysaccharides and sterols have been demonstrated to exhibit antiparasitic, anti-inflammatory, and antitumor effects. Omphalia has been used in clinical cancer treatment. Many studies on Omphalia have concentrated on its cytotoxicity and anticancer effects. However, the investigation of its natural metabolites remains a significant area for further research. This review presents a comprehensive analysis of the research progress concerning the pharmacological components of Omphalia. The aim of this discussion is to provide a reference for further in-depth study of Omphalia, with the objective of exploring its potential value. Therefore, the focus of this review was on the classification of metabolites in Omphalia and their mechanisms of action. Full article

(This article belongs to the Special Issue Cytotoxicity, Antioxidant and Anticancer Activity of Natural Products, 2nd Edition)

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