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Anticancer Activity of Natural Products and Related Compounds

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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 March 2025) | Viewed by 17363

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Dr. Srinivasa Reddy Bonam

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Guest Editor

Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
Interests: natural products and drug discovery; development of novel vaccine adjuvants (DENOVA); anticancer agents; autophagy; regulatory T cells
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Special Issue Information

Dear Colleagues,

Tumor is a widespread global disease with an extremely high mortality rate. Malignant tumors (cancer) have become one of the major diseases that seriously threaten the physical and mental health of people around the world, and the number of cases is increasing year by year. Thus, there is an urgent need to develop new anti-cancer drugs to selectively inhibit cancer cells, limit their chemoresistance and recurrence after treatment, and establish secondary cancer treatment options.

Carcinogenesis is a complex multistage process in which normal cells are transformed through changes in DNA structure/function into malignant cells with diverse properties, such as abnormal proliferation and reduced apoptosis. Research shows that natural products are one of the important sources of anti-tumor drugs. Many bioactive compounds from different natural sources in vitro and in vivo can affect the several pathways related to tumor development. Therefore, natural products are important and valuable resources for identifying and developing new cancer treatments.

This Special Issue will focus on the anti-tumor activity of functional molecular substances derived from natural products against all types of tumor diseases. Topics include isolation and structure elucidation, phytochemistry, synthesis, medicinal chemistry, pharmacology, chemical biology, molecular biology, mechanism of action of natural products, etc.

Dr. Srinivasa Reddy Bonam
Guest Editor

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Keywords

anticancer agent
natural product chemistry
isolation and structure elucidation
medicinal chemistry
molecular mechanism
targeted therapy
structure–activity relationships
phytochemistry
chemical biology

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Published Papers (9 papers)

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Research

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22 pages, 5118 KiB

Open AccessArticle

Panduratin A from Boesenbergia rotunda Effectively Inhibits EGFR/STAT3/Akt Signaling Pathways, Inducing Apoptosis in NSCLC Cells with Wild-Type and T790M Mutations in EGFR

by Wanna Eiamart, Piyanuch Wonganan, Sarin Tadtong and Weerasak Samee

Int. J. Mol. Sci. 2025, 26(5), 2350; https://doi.org/10.3390/ijms26052350 - 6 Mar 2025

Cited by 1 | Viewed by 681

Abstract

Non-small cell lung cancer (NSCLC) is a challenging disease, with the epidermal growth factor receptor (EGFR) being a key target for new, effective treatments crucial for the signaling pathways regulating cancer cell survival. Targeting EGFR-mediated signaling offers promising strategies to improve NSCLC therapies, particularly in overcoming resistance in EGFR-mutant lung cancer. In this study, we investigated the anticancer effects of panduratin A, a naturally occurring flavonoid from Boesenbergia rotunda, on human NSCLC cell lines expressing both wild-type EGFR (A549) and mutant EGFR (H1975) using in vitro experiments and molecular docking approaches. Cytotoxicity screening revealed that panduratin A exhibits potent effects on both A549 (IC₅₀ of 6.03 ± 0.21 µg/mL) and H1975 (IC₅₀ of 5.58 ± 0.15 µg/mL) cell lines while demonstrating low toxicity to normal MRC5 lung cells (12.96 ± 0.36 µg/mL). Furthermore, western blotting and flow cytometric analyses indicated that panduratin A induces apoptosis by inhibiting p-EGFR and its downstream effectors, p-STAT3 and p-Akt, in lung cancer cells. Additionally, the docking study showed lower binding energy between panduratin A and the target proteins, comparable to that of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs). The ADMET prediction also highlighted panduratin A’s exceptional drug-like properties. This study concludes that panduratin A shows significant promise as an anti-lung cancer candidate for NSCLC, offering an economical and effective strategy. Full article

(This article belongs to the Special Issue Anticancer Activity of Natural Products and Related Compounds)

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19 pages, 3393 KiB

Open AccessArticle

Anti-Cancer Potential of Isoflavone-Enriched Fraction from Traditional Thai Fermented Soybean against Hela Cervical Cancer Cells

by Amonnat Sukhamwang, Sirinada Inthanon, Pornngarm Dejkriengkraikul, Tistaya Semangoen and Supachai Yodkeeree

Int. J. Mol. Sci. 2024, 25(17), 9277; https://doi.org/10.3390/ijms25179277 - 27 Aug 2024

Cited by 2 | Viewed by 1424

Abstract

Cervical cancer is a leading cause of gynecological malignancies and cancer-related deaths among women worldwide. This study investigates the anti-cancer activity of Thua Nao, a Thai fermented soybean, against HeLa cervical carcinoma cells, and explores its underlying mechanisms. Our findings reveal that the ethyl acetate fraction of Thua Nao (TN-EA) exhibits strong anti-cancer potential against HeLa cells. High-performance liquid chromatography (HPLC) analysis identified genistein and daidzein as the major isoflavones in TN-EA responsible for its anti-cancer activity. TN-EA and genistein reduced cell proliferation and induced G2/M phase arrest, while daidzein induced G1 arrest. These responses were associated with the downregulation of cell cycle regulators, including Cyclin B1, cycle 25C (Cdc25C), and phosphorylated cyclin-dependent kinase 1 (CDK-1), and the upregulation of the cell cycle inhibitor p21. Moreover, TN-EA and its active isoflavones promoted apoptosis in HeLa cells through the intrinsic pathway, evidenced by increased levels of cleaved Poly (ADP-ribose) polymerase (PARP) and caspase-3, loss of mitochondrial membrane potential, and the downregulation of anti-apoptotic proteins B-cell leukemia/lymphoma 2 (Bcl-2), B-cell lymphoma-extra-large (Bcl-xL), cellular inhibitor of apoptosis proteins 1 (cIAP), and survivin. Additionally, TN-EA and its active isoflavones effectively reduced cell invasion and migration by downregulating extracellular matrix degradation enzymes, including Membrane type 1-matrix metalloproteinase (MT1-MMP), urokinase-type plasminogen activator (uPA), and urokinase-type plasminogen activator receptor (uPAR), and reduced the levels of the mesenchymal marker N-cadherin. At the molecular level, TN-EA suppressed STAT3 activation via the regulation of JNK and Erk1/2 signaling pathways, leading to reduced proliferation and invasion of HeLa cells. Full article

(This article belongs to the Special Issue Anticancer Activity of Natural Products and Related Compounds)

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16 pages, 2572 KiB

Open AccessArticle

Pretreatment of Melanoma Cells with Aqueous Ethanol Extract from Madhuca longifolia Bark Strongly Potentiates the Activity of a Low Dose of Dacarbazine

by Kamila Środa-Pomianek, Anna Barycka, Michał Gleńsk, Meena Rajbhandari, Magdalena Skonieczna, Anna Palko-Łabuz and Olga Wesołowska

Int. J. Mol. Sci. 2024, 25(13), 7220; https://doi.org/10.3390/ijms25137220 - 29 Jun 2024

Viewed by 1489

Abstract

Madhuca longifolia is an evergreen tree distributed in India, Nepal, and Sri Lanka. This tree is commonly known as Mahua and is used in traditional medicine. It was demonstrated that ethanol extract from the bark of M. longifolia possessed potent cytotoxic activity towards two melanoma cell lines, in contrast to aqueous extract that exhibited no activity. Apart from being selectively cytotoxic to cancer cells (with no activity towards non-cancerous fibroblasts), the studied extract induced apoptosis and increased reactive oxygen species generation in melanoma cells. Additionally, the use of the extract together with dacarbazine (both in non-toxic concentrations) resulted in the enhancement of their anticancer activity. Moreover, the pretreatment of melanoma cells with M. longifolia extract potentiated the activity of a low dose of dacarbazine to an even higher extent. It was concluded that ethanol extract of M. longifolia sensitized human melanoma cells to chemotherapeutic drugs. It can therefore be interesting as a promising source of compounds for prospective combination therapy. Full article

(This article belongs to the Special Issue Anticancer Activity of Natural Products and Related Compounds)

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13 pages, 2341 KiB

Open AccessArticle

Carnosic Acid against Lung Cancer: Induction of Autophagy and Activation of Sestrin-2/LKB1/AMPK Signalling

by Eric J. O’Neill, Newman Siu Kwan Sze, Rebecca E. K. MacPherson and Evangelia Tsiani

Int. J. Mol. Sci. 2024, 25(4), 1950; https://doi.org/10.3390/ijms25041950 - 6 Feb 2024

Cited by 8 | Viewed by 2691

Abstract

Non-small cell lung cancer (NSCLC) represents 80% of all lung cancer cases and is characterized by low survival rates due to chemotherapy and radiation resistance. Novel treatment strategies for NSCLC are urgently needed. Liver kinase B1 (LKB1), a tumor suppressor prevalently mutated in NSCLC, activates AMP-activated protein kinase (AMPK) which in turn inhibits mammalian target of rapamycin complex 1 (mTORC1) and activates unc-51 like autophagy activating kinase 1 (ULK1) to promote autophagy. Sestrin-2 is a stress-induced protein that enhances LKB1-dependent activation of AMPK, functioning as a tumor suppressor in NSCLC. In previous studies, rosemary (Rosmarinus officinalis) extract (RE) activated the AMPK pathway while inhibiting mTORC1 to suppress proliferation, survival, and migration, leading to the apoptosis of NSCLC cells. In the present study, we investigated the anticancer potential of carnosic acid (CA), a bioactive polyphenolic diterpene compound found in RE. The treatment of H1299 and H460 NSCLC cells with CA resulted in concentration and time-dependent inhibition of cell proliferation assessed with crystal violet staining and ³H-thymidine incorporation, and concentration-dependent inhibition of survival, assessed using a colony formation assay. Additionally, CA induced apoptosis of H1299 cells as indicated by decreased B-cell lymphoma 2 (Bcl-2) levels, increased cleaved caspase-3, -7, poly (ADP-ribose) polymerase (PARP), Bcl-2-associated X protein (BAX) levels, and increased nuclear condensation. These antiproliferative and proapoptotic effects coincided with the upregulation of sestrin-2 and the phosphorylation/activation of LKB1 and AMPK. Downstream of AMPK signaling, CA increased levels of autophagy marker light chain 3 (LC3), an established marker of autophagy; inhibiting autophagy with 3-methyladenine (3MA) blocked the antiproliferative effect of CA. Overall, these data indicate that CA can inhibit NSCLC cell viability and that the underlying mechanism of action of CA involves the induction of autophagy through a Sestrin-2/LKB1/AMPK signaling cascade. Future experiments will use siRNA and small molecule inhibitors to better elucidate the role of these signaling molecules in the mechanism of action of CA as well as tumor xenograft models to assess the anticancer properties of CA in vivo. Full article

(This article belongs to the Special Issue Anticancer Activity of Natural Products and Related Compounds)

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14 pages, 1686 KiB

Open AccessArticle

Design, Synthesis and Gene Modulation Insights into Pigments Derived from Tryptophan-Betaxanthin, Which Act against Tumor Development in Caenorhabditis elegans

by Paula Henarejos-Escudero, Fernando F. Méndez-García, Samanta Hernández-García, Pedro Martínez-Rodríguez and Fernando Gandía-Herrero

Int. J. Mol. Sci. 2024, 25(1), 63; https://doi.org/10.3390/ijms25010063 - 20 Dec 2023

Cited by 1 | Viewed by 1549

Abstract

The use of betalains, which are nitrogenous plant pigments, by the food industry is widespread and reflects their safety after intake. The recent research showed outstanding results for L-tryptophan-betaxanthin, a phytochemical present in traditional Chinese medicine, as an antitumoral agent when the activity was evaluated in the animal model Caenorhabditis elegans. Thus, L-tryptophan-betaxanthin is now presented as a lead compound, from which eleven novel structurally related betaxanthins have been designed, biotechnologically produced, purified, and characterized. The antitumoral effect of the derived compounds was evaluated on the JK1466 tumoral strain of C. elegans. All the tested molecules significantly reduced the tumoral gonad sizes in a range between 31.4% and 43.0%. Among the novel compounds synthesized, tryptophan methyl ester-betaxanthin and tryptophan benzyl ester-betaxanthin, which are the first betalains to contain an ester group in their structures, caused tumor size reductions of 43.0% and 42.6%, respectively, after administration to the model animal. Since these were the two most effective molecules, their mechanism of action was investigated by microarray analysis. Differential gene expression analysis showed that tryptophan methyl ester-betaxanthin and tryptophan benzyl ester-betaxanthin were able to down-regulate the key genes of the mTOR pathway, such as daf-15 and rict-1. Full article

(This article belongs to the Special Issue Anticancer Activity of Natural Products and Related Compounds)

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Review

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14 pages, 1036 KiB

Open AccessReview

Applications of the Cellular Thermal Shift Assay to Drug Discovery in Natural Products: A Review

by Jayoung Song

Int. J. Mol. Sci. 2025, 26(9), 3940; https://doi.org/10.3390/ijms26093940 - 22 Apr 2025

Viewed by 229

Abstract

Natural products play a crucial role in drug discovery because of their structural diversity and biological activity. However, identifying their molecular targets remains a challenge. Traditional target identification approaches such as affinity-based protein profiling and activity-based protein profiling are limited by the need for chemical modification or reactive groups in natural products. The emergence of label-free techniques offers a powerful alternative for studying drug–target engagement in a physiological context. In particular, the cellular thermal shift assay (CETSA) exploits ligand-induced protein stabilization—a phenomenon where ligand binding enhances a protein’s thermal stability by reducing conformational flexibility—to assess drug binding without requiring chemical modifications. CETSA’s integration with advanced mass spectrometry and high-throughput platforms has dramatically expanded proteome coverage and sensitivity, enabling the simultaneous quantification of thousands of proteins and the identification of low-abundance targets in native cellular environments. This review highlights the application of key CETSA-based methods to target identification in natural products including Western blot-based CETSA, isothermal dose–response CETSA, mass spectrometry-based CETSA, and high-throughput CETSA. Case studies are presented that demonstrate their effectiveness in uncovering the mechanisms of action of different drugs. The current limitations of CETSA-based strategies are also explored, and future improvements to optimize their potential for drug discovery are discussed. Integrating CETSA with complementary approaches can enhance the target identification accuracy and efficiency for natural products and ultimately advance development of therapeutic applications. Full article

(This article belongs to the Special Issue Anticancer Activity of Natural Products and Related Compounds)

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20 pages, 4992 KiB

Open AccessReview

Geldanamycins: Potent Hsp90 Inhibitors with Significant Potential in Cancer Therapy

by Omeima Abdullah and Ziad Omran

Int. J. Mol. Sci. 2024, 25(20), 11293; https://doi.org/10.3390/ijms252011293 - 20 Oct 2024

Cited by 1 | Viewed by 2045

Abstract

Geldanamycin, an ansa-macrolide composed of a rigid benzoquinone ring and an aliphatic ansa-bridge, was isolated from Streptomyces hygroscopicus. Geldanamycin is a potent heat shock protein inhibitor with remarkable antiproliferative activity. However, it shows pronounced hepatotoxicity in animal models and unfavorable pharmacokinetic properties. Four geldanamycin analogs have progressed through various phases of clinical trials, but none have yet completed clinical evaluation or received FDA approval. To enhance the efficacy of these Hsp90 inhibitors, strategies such as prodrug approaches or nanocarrier delivery systems could be employed to minimize systemic and organ toxicity. Furthermore, exploring new drug combinations may help overcome resistance, potentially improving therapeutic outcomes. This review discusses the mechanism of action of geldanamycin, its pharmacokinetic properties, and the various approaches employed to alleviate its toxicity and maximize its clinical efficacy. The main focus is on those derivatives that have progressed to clinical trials or that have shown important in vivo activity in preclinical models. Full article

(This article belongs to the Special Issue Anticancer Activity of Natural Products and Related Compounds)

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42 pages, 2288 KiB

Open AccessReview

Ferroptosis-Regulated Natural Products and miRNAs and Their Potential Targeting to Ferroptosis and Exosome Biogenesis

by Ya-Ting Chuang, Ching-Yu Yen, Tsu-Ming Chien, Fang-Rong Chang, Yi-Hong Tsai, Kuo-Chuan Wu, Jen-Yang Tang and Hsueh-Wei Chang

Int. J. Mol. Sci. 2024, 25(11), 6083; https://doi.org/10.3390/ijms25116083 - 31 May 2024

Cited by 3 | Viewed by 2288

Abstract

Ferroptosis, which comprises iron-dependent cell death, is crucial in cancer and non-cancer treatments. Exosomes, the extracellular vesicles, may deliver biomolecules to regulate disease progression. The interplay between ferroptosis and exosomes may modulate cancer development but is rarely investigated in natural product treatments and their modulating miRNAs. This review focuses on the ferroptosis-modulating effects of natural products and miRNAs concerning their participation in ferroptosis and exosome biogenesis (secretion and assembly)-related targets in cancer and non-cancer cells. Natural products and miRNAs with ferroptosis-modulating effects were retrieved and organized. Next, a literature search established the connection of a panel of ferroptosis-modulating genes to these ferroptosis-associated natural products. Moreover, ferroptosis-associated miRNAs were inputted into the miRNA database (miRDB) to bioinformatically search the potential targets for the modulation of ferroptosis and exosome biogenesis. Finally, the literature search provided a connection between ferroptosis-modulating miRNAs and natural products. Consequently, the connections from ferroptosis–miRNA–exosome biogenesis to natural product-based anticancer treatments are well-organized. This review sheds light on the research directions for integrating miRNAs and exosome biogenesis into the ferroptosis-modulating therapeutic effects of natural products on cancer and non-cancer diseases. Full article

(This article belongs to the Special Issue Anticancer Activity of Natural Products and Related Compounds)

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14 pages, 1010 KiB

Open AccessReview

Quercetin Derivatives as Potential Therapeutic Agents: An Updated Perspective on the Treatment of Nicotine-Induced Non-Small Cell Lung Cancer

by Naser A. Alsharairi

Int. J. Mol. Sci. 2023, 24(20), 15208; https://doi.org/10.3390/ijms242015208 - 15 Oct 2023

Cited by 12 | Viewed by 3716

Abstract

Flavonoids are the largest group of polyphenols, represented by many compounds that exhibit high anticancer properties. Quercetin (Q) and its main derivatives (rutin, quercitrin, isoquercitrin, isorhamnetin, tamarixetin, rhamnetin, and hyperoside) in the class of flavonols have been documented to exert anticancer activity. Q has been shown to be useful in the treatment of non-small cell lung cancer (NSCLC), as demonstrated by in vitro/in vivo studies, due to its antitumor, anti-inflammatory, anti-proliferative, anti-angiogenesis, and apoptotic properties. Some flavonoids (flavone, anthocyanins, and proanthocyanidins) have been demonstrated to be effective in nicotine-induced NSCLC treatment. However, the molecular mechanisms of quercetin derivatives (QDs) in nicotine-induced NSCLC treatment remain unclear. Thus, this review aims to summarize the available literature on the therapeutic effects of QDs in nicotine-induced NSCLC. Full article

(This article belongs to the Special Issue Anticancer Activity of Natural Products and Related Compounds)

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