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Advances in Anticancer Activity of Natural Products and Related Compounds
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Advances in Anticancer Activity of Natural Products and Related Compounds

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: 31 May 2026 | Viewed by 6057

Special Issue Editor

Dr. Alexandra Mioc

E-Mail Website
Guest Editor
Department of Pharmacology—Pharmacotherapy, Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy, 2 Eftimie Murgu, 300041 Timisoara, Romania
Interests: natural products; molecular mechanisms of action; structure-activity relationships; delivery systems

Special Issue Information

Dear Colleagues,

The exploration of natural products and their derivatives has long served as a foundation in the discovery of novel anticancer agents. Nature offers a vast chemical diversity, providing compounds with unique structures and potent bioactivities. This Special Issue, entitled “Advances in Anticancer Activity of Natural Products and Related Compounds”, seeks to highlight the recent advances in the identification, characterization, and application of natural compounds in cancer research. We welcome the submission of original research articles and reviews that bring about novel insights into the molecular mechanisms of action, structure–activity relationships, and innovative delivery systems of these bioactive agents. Studies on the synergistic effects of natural products with conventional therapies, as well as investigations into overcoming drug resistance, are also encouraged. This Special Issue aims to inspire interdisciplinary collaborations and foster the development of natural product-based cancer therapeutics that will ultimately contribute to improvements in patient outcomes.

Dr. Alexandra Mioc
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 250 words) can be sent to the Editorial Office for assessment.

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. Molecules is an international peer-reviewed open access semimonthly 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 2700 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 compounds
  • anticancer activity
  • bioactive compounds
  • cancer therapeutics
  • drug resistance
  • synergistic effect

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Published Papers (5 papers)

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Research

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24 pages, 2981 KB  
Article
Cudratricusxanthone A Exhibits Antitumor Activities Against NSCLC Harboring EGFR L792H and G796R Triple Mutations via Regulating EGFR-ERK/AKT/STAT3 Signaling
by Yinghao Wang, Jiamin Xian, Zhuoyi Wang, Jingmeng Wang, Ruohan Zhang, Jun Sheng, Jing Wang and Peiyuan Sun
Molecules 2026, 31(9), 1504; https://doi.org/10.3390/molecules31091504 (registering DOI) - 30 Apr 2026
Abstract
Background: Acquired resistance to the third-generation EGFR tyrosine kinase inhibitor osimertinib, often mediated by EGFR triple mutations, poses a major clinical challenge in non-small cell lung cancer (NSCLC) treatment. Among these, some rare mutations, such as L858R/T790M/L792H and L858R/T790M/G796R, create steric hindrance that [...] Read more.
Background: Acquired resistance to the third-generation EGFR tyrosine kinase inhibitor osimertinib, often mediated by EGFR triple mutations, poses a major clinical challenge in non-small cell lung cancer (NSCLC) treatment. Among these, some rare mutations, such as L858R/T790M/L792H and L858R/T790M/G796R, create steric hindrance that directly interferes with osimertinib binding, yet effective targeted therapeutic strategies for these specific mutations remain lacking. Cudratricusxanthone A (CTXA), a natural xanthone derivative isolated from Cudrania tricuspidata Bur., has demonstrated various pharmacological activities, but its effects against EGFR triple-mutant NSCLC have not been systematically investigated. Methods: Stable Ba/F3 and NIH/3T3 cell lines expressing EGFR L858R/T790M/L792H or L858R/T790M/G796R triple mutations were generated via electroporation. The antiproliferative effects of CTXA were evaluated by MTT/MTS assays, colony formation, and wound healing assays. Cell cycle distribution and apoptosis were analyzed by flow cytometry. Protein expression of EGFR signaling pathway components (p-EGFR, p-ERK, p-AKT, p-STAT3) and cell cycle regulators (Cyclin D1, CDK4) were examined by Western blotting. Molecular docking and 200 ns molecular dynamics simulations were performed to investigate the stability and binding modes of CTXA to the mutant EGFR kinase domains. Results: The successfully established triple-mutant cell lines exhibited high EGFR expression, IL-3-independent growth, and significant resistance to osimertinib. CTXA inhibited the proliferation of all triple-mutant cell lines in a time- and concentration-dependent manner, with 48 h IC50 values ranging from 0.362 to 2.488 μM. Mechanistically, CTXA suppressed EGFR autophosphorylation and downregulated downstream p-ERK, p-AKT, and p-STAT3. CTXA induced G1 phase cell cycle arrest by downregulating Cyclin D1 and CDK4, significantly promoted apoptosis, and inhibited cell migration. Molecular docking revealed that while osimertinib binding was blocked by steric hindrance from His-792 or Arg-796, CTXA adapted to the mutated ATP-binding pockets through multiple hydrogen bonds and extensive hydrophobic interactions. Molecular dynamics simulations confirmed the stable binding of CTXA to both mutant EGFR proteins over the 200 ns simulations. Conclusions: This study demonstrates for the first time that the natural compound CTXA possesses antitumor efficacy against EGFR L858R/T790M/L792H and L858R/T790M/G796R mutants by regulating EGFR-ERK/AKT/STAT3 signaling. Our findings position CTXA as a promising lead compound for tackling this challenging form of acquired resistance and highlight the value of natural products in multi-target antitumor drug discovery. Full article
(This article belongs to the Special Issue Advances in Anticancer Activity of Natural Products and Related Compounds)
18 pages, 5662 KB  
Article
Synthesis and Biological Evaluation of Isomeric Artemisinin Trimers as Novel Antitumor Agents
by Zejin Zhang, Along Li, Bingying Jiang, Typhaine Bejoma, Yongxi Zhao, Fujiang Guo, Yajuan Li, Huiyu Li and Qingjie Zhao
Molecules 2026, 31(8), 1228; https://doi.org/10.3390/molecules31081228 - 8 Apr 2026
Viewed by 470
Abstract
While artemisinin and its derivatives demonstrate broad antitumor potential, the stereochemical influence on the bioactivity of higher-order artemisinin assemblies remains inadequately characterized. Herein, we report the synthesis, chromatographic separation, and structural elucidation of four stereoisomeric artemisinin trimers, followed by systematic evaluation of their [...] Read more.
While artemisinin and its derivatives demonstrate broad antitumor potential, the stereochemical influence on the bioactivity of higher-order artemisinin assemblies remains inadequately characterized. Herein, we report the synthesis, chromatographic separation, and structural elucidation of four stereoisomeric artemisinin trimers, followed by systematic evaluation of their antitumor efficacy against MCF-7 and MDA-MB-231 breast cancer cell lines. All trimers exhibited potent cytotoxicity against MCF-7 cells (IC50 < 0.09 μM), with trimer 6a (β, β, β) demonstrating robust antitumor activity in both in vitro and in vivo xenograft models. Remarkably, pronounced stereochemistry-dependent activity emerged against MDA-MB-231 cells: 6a displayed approximately 100-fold greater potency than 6b (β, β, α) and 6.6-fold superiority over gemcitabine. Mechanistic investigations revealed that 6a downregulates Cyclin D1, CDK4, and CDK6 expression, thereby inducing G0/G1 phase cell cycle arrest. These findings underscore the pivotal role of stereochemical configuration in modulating artemisinin trimer bioactivity and provide rational guidance for structure-based design of artemisinin-derived anticancer therapeutics. Full article
(This article belongs to the Special Issue Advances in Anticancer Activity of Natural Products and Related Compounds)
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24 pages, 2905 KB  
Article
Evaluation of Cedrus atlantica Essential Oil: Chemical Composition, Anticancer Activity and Molecular Docking Studies
by Silvia Gruin, Octavian Crețu, Alexandra Mioc, Marius Mioc, Alexandra Prodea, Elisabeta Atyim, Alexandra Teodora Lukinich-Gruia, Maria-Alexandra Pricop, Armand Gogulescu and Codruța Șoica
Molecules 2026, 31(1), 46; https://doi.org/10.3390/molecules31010046 - 22 Dec 2025
Cited by 2 | Viewed by 1206
Abstract
Due to their high content of bioactive compounds with anticancer properties, essential oils (EO) are increasingly viewed as valuable therapeutic strategies in oncology. The aim of this study was to evaluate the chemical composition and anticancer activity of Cedrus atlantica EO (CAEO) and [...] Read more.
Due to their high content of bioactive compounds with anticancer properties, essential oils (EO) are increasingly viewed as valuable therapeutic strategies in oncology. The aim of this study was to evaluate the chemical composition and anticancer activity of Cedrus atlantica EO (CAEO) and its PEG-400 and Tween 20 formulations. The gas-chromatography (GC) analysis revealed a sesquiterpene-rich profile, with β-himachalene (39.32%) as the major constituent, followed by α-Himachalene (16.76%) and γ-Himachalene (12.92%). The cytotoxicity studies, performed using Alamar Blue assay on normal HaCaT human keratinocytes and A375 human melanoma and HT-29 colorectal carcinoma cell lines, revealed that CAEO displayed minimal toxicity on HaCaT cells, while significantly reducing A735 and HT-29 cell viability, at any of the concentrations tested. The PEG- and Tween-based formulations of CAEO exhibited the same effect on cell viability as the simple water dispersion of CAEO. The immunofluorescence-based examination of cellular morphology suggested that CAEO induces apoptosis in both cancer cell lines: A375 and HT-29; this apoptosis-related mechanism was further supported by the caspase-3/7 assay, which revealed a significant increase in caspase-3/7 activity after CAEO treatment. To further investigate the underlying mechanism, the JC-1 staining and high-resolution respirometry assays demonstrated that CAEO induces mitochondrial membrane depolarization and reduced mitochondrial active respiration (OXPHOS). Molecular docking further indicated that isoledene and β-himachalene exhibit the highest predicted affinity for PI3Kγ, suggesting a potential involvement of PI3K-related signaling in the pro-apoptotic activity of CAEO. Together, these results suggest that CAEO induces apoptosis through a mitochondria-mediated mechanism. Full article
(This article belongs to the Special Issue Advances in Anticancer Activity of Natural Products and Related Compounds)
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25 pages, 6142 KB  
Article
Cancer Chemopreventive Potential of Claoxylon longifolium Grown in Southern Thailand: A Bioassay-Guided Isolation of Vicenin 1 as the Active Compound and In Silico Studies on Related C-Glycosyl Flavones
by Chuanchom Khuniad, Lutfun Nahar, Anupam D. Talukdar, Rajat Nath, Kenneth J. Ritchie and Satyajit D. Sarker
Molecules 2025, 30(15), 3173; https://doi.org/10.3390/molecules30153173 - 29 Jul 2025
Cited by 1 | Viewed by 1337
Abstract
Claoxylon longifolium (Euphorbiaceae) is an indigenous vegetable that has been used in southern Thai traditional medicine and cuisine. A bioassay-guided approach was adopted to investigate the phytochemicals and chemopreventive potential of C. longifolium leaves and stems. Phytochemical investigation of the active MeOH fractions [...] Read more.
Claoxylon longifolium (Euphorbiaceae) is an indigenous vegetable that has been used in southern Thai traditional medicine and cuisine. A bioassay-guided approach was adopted to investigate the phytochemicals and chemopreventive potential of C. longifolium leaves and stems. Phytochemical investigation of the active MeOH fractions afforded six known compounds, including caffeic acid (1), isovitexin (2), and vicenins 1–3 (3–5) from leaves and hexadecanoic acid methyl ester (6) from stems. Their structures were determined by spectroscopic means. Ten constituents were tentatively identified from the oily fractions of stems by GC-MS. Non-cytotoxic concentrations of compounds 1–6 were identified using the MTT cell viability assay. The ability of compounds 1–6 at non-cytotoxic concentrations to induce Nrf2 activation, correlating to their potential chemopreventive properties, was determined using a luciferase reporter assay in the AREc32 cell line. Only vicenin 1 (3) was considered to be a potent chemopreventive compound, as it increased luciferase activity by 2.3-fold. In silico studies on compounds 2–5 and vitexin (16) revealed the potential of these compounds as cancer chemopreventive and chemotherapeutic agents. This study provides the first report on the chemopreventive properties of C. longifolium. All identified and isolated compounds are reported here for the first time from this species. Full article
(This article belongs to the Special Issue Advances in Anticancer Activity of Natural Products and Related Compounds)
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Review

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32 pages, 2453 KB  
Review
Natural Products Targeting BCR-ABL: A Plant-Based Approach to Chronic Myeloid Leukemia Treatment
by Louisa Pechlivani, Alexandros Giannakis, Chrissa Sioka, Georgios A. Alexiou and Athanassios P. Kyritsis
Molecules 2025, 30(21), 4160; https://doi.org/10.3390/molecules30214160 - 22 Oct 2025
Cited by 1 | Viewed by 2379
Abstract
The BCR-ABL fusion oncoprotein, a constitutively active tyrosine kinase, plays a central role in the pathogenesis of chronic myeloid leukemia (CML). While tyrosine kinase inhibitors (TKIs) have transformed CML treatment, issues such as drug resistance, particularly involving mutations like T315I, and adverse effects [...] Read more.
The BCR-ABL fusion oncoprotein, a constitutively active tyrosine kinase, plays a central role in the pathogenesis of chronic myeloid leukemia (CML). While tyrosine kinase inhibitors (TKIs) have transformed CML treatment, issues such as drug resistance, particularly involving mutations like T315I, and adverse effects underscore the need for alternative or complementary therapeutic strategies. Natural products derived from plants have long served as a reservoir for anticancer agents, offering structural diversity and multi-targeted bioactivity. Notably, many plant-based compounds exhibit anticancer effects with comparatively lower toxicity and fewer side effects than synthetic TKIs, making them attractive candidates for safer long-term use. This review explores the recent advances in plant-based natural compounds that directly or indirectly inhibit BCR-ABL kinase activity and its downstream signaling pathways. Key compounds are discussed with respect to their mechanisms of action, structure–activity relationships, and potential to overcome TKI resistance. Several of these compounds directly target BCR-ABL or promote its degradation, while others inhibit downstream effectors such as STAT5 and PI3K/Akt, leading to apoptosis and growth inhibition of leukemic cells. The synergistic potential of these natural products with existing TKIs and their promise to target drug-resistant CML cells further highlight their translational value. By integrating insights from molecular pharmacology, medicinal chemistry, and leukemia biology, this review supports the continued investigation of plant-derived agents as novel or adjunctive therapies against BCR-ABL-driven leukemias. Full article
(This article belongs to the Special Issue Advances in Anticancer Activity of Natural Products and Related Compounds)
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