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Antitumor Activity of Natural Products

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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 2026) | Viewed by 9085

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Prof. Dr. Spiro Mihaylov Konstantinov

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Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, Sofia, Bulgaria
Interests: leukemia; lymphoma; solid tumors; antineoplastic agents; cell death induction; signal transduction; predictive biomarkers
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Dear Colleagues,

Vincristine, irinotecan, etoposide, and paclitaxel are examples of plant-derived compounds that are being employed in cancer treatment, and dactinomycin, bleomycin, and doxorubicin are anticancer agents derived from microbial sources. Cytarabine is an example of an anticancer agent originating from a marine source. Recently, some products of natural origin were reclassified as targeted drugs, e.g., alvocidib (flavopiridol), which acts as a CDK9 inhibitor; staurosporine, which acts as a precursor of the novel protein kinase inhibitor midostaurin, as well as many other examples. It can be expected that natural products with lower toxicity may serve as a source of new antitumor drugs with preferential pharmacological properties against different types of cancer in humans. Additionally, natural products may contribute to a reduction in or the amelioration of the side effects of contemporary antineoplastic therapy. In this Special Issue, we invite authors to present their achievements in this research area of great interest. Studies on the molecular mechanisms of the antineoplastic activity of known and new natural products are welcome to be submitted. High-quality chemical and pharmacological analyses are also welcome, as these may lead to the specific discovery of synergistic interactions between different naturally occurring compounds in plant and animal extracts.

Prof. Dr. Spiro Mihaylov Konstantinov
Guest Editor

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Keywords

natural compounds and extracts with antitumor activity
studies on molecular mechanisms
signal transduction modulation in tumor cells
immunomodulating activity
mitosis inhibition
cell differentiation
cell death induction (apoptosis/autophagy)

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Published Papers (6 papers)

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Research

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15 pages, 3210 KB

Open AccessArticle

Preclinical Evaluation of Triptophenolide-Induced Apoptosis in Hepatoblastoma (HepG2) and Hepatocellular Carcinoma (HuH7) Cell Lines

by Zufa Sabeel, Ruolan Chen, Yan Liu, Xiaoyang Chen, Wenjing Zhang, Shangyang Pan, Lu Ying, Changyuan Yu and Zhao Yang

Int. J. Mol. Sci. 2026, 27(7), 3251; https://doi.org/10.3390/ijms27073251 - 3 Apr 2026

Viewed by 472

Abstract

Liver cancer is one of the most prevalent and lethal cancers worldwide, characterized by poor prognosis and limited treatment options. Triptophenolide (TRI), a diterpenoid compound, has shown anti-proliferative activity in breast and pancreatic cancers, but its role in liver cancer remains largely unexplored. In this study, TRI significantly inhibited the proliferation of HepG2 (hepatoblastoma) and HuH7 (hepatocellular carcinoma) cells in a dose-dependent manner, with IC₅₀ values decreasing from 279.9 to 229.4 µg/mL (24–48 h) in HepG2 and from 441.1 to 282.6 µg/mL in HuH7. Colony formation assays confirmed the suppression of HCC cell growth. TRI also promoted apoptosis, increasing apoptotic rates to 68.99% in HepG2 and 43.34% in HuH7 at 400 µg/mL (48 h). Cell cycle analysis revealed S-phase arrest, with TRI raising the S-phase population to 42.02% and 45.38%, respectively. Mechanistically, TRI upregulated pro-apoptotic genes (TP53, CASP3/9/10, BAX, BAK1, BID, BIM) and proteins, activating the mitochondrial apoptotic pathway. In vivo, TRI (10 mg/kg) markedly reduced tumor volumes in HepG2 and HuH7 xenografts compared with controls, without obvious systemic toxicity. These findings suggest that TRI exerts anti-proliferative, pro-apoptotic, and cell cycle regulatory effects in HCC. However, further preclinical studies are warranted to elucidate its mechanisms and evaluate its safety profile. Full article

(This article belongs to the Special Issue Antitumor Activity of Natural Products)

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15 pages, 2147 KB

Open AccessArticle

Suppressive Potential of Ethanolic Extracts of Parkia speciosa Hassk. Empty Pods Against Colon Cancer Cell Migration and Invasion

by Athit Chaiwichien, Supawadee Osotprasit, Tepparit Samrit, Pornanan Kueakhai and Narin Changklungmoa

Int. J. Mol. Sci. 2026, 27(4), 2072; https://doi.org/10.3390/ijms27042072 - 23 Feb 2026

Viewed by 540

Abstract

Parkia speciosa (P. speciosa), a plant utilized in traditional medicine, has shown promise in various therapeutic applications and contains multiple bioactive components (saponins, alkaloids, flavonoids, polyphenols, and terpenoids). These bioactive compounds have attracted increasing scientific interest due to their ability to modulate key cancer-associated pathways, including the inhibition of cell proliferation and migration and the suppression of oxidative stress and inflammation mechanisms. However, despite P. speciosa’s historically long and wide-ranging usage, a comprehensive investigation of these properties has not been conducted for its pod. This study investigated the effects of P. speciosa empty pod extract (PSET) on human colorectal cancer cells. The extract demonstrated significant dose-dependent inhibition of colorectal cell migration, invasion, and colony formation while exhibiting no cytotoxicity toward normal colon epithelial cells. Western blot analysis confirmed reduced expression of Matrix metalloproteinases 2 (MMP2), Matrix metalloproteinases 9 (MMP9), and N-cadherin, indicating suppression of the epithelial–mesenchymal transition (EMT). These findings demonstrate that the PSET effectively inhibits metastasis in colorectal cancer cells through the EMT pathway, suggesting its potential as a dietary supplement or therapeutic agent for colorectal cancer treatment. Our research provides support for the development of natural, less toxic alternative cancer treatments. Therefore, PSET shows potential for development as a dietary supplement or therapeutic agent for the treatment of colon cancer. Full article

(This article belongs to the Special Issue Antitumor Activity of Natural Products)

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22 pages, 2725 KB

Open AccessArticle

Chelidonine Induces Concurrent Elevation of pSer-STAT3 and Bcl-2 Levels in a Mitotic Subpopulation of Human T-Leukemia/Lymphoma Cells

by Saraa Baddour, János Szöllősi, László Mátyus, György Vámosi, István Csomós and Andrea Bodnár

Int. J. Mol. Sci. 2026, 27(3), 1200; https://doi.org/10.3390/ijms27031200 - 25 Jan 2026

Viewed by 499

Abstract

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates a broad spectrum of genes with oncogenic potential, thereby serving as a critical driver of tumorigenesis. Canonical STAT3 function is mediated through tyrosine phosphorylation, which enables dimerization and transcriptional activation, whereas serine phosphorylation of STAT3 has a postulated role in fine-tuning canonical functions and contributes to non-canonical roles as well. One of the transcriptional targets of STAT3 is the anti-apoptotic B-cell lymphoma 2 (Bcl-2) protein, itself subject to phosphorylation-dependent regulation. In this study, we investigated the effect of chelidonine, an alkaloid component of Chelidonium majus L., on STAT3/Bcl-2 signaling in human T leukemia/lymphoma cells, reported to have numerous effects in common with microtubule-targeting agents (MTAs). Flow cytometry and confocal microscopy revealed that chelidonine transiently increased both serine-phosphorylated STAT3 (pSer-STAT3) and Bcl-2 levels in a distinct subpopulation of cells, with near-complete overlap between the affected cells. This effect appeared at least partially independent of interleukin-2 (IL-2) and was associated with the M-phase of the cell cycle, as indicated by enhanced phosphorylation of Bcl-2 at serine 70 and nuclear morphology characteristic of mitosis. Our study provides the first single-cell evidence that STAT3 and Bcl-2 undergo concurrent serine phosphorylation as a response to chelidonine treatment, with the effect tightly linked to the M-phase. Full article

(This article belongs to the Special Issue Antitumor Activity of Natural Products)

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26 pages, 4795 KB

Open AccessArticle

Deciphering the Mechanisms Underlying the Antitumor Effects of Eucalyptus Essential Oil and Its Component 3-Cyclohexene-1-Methanol Against Human Colon Cancer Cells

by Sonia Ben Hamouda, Ons Zakraoui, Sonia Souissi, Rania Bouzeyen, Makram Essafi and Khadija Essafi-Benkhadir

Int. J. Mol. Sci. 2025, 26(18), 8876; https://doi.org/10.3390/ijms26188876 - 12 Sep 2025

Cited by 2 | Viewed by 1883

Abstract

The development of non-toxic, novel anti-tumor alternatives that target key hallmark events of tumor progression is of a high priority for cancer therapy. Natural compounds, such as Essential oils (EOs) derived from plant extracts are a mixture of chemical components known for their diverse pharmacological properties, including anticancer potential. For this purpose, we investigated the antitumor activity of Eucalyptus globulus essential oil (EEO) and its major constituents against colorectal cancer cells in vitro. EEO significantly reduced the viability of colon cancer LS174 cells, induced caspase-dependent apoptosis and triggered cell cycle arrest by modulating the expression of several effectors involved in these processes. Mechanistically, EEO exhibited its activity by targeting p38, SAPK/JNK, ERK1/2, and AKT kinases in LS174 cells. Considering the pivotal role of p53 status in mediating the response to anticancer therapies, we further investigated the effects of Eucalyptol, 3-Cyclohexene-1-methanol, α-Pinene, and α-Terpineol, identified as major components of EEO, on the viability of human colon adenocarcinoma LS174 (wild type p53) and HT29 (mutant p53) cell lines. Interestingly, we highlighted for the first time that 3-Cyclohexene-1-methanol exhibited the most anti-proliferative activity against both tumor cells irrespective to their p53 status. It exerted its effect by inducing apoptotic cell death, disturbing cell cycle progression along with reducing the phosphorylation of key components of the proliferation and survival pathways p38, ERK1/2, and AKT kinases. Our results suggest that Eucalyptus essential oil and its component, 3-Cyclohexene-1-methanol represent promising multi-targeting candidates for colorectal cancer therapy. Full article

(This article belongs to the Special Issue Antitumor Activity of Natural Products)

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20 pages, 4073 KB

Open AccessArticle

Anti-Cancer and Pro-Immune Effects of Lauric Acid on Colorectal Cancer Cells

by Shiori Mori, Rina Fujiwara-Tani, Ruiko Ogata, Hitoshi Ohmori, Kiyomu Fujii, Yi Luo, Takamitsu Sasaki, Yukiko Nishiguchi, Ujjal Kumar Bhawal, Shingo Kishi and Hiroki Kuniyasu

Int. J. Mol. Sci. 2025, 26(5), 1953; https://doi.org/10.3390/ijms26051953 - 24 Feb 2025

Cited by 7 | Viewed by 3608

Abstract

Lauric acid (LAA) is a 12-carbon medium-chain fatty acid that reportedly has antitumor and muscle-protecting effects. However, the details of these antitumor effects remain unclear. Therefore, in this study, we investigated the mechanism underlying the antitumor effects of LAA in CT26 and HT29 colorectal cancer (CRC) cell lines. Our in vitro findings demonstrated that LAA suppressed CRC cell proliferation, induced mitochondrial oxidative stress (reactive oxygen species (ROS)), inhibited oxidative phosphorylation (OXPHOS), and induced apoptosis. Moreover, in vivo analysis of LAA showed a more pronounced antitumor effect in CT26 cells in a syngeneic mouse tumor model than in vitro; therefore, we further investigated its impact on host antitumor immunity. We observed that LAA increased the number of effector T cells in mouse tumors, while in vitro LAA activated mouse splenocytes (SplC) and promoted OXPHOS. In two-dimensional co-culture of SplC and CT26 cells, LAA induced cell death in cancer cells. In three-dimensional co-culture, LAA promoted SplC infiltration and suppressed the formation of tumor spheres. Thus, LAA may exert antitumor effects through increased ROS production in cancer cells and effector T cell activation via increased energy metabolism. These results suggest that LAA, when used in combination with existing anti-cancer drugs, is likely to exhibit sensitizing effects in terms of both antitumor and antitumor immune effects, and future clinical studies are anticipated. Full article

(This article belongs to the Special Issue Antitumor Activity of Natural Products)

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Review

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18 pages, 2289 KB

Open AccessReview

Naturally Derived SENP1 Inhibitors with Anticancer Activity

by Renata Krupa and Katarzyna Woźniak

Int. J. Mol. Sci. 2025, 26(22), 11210; https://doi.org/10.3390/ijms262211210 - 20 Nov 2025

Cited by 1 | Viewed by 1164

Abstract

SENP1 (sentrin-specific protease 1) mediates sumoylation, a reversible post-translational modification that attaches the SUMO (small ubiquitin-like modifier) protein to target proteins. These modified proteins are essential in many key cellular processes, including cell cycle regulation, DNA repair, and apoptosis. Disruptions in the balance between sumoylated and desumoylated proteins can lead to various pathological conditions, such as cancer. Experimental data suggest that certain natural compounds, including momordin Ic (Mc), hinokiflavone (HNK), triptolide (TPL), ursolic acid (UA), streptonigrin (SN), vialinin A (VA), thelephantin G (TG), and others, effectively inhibit SENP1 activity, thereby influencing the levels of sumoylated proteins and cellular processes. This article reviews existing knowledge on the structure and function of natural SENP1 inhibitors, particularly their potential application in cancer therapy, including their capacity to overcome resistance to conventional chemotherapies. Some of the natural SENP1 inhibitors tested so far interact directly with the enzyme’s active site. The current understanding of how this interaction occurs is also discussed. Full article

(This article belongs to the Special Issue Antitumor Activity of Natural Products)

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