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Anticancer Drug Discovery Based on Natural Products: From Computational Approaches to Clinical Studies

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Drug Development".

Deadline for manuscript submissions: 31 December 2024 | Viewed by 12681

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Special Issue Editors

Dr. Rajeev K. Singla

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Guest Editor

Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
Interests: molecular mechanisms; cheminformatics; metabolic disorders; natural products

Prof. Dr. Anupam Bishayee

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Guest Editor

College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA
Interests: bioactive natural compounds; cancer prevention; phytopharmacology; molecular mechanisms
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Special Issue Information

Dear Colleagues,

Cancer’s heterogeneous and dynamic nature, its drug resistance because of high vulnerability to point mutations, and its aberrant pathways are making it quite challenging to efficiently address and manage it. Natural products have always been a mainstream source of anticancer drugs due to the modulation of multiple hallmark traits of cancer. Nevertheless, the anticancer drugs available today are not efficient in treating patients with advanced-stage cancers and also exert quite serious side effects. One thing that clinicians and researchers have thoroughly understood so far is that highly specific drugs with only a single mechanism of action are not a prime choice. Thus, polypharmacologically active drugs with detailed knowledge about the genes and pathways that they modulate are what researchers and clinicians are presently looking for. Gene and pathway knowledge will also help us to understand the possible side effects of any drugs in advance since most genes are not specific to a particular location or responsible only for a particular disease. The majority of genes influence other genes as they are connected through the related pathways. Cheminformatics- and bioinformatics-based studies such as network-pharmacology-based studies, ADMET prediction, molecular docking, and molecular dynamics simulations are quite important in aiding and expediting research towards the translational level.

Translational aspects of preclinical studies to clinical level are of utmost importance for natural products to progress from bench to bedside.

In this Special Issue, original research articles and reviews are welcome. Research areas may include (but are not limited to) the following:

Bioactive natural compounds from diverse sources, including plants, animals, microbes, and marine organisms, against various cancers: Computational, preclinical, and clinical studies;
Mechanism-based anticancer activity of natural compounds (botanical drugs, uncharacterized plant extracts, and fractions are excluded);
Nanoformulations for site-targeted anticancer drug delivery;
Cheminformatics and bioinformatics integrating genomic data and computational modeling;
Role of translational informatics in natural-product-based anticancer drug discovery.

Note: Authors should also follow the below guidelines from the journal before submitting their manuscripts:

Manuscripts describing the effects of botanical or natural drugs/extracts/fractions will not be considered;
The active ingredients or constituents of the natural agents should be determined or presented;
The toxicity of the natural compounds should be evaluated in both in vitro and in vivo studies.

We look forward to receiving your contributions.

Dr. Rajeev K. Singla
Prof. Dr. Anupam Bishayee
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. Cancers 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 2900 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
cancer
anticancer effects
cytotoxic agents
cheminformatics
plant secondary metabolites
malignant tumor
drug resistance
hallmark traits
molecular mechanisms

Published Papers (7 papers)

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Research

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15 pages, 3295 KiB

Open AccessArticle

The Therapeutic Efficacy and Mechanism of Action of Gnetin C, a Natural Compound from the Melinjo Plant, in a Preclinical Mouse Model of Advanced Prostate Cancer

by Gisella Campanelli, Ekniel Francois, Prashanth Parupathi, Lakshmi Sirisha Devarakonda, Ching Yang, Avinash Kumar and Anait S. Levenson

Cancers 2024, 16(7), 1344; https://doi.org/10.3390/cancers16071344 - 29 Mar 2024

Viewed by 530

Abstract

The metastasis-associated protein 1/protein kinase B (MTA1/AKT) signaling pathway has been shown to cooperate in promoting prostate tumor growth. Targeted interception strategies by plant-based polyphenols, specifically stilbenes, have shown great promise against MTA1-mediated prostate cancer progression. In this study, we employed a prostate-specific transgenic mouse model with MTA1 overexpression on the background of phosphatase and tensin homolog (Pten) null (R26^MTA1; Pten^f/f) and PC3M prostate cancer cells which recapitulate altered molecular pathways in advanced prostate cancer. Mechanistically, the MTA1 knockdown or pharmacological inhibition of MTA1 by gnetin C (dimer resveratrol) in cultured PC3M cells resulted in the marked inactivation of mammalian target of rapamycin (mTOR) signaling. In vivo, mice tolerated a daily intraperitoneal treatment of gnetin C (7 mg/kg bw) for 12 weeks without any sign of toxicity. Treatment with gnetin C markedly reduced cell proliferation and angiogenesis and promoted apoptosis in mice with advanced prostate cancer. Further, in addition to decreasing MTA1 levels in prostate epithelial cells, gnetin C significantly reduced mTOR signaling activity in prostate tissues, including the activity of mTOR-target proteins: p70 ribosomal protein S6 kinase (S6K) and eukaryotic translational initiation factor 4E (elF4E)-binding protein 1 (4EBP1). Collectively, these findings established gnetin C as a new natural compound with anticancer properties against MTA1/AKT/mTOR-activated prostate cancer, with potential as monotherapy and as a possible adjunct to clinically approved mTOR pathway inhibitors in the future. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery Based on Natural Products: From Computational Approaches to Clinical Studies)

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19 pages, 5171 KiB

Open AccessArticle

Naringin–Dextrin Nanocomposite Abates Diethylnitrosamine/Acetylaminofluorene-Induced Lung Carcinogenesis by Modulating Oxidative Stress, Inflammation, Apoptosis, and Cell Proliferation

by Eman E. Mohamed, Osama M. Ahmed, Khairy M. A. Zoheir, Ahmed A. G. El-Shahawy, Shadi Tamur, Anwar Shams, Jack T. Burcher, Anupam Bishayee and Adel Abdel-Moneim

Cancers 2023, 15(20), 5102; https://doi.org/10.3390/cancers15205102 - 22 Oct 2023

Cited by 2 | Viewed by 1265

Abstract

Nanotechnology has proven advantageous in numerous scientific applications, one being to enhance the delivery of chemotherapeutic agents. This present study aims to evaluate the mechanisms underlying the chemopreventive action of naringin–dextrin nanocomposites (Nar-Dx-NCs) against diethylnitrosamine (DEN)/2-acetylaminofluorene (2AAF)-induced lung carcinogenesis in male Wistar rats. DEN was administered intraperitoneally (i.p.) (150 mg/kg/week) for two weeks, followed by the oral administration of 2AAF (20 mg/kg) four times a week for three weeks. Rats receiving DEN/2AAF were concurrently treated with naringin or Nar-Dx-NCs orally at a dose of 10 mg/kg every other day for 24 weeks. Naringin and Nar-Dx-NCs treatments prevented the formation of tumorigenic cells within the alveoli of rats exposed to DEN/2AAF. These findings were associated with a significant decrease in lipid peroxidation, upregulation of antioxidant enzyme (glutathione peroxidase and superoxide dismutase) activity, and enhanced glutathione and nuclear factor erythroid 2–related factor 2 expression in the lungs. Naringin and Nar-Dx-NCs exerted anti-inflammatory actions manifested by a decrease in lung protein expression of tumor necrosis factor-α and interleukin-1β and mRNA expression of interleukin-6, interferon-γ, nuclear factor-κB, and inducible nitric oxide synthase, with a concurrent increase in interleukin-10 expression. The anti-inflammatory effect of Nar-Dx-NCs was more potent than naringin. Regarding the effect on apoptosis, both naringin and Nar-Dx-NCs significantly reduced Bcl-2 and increased Bax and P53 expressions. Moreover, naringin or Nar-Dx-NCs induced a significant decrease in the expression of the proliferator marker, Ki-67, and the effect of Nar-Dx-NCs was more marked. In conclusion, Nar-Dx-NCs improved naringin’s preventive action against DEN/2AAF-induced lung cancer and exerted anticarcinogenic effects by suppressing oxidative stress and inflammation and improving apoptotic signal induction and propagation. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery Based on Natural Products: From Computational Approaches to Clinical Studies)

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26 pages, 5403 KiB

Open AccessArticle

In Silico, In Vitro, and In Vivo Investigations on Adapalene as Repurposed Third Generation Retinoid against Multiple Myeloma and Leukemia

by Joelle C. Boulos, Manik Chatterjee, Letian Shan and Thomas Efferth

Cancers 2023, 15(16), 4136; https://doi.org/10.3390/cancers15164136 - 16 Aug 2023

Viewed by 1359

Abstract

The majority of hematopoietic cancers in adults are incurable and exhibit unpredictable remitting-relapsing patterns in response to various therapies. The proto-oncogene c-MYC has been associated with tumorigenesis, especially in hematological neoplasms. Therefore, targeting c-MYC is crucial to find effective, novel treatments for blood malignancies. To date, there are no clinically approved c-MYC inhibitors. In this study, we virtually screened 1578 Food and Drug Administration (FDA)-approved drugs from the ZINC15 database against c-MYC. The top 117 compounds from PyRx-based screening with the best binding affinities to c-MYC were subjected to molecular docking studies with AutoDock 4.2.6. Retinoids consist of synthetic and natural vitamin A derivatives. All-trans-retinoic acid (ATRA) were highly effective in hematological malignancies. In this study, adapalene, a third-generation retinoid usually used to treat acne vulgaris, was selected as a potent c-MYC inhibitor as it robustly bound to c-MYC with a lowest binding energy (LBE) of −7.27 kcal/mol, a predicted inhibition constant (pKi) of 4.69 µM, and a dissociation constant (K_d value) of 3.05 µM. Thus, we examined its impact on multiple myeloma (MM) cells in vitro and evaluated its efficiency in vivo using a xenograft tumor zebrafish model. We demonstrated that adapalene exerted substantial cytotoxicity against a panel of nine MM and two leukemic cell lines, with AMO1 cells being the most susceptible one (IC₅₀ = 1.76 ± 0.39 µM) and, hence, the focus of this work. Adapalene (0.5 × IC₅₀, 1 × IC₅₀, 2 × IC₅₀) decreased c-MYC expression and transcriptional activity in AMO1 cells in a dose-dependent manner. An examination of the cell cycle revealed that adapalene halted the cells in the G₂/M phase and increased the portion of cells in the sub-G₀/G₁ phase after 48 and 72 h, indicating that cells failed to initiate mitosis, and consequently, cell death was triggered. Adapalene also increased the number of p-H3(Ser10) positive AMO1 cells, which is a further proof of its ability to prevent mitotic exit. Confocal imaging demonstrated that adapalene destroyed the tubulin network of U2OS cells stably transfected with a cDNA coding for α-tubulin-GFP, refraining the migration of malignant cells. Furthermore, adapalene induced DNA damage in AMO1 cells. It also induced apoptosis and autophagy, as demonstrated by flow cytometry and western blotting. Finally, adapalene impeded tumor growth in a xenograft tumor zebrafish model. In summary, the discovery of the vitamin A derivative adapalene as a c-MYC inhibitor reveals its potential as an avant-garde treatment for MM. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery Based on Natural Products: From Computational Approaches to Clinical Studies)

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19 pages, 8229 KiB

Open AccessArticle

Combining Crocin and Sorafenib Improves Their Tumor-Inhibiting Effects in a Rat Model of Diethylnitrosamine-Induced Cirrhotic-Hepatocellular Carcinoma

by Basma Awad, Alaaeldin Ahmed Hamza, Amna Al-Maktoum, Suhail Al-Salam and Amr Amin

Cancers 2023, 15(16), 4063; https://doi.org/10.3390/cancers15164063 - 11 Aug 2023

Cited by 12 | Viewed by 1428

Abstract

Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies, with continuously increasing cases and fatalities. Diagnosis often occurs in the advanced stages, confining patients to systemic therapies such as sorafenib. Sorafenib (SB), a multi-kinase inhibitor, has not yet demonstrated sufficient efficacy against advanced HCC. There is a strong argument in favor of studying its use in combination with other medications to optimize the therapeutic results. According to our earlier work, crocin (CR), a key bioactive component of saffron, hinders HCC development and liver cancer stemness. In this study, we investigated the therapeutic use of CR or its combination with SB in a cirrhotic rat model of HCC and evaluated how effectively SB and CR inhibited tumor growth in this model. Diethylnitrosamine (DEN) was administered intraperitoneally to rats once a week for 15 weeks, leading to cirrhosis, and then 19 weeks later, leading to multifocal HCC. After 16 weeks of cancer induction, CR (200 mg/kg daily) and SB (10 mg/kg daily) were given orally to rats for three weeks, either separately or in combination. Consistently, the combination treatment considerably decreased the incidence of dyschromatic nodules, nodule multiplicity, and dysplastic nodules when compared to the HCC group of single therapies. Combined therapy also caused the highest degree of apoptosis, along with decreased proliferating and β-catenin levels in the tumor tissues. Additionally, when rats received combined therapy with CR, it showed anti-inflammatory characteristics where nuclear factor kappa B (NF-κB) and cyclooxygenase-2 (Cox-2) were considerably and additively lowered. As a result, CR potentiates the suppressive effects of SB on tumor growth and provides the opportunity to strengthen the therapeutic effects of SB in the treatment of HCC. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery Based on Natural Products: From Computational Approaches to Clinical Studies)

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Review

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62 pages, 2159 KiB

Open AccessReview

Nature’s Green Potential: Anticancer Properties of Plants of the Euphorbiaceae Family

by Víctor Jiménez-González, Tomasz Kowalczyk, Janusz Piekarski, Janusz Szemraj, Patricia Rijo and Przemysław Sitarek

Cancers 2024, 16(1), 114; https://doi.org/10.3390/cancers16010114 - 25 Dec 2023

Cited by 1 | Viewed by 1317

Abstract

The number of cancer cases will reach 24 million in 2040, according to the International Agency for Research on Cancer. Current treatments for cancer are not effective and selective for most patients; for this reason, new anticancer drugs need to be developed and researched enough. There are potentially useful drugs for cancer isolated from plants that are being used in the clinic. Available information about phytochemistry, traditional uses, in vitro and in vivo experiments with plants, and pure compounds isolated from the Euphorbiaceae family indicates that this family of plants has the potential to develop anticancer drugs. This review examines selected species from the Euphorbiaceae family and their bioactive compounds that could have potential against different types of cancer cells. It reviews the activity of crude extracts, isolated compounds, and nanoparticles and the potential underlying mechanisms of action. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery Based on Natural Products: From Computational Approaches to Clinical Studies)

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60 pages, 4226 KiB

Open AccessReview

Targeting Cell Signaling Pathways in Lung Cancer by Bioactive Phytocompounds

by Neeraj Choudhary, Sweta Bawari, Jack T. Burcher, Dona Sinha, Devesh Tewari and Anupam Bishayee

Cancers 2023, 15(15), 3980; https://doi.org/10.3390/cancers15153980 - 05 Aug 2023

Cited by 1 | Viewed by 2844

Abstract

Lung cancer is a heterogeneous group of malignancies with high incidence worldwide. It is the most frequently occurring cancer in men and the second most common in women. Due to its frequent diagnosis and variable response to treatment, lung cancer was reported as the top cause of cancer-related deaths worldwide in 2020. Many aberrant signaling cascades are implicated in the pathogenesis of lung cancer, including those involved in apoptosis (B cell lymphoma protein, Bcl-2-associated X protein, first apoptosis signal ligand), growth inhibition (tumor suppressor protein or gene and serine/threonine kinase 11), and growth promotion (epidermal growth factor receptor/proto-oncogenes/phosphatidylinositol-3 kinase). Accordingly, these pathways and their signaling molecules have become promising targets for chemopreventive and chemotherapeutic agents. Recent research provides compelling evidence for the use of plant-based compounds, known collectively as phytochemicals, as anticancer agents. This review discusses major contributing signaling pathways involved in the pathophysiology of lung cancer, as well as currently available treatments and prospective drug candidates. The anticancer potential of naturally occurring bioactive compounds in the context of lung cancer is also discussed, with critical analysis of their mechanistic actions presented by preclinical and clinical studies. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery Based on Natural Products: From Computational Approaches to Clinical Studies)

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33 pages, 4444 KiB

Open AccessReview

Potential of Synthetic and Natural Compounds as Novel Histone Deacetylase Inhibitors for the Treatment of Hematological Malignancies

by Dilipkumar Pal, Khushboo Raj, Shyam Sundar Nandi, Surajit Sinha, Abhishek Mishra, Arijit Mondal, Ricardo Lagoa, Jack T. Burcher and Anupam Bishayee

Cancers 2023, 15(10), 2808; https://doi.org/10.3390/cancers15102808 - 17 May 2023

Cited by 5 | Viewed by 2159

Abstract

Histone deacetylases (HDACs) and histone acetyltransferases (HATs) are enzymes that remove or add acetyl groups to lysine residues of histones, respectively. Histone deacetylation causes DNA to more snugly encircle histones and decreases gene expression, whereas acetylation has the opposite effect. Through these small alterations in chemical structure, HATs and HDACs regulate DNA expression. Recent research indicates histone deacetylase inhibitors (HDACis) may be used to treat malignancies, including leukemia, B-cell lymphoma, virus-associated tumors, and multiple myeloma. These data suggest that HDACis may boost the production of immune-related molecules, resulting in the growth of CD8-positive T-cells and the recognition of nonreactive tumor cells by the immune system, thereby diminishing tumor immunity. The argument for employing epigenetic drugs in the treatment of acute myeloid leukemia (AML) patients is supported by evidence that both epigenetic changes and mutations in the epigenetic machinery contribute to AML etiology. Although hypomethylating drugs have been licensed for use in AML, additional epigenetic inhibitors, such as HDACis, are now being tested in humans. Preclinical studies evaluating the efficacy of HDACis against AML have shown the ability of specific agents, such as anobinostat, vorinostat, and tricostatin A, to induce growth arrest, apoptosis, autophagy and cell death. However, these inhibitors do not seem to be successful as monotherapies, but instead achieve results when used in conjunction with other medications. In this article, we discuss the mounting evidence that HDACis promote extensive histone acetylation, as well as substantial increases in reactive oxygen species and DNA damage in hematological malignant cells. We also evaluate the potential of various natural product-based HDACis as therapeutic agents to combat hematological malignancies. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery Based on Natural Products: From Computational Approaches to Clinical Studies)

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