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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 April 2025) | Viewed by 13601

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Special Issue Editors

Dr. Patricia M. A. Silva

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1. UNIPRO – Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS-CESPU), 4585-116 Gandra, Portugal
2. TOXRUN – Toxicology Research Unit, University Institute of Health Sciences, CESPU, CRL, 4585-116 Gandra, Portugal
Interests: anticancer strategies; targeted therapy; mitosis; apoptosis; drug screening; bioactive compounds
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Dr. Honorina Cidade

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Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira n° 228, 4050-313 Porto, Portugal
Interests: medicinal chemistry; organic synthesis; drug discovery; anticancer activity; antimicrobial activity; chiral drugs; natural products
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Dr. Hassan Bousbaa

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UNIPRO—Unidade de Investigação em Patologia e Reabilitação Oral, IUCS, CESPU, Rua Central de Gandra, 1317, 4585-116 Gandra PRD, Portugal
Interests: targeted anticancer therapy; targeting mitosis for cancer therapy; antimitotic agents; biological evaluation of natural and synthetic compounds; cancer biomarkers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer is one of the leading causes of death worldwide, and its incidence continues to increase dramatically. The estimated number of new cases from 2020 to 2040 is 10.9 million (a 56.5% increase), and thus this topic continues to be relevant. The complexity of cancer identities, the individuality of each patient, and the emergence of resistance to cancer treatment make it difficult to obtain the desired clinical benefit, largely contributing to the large numbers. In the cancer research field, several therapeutic strategies have been extensively explored, from the discovery of new bioactive compounds to the repurposing of currently available drugs, yet challenges remain. In this regard, and given the chemistry diversity in nature, the use of compounds based on natural sources, including plants, bacteria, or other living organisms, has gained particular attention as they could be more reliable, economical, and safer.

Hence, this research topic aims to highlight the recent advances and breakthroughs in emerging anticancer strategies based on bioactive compounds alone or in combination with other clinical standard treatments, providing scientific evidence on their mechanisms of action.

We welcome submissions of original research and review articles. Topics for this Special Issue include, but are not limited to:

Identification of novel bioactive compounds with anticancer potential;
Characterization/Elucidation of the mechanism of action of new or old bioactive compounds;
Methodologies and models to study and characterize bioactive compounds in cancers;
Strategies of drug delivery for bioactive compounds in cancers.

Dr. Patricia M. A. Silva
Dr. Honorina Cidade
Dr. Hassan Bousbaa
Guest Editors

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

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

anticancer strategies
bioactive compounds
natural products
synthetic products
medicinal chemistry
drug repurposing
drug delivery systems

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Published Papers (8 papers)

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Research

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15 pages, 7611 KiB

Open AccessArticle

Pomiferin Induces Antiproliferative and Pro-Death Effects in High-Risk Neuroblastoma Cells by Modulating Multiple Cell Death Pathways

by Manu Gnanamony, Maria Thomas, Thu Hien Nguyen, Korey Brownstein and Pedro A. de Alarcon

Int. J. Mol. Sci. 2025, 26(8), 3600; https://doi.org/10.3390/ijms26083600 - 11 Apr 2025

Viewed by 184

Abstract

Resistance to chemotherapy-induced apoptosis significantly hinders the successful treatment of high-risk neuroblastoma (NB). Natural compounds, such as osajin and pomiferin—isoflavones extracted from Osage orange (Maclura pomifera [Raf.] Schneid.)—have known anti-inflammatory and anticancer properties and may have the potential as a therapeutic agent to target conventional drug resistance in NB. In this study, we investigated the antiproliferative and cytotoxic potential of osajin and pomiferin in NB cell lines. Both compounds reduced proliferation and induced cytotoxicity, with pomiferin showing a lower IC50 than osajin. Using multiple techniques, we show that pomiferin induced a dose-dependent increase in apoptosis. In addition to apoptosis, we identified the activation of multiple cell death pathways. Pomiferin induced ferroptosis by inhibiting GPX4 and increasing lipid peroxidation. In addition, pomiferin treatment significantly impaired autophagic machinery. LAN5, a MYCN-amplified cell line, showed increased gasdermin E cleavage in response to pomiferin, suggesting pyroptosis. No changes were observed in phosphorylated MLKL, indicating the absence of necroptosis. In conclusion, our comprehensive evaluation demonstrates that pomiferin activates multiple cell death pathways in high-risk NB cells, potentially offering a valuable strategy to overcome drug resistance to conventional chemotherapy. Full article

(This article belongs to the Special Issue Bioactive Compounds in Cancers)

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22 pages, 4169 KiB

Open AccessArticle

Rhodanine–Piperazine Hybrids as Potential VEGFR, EGFR, and HER2 Targeting Anti-Breast Cancer Agents

by Jacek Szczepański, Dmytro Khylyuk, Agnieszka Korga-Plewko, Mariola Michalczuk, Sławomir Mańdziuk, Magdalena Iwan and Nazar Trotsko

Int. J. Mol. Sci. 2024, 25(22), 12401; https://doi.org/10.3390/ijms252212401 - 19 Nov 2024

Cited by 1 | Viewed by 976

Abstract

Breast cancer is one of the most common malignancies affecting women worldwide, with a significant need for novel therapeutic agents to target specific molecular pathways involved in tumor progression. In this study, a series of rhodanine–piperazine hybrids were designed, synthesized, and evaluated for their anticancer activity, targeting key tyrosine kinases such as VEGFR, EGFR, and HER2. Biological screening against breast cancer cell lines (MCF-7, MDA-MB-231, T47D, and MDA-MB-468) revealed 3 of the 13 tested compounds as the most potent, with 5-({4-[bis(4-fluorophenyl)methyl]piperazin-1-yl}methylidene)-2-thioxo-1,3-thiazolidin-4-one (12) showing the strongest activity, particularly against the MCF-7 and MDA-MB-468 cell lines. Molecular docking studies indicated favorable binding interactions of compound 12 and its 3-phenyl-2-thioxo-1,3-thiazolidin-4-one analogue (15) with HER2, VEGFR, and EGFR, and molecular dynamics simulations further confirmed their stable binding to HER2. These findings highlight the potential of rhodanine–piperazine hybrids as promising leads for developing new anticancer agents targeting breast cancer, particularly HER2-positive subtypes. Further structural optimization could enhance their efficacy and therapeutic profile. Full article

(This article belongs to the Special Issue Bioactive Compounds in Cancers)

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19 pages, 22347 KiB

Open AccessArticle

GdVO₄:Eu³⁺ and LaVO₄:Eu³⁺ Nanoparticles Exacerbate Oxidative Stress in L929 Cells: Potential Implications for Cancer Therapy

by Yuriy Kot, Vladimir Klochkov, Volodymyr Prokopiuk, Olha Sedyh, Liliya Tryfonyuk, Ganna Grygorova, Nina Karpenko, Oleksandr Tomchuk, Kateryna Kot, Anatolii Onishchenko, Svetlana Yefimova and Anton Tkachenko

Int. J. Mol. Sci. 2024, 25(21), 11687; https://doi.org/10.3390/ijms252111687 - 30 Oct 2024

Viewed by 1407

Abstract

The therapeutic potential of redox-active nanoscale materials as antioxidant- or reactive oxygen species (ROS)-inducing agents was intensely studied. Herein, we demonstrate that the synthesized and characterized GdVO₄:Eu³⁺ and LaVO₄:Eu³⁺ nanoparticles, which have been already shown to have redox-active, anti-inflammatory, antibacterial, and wound healing properties, both in vitro and in vivo, worsen oxidative stress of L929 cells triggered by hydrogen peroxide or tert-butyl hydroperoxide (tBuOOH) at the concentrations that are safe for intact L929 cells. This effect was observed upon internalization of the investigated nanosized materials and is associated with the cleavage of caspase-3 and caspase-9 without recruitment of caspase-8. Such changes in the caspase cascade indicate activation of the intrinsic caspase-9-dependent mitochondrial but not the extrinsic death, receptor-mediated, and caspase-8-dependent apoptotic pathway. The GdVO₄:Eu³⁺ and LaVO₄:Eu³⁺ nanoparticle-induced apoptosis of oxidatively compromised L929 cells is mediated by ROS overgeneration, Ca²⁺ overload, endoplasmic reticulum stress-associated JNK (c-Jun N-terminal kinase), and DNA damage-inducible transcript 3 (DDIT3). Our findings demonstrate that GdVO₄:Eu³⁺ and LaVO₄:Eu³⁺ nanoparticles aggravate the oxidative stress-induced damage to L929 cells, indicating that they might potentially be applied as anti-cancer agents. Full article

(This article belongs to the Special Issue Bioactive Compounds in Cancers)

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17 pages, 4397 KiB

Open AccessArticle

Exploring the Anticancer Potential of Phenolic nor-Triterpenes from Celastraceae Species

by Carolina P. Reyes, Alejandro Ardiles, Laura Anaissi-Afonso, Aday González-Bakker, José M. Padrón, Ignacio A. Jiménez, Félix Machín and Isabel L. Bazzocchi

Int. J. Mol. Sci. 2024, 25(17), 9470; https://doi.org/10.3390/ijms25179470 - 30 Aug 2024

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Abstract

To explore new compounds with antitumour activity, fifteen phenolic nor-tripterpenes isolated from Celastraceae species, Maytenus jelskii, Maytenus cuzcoina, and Celastrus vulcanicola, have been studied. Their chemical structures were elucidated through spectroscopic and spectrometric techniques, resulting in the identification of three novel chemical compounds. Evaluation on human tumour cell lines (A549 and SW1573, non-small cell lung; HBL-100 and T-47D, breast; HeLa, cervix, and WiDr, colon) revealed that three compounds, named 6-oxo-pristimerol, demethyl-zeylasteral, and zeylasteral, exhibited significant activity (GI₅₀ ranging from 0.45 to 8.6 µM) on at least five of the cell lines tested. Continuous live cell imaging identified apoptosis as the mode of action of selective cell killing in HeLa cells. Furthermore, their effect on a drug-sensitive Saccharomyces cerevisiae strain has been investigated to deepen on their mechanism of action. In dose-response growth curves, zeylasteral and 7α-hydroxy-blepharodol were markedly active. Additionally, halo assays were conducted to assess the involvement of oxidative stress and/or mitochondrial function in the anticancer profile, ruling out these modes of action for the active compounds. Finally, we also delve into the structure-activity relationship, providing insights into how the molecular structure of these compounds influences their biological activity. This comprehensive analysis enhances our understanding of the therapeutic potential of this triterpene type and underscores its relevance for further research in this field. Full article

(This article belongs to the Special Issue Bioactive Compounds in Cancers)

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22 pages, 3850 KiB

Open AccessArticle

Synthesis, Anticancer Activity, and Docking Studies of Novel Hydroquinone-Chalcone-Pyrazoline Hybrid Derivatives

by Javier Maldonado, Alfonso Oliva, Leda Guzmán, Aurora Molinari and Waldo Acevedo

Int. J. Mol. Sci. 2024, 25(13), 7281; https://doi.org/10.3390/ijms25137281 - 2 Jul 2024

Viewed by 1882

Abstract

A novel series of antitumor hybrids was synthesized using 1,4-benzohydroquinone and chalcone, furane, or pyrazoline scaffolds. This were achieved through isosteric substitution of the aryl group of the chalcone β-carbon with the furanyl moiety and structural modification of the α,β-unsaturated carbonyl system. The potential antitumor activity of these hybrids was evaluated in vivo on MCF-7 breast adenocarcinoma and HT-29 colorectal carcinoma cells, demonstrating cytotoxic activity with IC₅₀ values ranging from 28.8 to 124.6 µM. The incorporation of furan and pyrazoline groups significantly enhanced antiproliferative properties compared to their analogues and precursors (VII–X), which were inactive against both neoplastic cell lines. Compounds 4, 5, and 6 exhibited enhanced cytotoxicity against both cell lines, whereas compound 8 showed higher cytotoxic activity against HT-29 cells. Molecular docking studies revealed superior free-energy values (ΔG_bin) for carcinogenic pathway-involved kinase proteins, with our in silico data suggesting that these derivatives could be promising chemotherapeutic agents targeting kinase pathways. Among all the synthesized PIBHQ compounds, derivatives 7 and 8 exhibited the best drug-likeness properties, with values of 0.53 and 0.83, respectively. ADME results collectively suggest that most of these compounds hold promise as potential candidates for preclinical assays. Full article

(This article belongs to the Special Issue Bioactive Compounds in Cancers)

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19 pages, 6375 KiB

Open AccessArticle

Evaluation of Antitumor Activity of Xanthones Conjugated with Amino Acids

by Flávia Barbosa, Joana Araújo, Virgínia M. F. Gonçalves, Andreia Palmeira, Andrea Cunha, Patrícia M. A. Silva, Carla Fernandes, Madalena Pinto, Hassan Bousbaa, Odília Queirós and Maria Elizabeth Tiritan

Int. J. Mol. Sci. 2024, 25(4), 2121; https://doi.org/10.3390/ijms25042121 - 9 Feb 2024

Cited by 1 | Viewed by 1870

Abstract

Cancer is a complex disease characterized by several alterations, which confer, to the cells, the capacity to proliferate uncontrollably and to resist cellular death. Multiresistance to conventional chemotherapy drugs is often the cause of treatment failure; thus, the search for natural products or their derivatives with therapeutic action is essential. Chiral derivatives of xanthones (CDXs) have shown potential inhibitory activity against the growth of some human tumor cell lines. This work reports the screening of a library of CDXs, through viability assays, in different cancer cell lines: A375-C5, MCF-7, NCI-H460, and HCT-15. CDXs’ effect was analyzed based on several parameters of cancer cells, and it was also verified if these compounds were substrates of glycoprotein-P (Pgp), one of the main mechanisms of resistance in cancer therapy. Pgp expression was evaluated in all cell lines, but no expression was observed, except for HCT-15. Also, when a humanized yeast expressing the human gene MDR1 was used, no conclusions could be drawn about CDXs as Pgp substrates. The selected CDXs did not induce significant differences in the metabolic parameters analyzed. These results show that some CDXs present promising antitumor activity, but other mechanisms should be triggered by these compounds. Full article

(This article belongs to the Special Issue Bioactive Compounds in Cancers)

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20 pages, 5517 KiB

Open AccessArticle

BP-M345 as a Basis for the Discovery of New Diarylpentanoids with Promising Antimitotic Activity

by Joana Moreira, Patrícia M. A. Silva, Eliseba Castro, Lucília Saraiva, Madalena Pinto, Hassan Bousbaa and Honorina Cidade

Int. J. Mol. Sci. 2024, 25(3), 1691; https://doi.org/10.3390/ijms25031691 - 30 Jan 2024

Cited by 1 | Viewed by 1460

Abstract

Recently, the diarylpentanoid BP-M345 (5) has been identified as a potent in vitro growth inhibitor of cancer cells, with a GI₅₀ value between 0.17 and 0.45 µM, showing low toxicity in non-tumor cells. BP-M345 (5) promotes mitotic arrest by interfering with mitotic spindle assembly, leading to apoptotic cell death. Following on from our previous work, we designed and synthesized a library of BP-M345 (5) analogs and evaluated the cell growth inhibitory activity of three human cancer cell lines within this library in order to perform structure–activity relationship (SAR) studies and to obtain compounds with improved antimitotic effects. Four compounds (7, 9, 13, and 16) were active, and the growth inhibition effects of compounds 7, 13, and 16 were associated with a pronounced arrest in mitosis. These compounds exhibited a similar or even higher mitotic index than BP-M345 (5), with compound 13 displaying the highest antimitotic activity, associated with the interference with mitotic spindle dynamics, inducing spindle collapse and, consequently, prolonged mitotic arrest, culminating in massive cancer cell death by apoptosis. Full article

(This article belongs to the Special Issue Bioactive Compounds in Cancers)

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Review

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24 pages, 2272 KiB

Open AccessReview

Natural Alkaloids in Cancer Therapy: Berberine, Sanguinarine and Chelerythrine against Colorectal and Gastric Cancer

by Anna Duda-Madej, Szymon Viscardi, Wiktoria Szewczyk and Ewa Topola

Int. J. Mol. Sci. 2024, 25(15), 8375; https://doi.org/10.3390/ijms25158375 - 31 Jul 2024

Cited by 3 | Viewed by 3030

Abstract

The rising incidence of colorectal cancer (CRC) and gastric cancer (GC) worldwide, coupled with the limited effectiveness of current chemotherapeutic agents, has prioritized the search for new therapeutic options. Natural substances, which often exhibit cytostatic properties, hold significant promise in this area. This review evaluates the anticancer properties of three natural alkaloids—berberine, sanguinarine, and chelerythrine—against CRC and GC. In vivo and in vitro studies have demonstrated that these substances can reduce tumor volume and inhibit the epithelial–mesenchymal transition (EMT) of tumors. At the molecular level, these alkaloids disrupt key signaling pathways in cancer cells, including mTOR, MAPK, EGFR, PI3K/AKT, and NF-κB. Additionally, they exhibit immunomodulatory effects, leading to the induction of programmed cell death through both apoptosis and autophagy. Notably, these substances have shown synergistic effects when combined with classical cytostatic agents such as cyclophosphamide, 5-fluorouracil, cetuximab, and erlotinib. Furthermore, berberine has demonstrated the ability to restore sensitivity in individuals originally resistant to cisplatin GC. Given these findings, natural compounds emerge as a promising option in the chemotherapy of malignant gastrointestinal tumors, particularly in cases with limited treatment options. However, more research is necessary to fully understand their therapeutic potential. Full article

(This article belongs to the Special Issue Bioactive Compounds in Cancers)

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