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Plant-Based Cancer Drug Discovery: Natural Products with Anti-Cancer Activity

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 30652

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Special Issue Editor

Prof. Dr. Jamal Mahajna

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Guest Editor

1. Department of Nutrition and Natural Products, Migal—Galilee Research Institute, Kiryat Shmona 11016, Israel
2. Faculty of Science and Technology, Department of Biotechnology, Tel Hai College, Kiryat shmona, Israel
Interests: natural products as cancer therapeutics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Natural products have been used by humans since ancient times, have been an extremely productive source for new medicines in all cultures, continue to deliver a great diversity of structural templates, and can act as drug prototypes and/or be used as pharmacological tools for different targets involved in carcinogenesis. Thus, this special issue will focus on the discovery of new anticancer activities of plant-derived natural products.

This Special Issue welcomes original research articles and reviews concerning various aspects of the anti-cancer properties of isolated natural products. Special focus will be on the investigation of mechanisms of action of natural products with potential anti-cancer activity. In vivo studies and the design of novel natural product derivatives with improved efficacy are also welcome. Studies that were performed with natural extracts must include a phytochemical characterization of the extracts. This Special Issue will focus on plant-derived natural products in cancer therapy.

Prof. Jamal Mahajna
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 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.

Prof. Jamal Mahajna
Guest Editor

Manuscript Submission Information

Prof. Dr. Jamal Mahajna
Guest Editor

Manuscript Submission Information

Keywords

Cancer cell proliferation
Cancer angiogenesis
Cancer metastasis
Cancer and epithelial–mesenchymal transition (EMT)
Cancer stem cells
Overcoming drug resistance in cancer
Cancer epigenetics
miRNA and carcinogenesis

Published Papers (7 papers)

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Research

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16 pages, 3952 KiB

Open AccessArticle

Inhibition of Cell Proliferation and Metastasis by Scutellarein Regulating PI3K/Akt/NF-κB Signaling through PTEN Activation in Hepatocellular Carcinoma

by Sang Eun Ha, Seong Min Kim, Preethi Vetrivel, Hun Hwan Kim, Pritam Bhagwan Bhosale, Jeong Doo Heo, Ho Jeong Lee and Gon Sup Kim

Int. J. Mol. Sci. 2021, 22(16), 8841; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168841 - 17 Aug 2021

Cited by 21 | Viewed by 2294

Abstract

Scutellarein (SCU) is a well-known flavone with a broad range of biological activities against several cancers. Human hepatocellular carcinoma (HCC) is major cancer type due to its poor prognosis even after treatment with chemotherapeutic drugs, which causes a variety of side effects in patients. Therefore, efforts have been made to develop effective biomarkers in the treatment of HCC in order to improve therapeutic outcomes using natural based agents. The current study used SCU as a treatment approach against HCC using the HepG2 cell line. Based on the cell viability assessment up to a 200 μM concentration of SCU, three low-toxic concentrations of (25, 50, and 100) μM were adopted for further investigation. SCU induced cell cycle arrest at the G2/M phase and inhibited cell migration and proliferation in HepG2 cells in a dose-dependent manner. Furthermore, increased PTEN expression by SCU led to the subsequent downregulation of PI3K/Akt/NF-κB signaling pathway related proteins. In addition, SCU regulated the metastasis with EMT and migration-related proteins in HepG2 cells. In summary, SCU inhibits cell proliferation and metastasis in HepG2 cells through PI3K/Akt/NF-κB signaling by upregulation of PTEN, suggesting that SCU might be used as a potential agent for HCC therapy. Full article

(This article belongs to the Special Issue Plant-Based Cancer Drug Discovery: Natural Products with Anti-Cancer Activity)

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19 pages, 5453 KiB

Open AccessArticle

4-Acetyl-Antroquinonol B Improves the Sensitization of Cetuximab on Both Kras Mutant and Wild Type Colorectal Cancer by Modulating the Expression of Ras/Raf/miR-193a-3p Signaling Axis

by Yi Cheng Chu, Tung-Yao Tsai, Vijesh Kumar Yadav, Li Deng, Chun-Chih Huang, Yew-Min Tzeng, Chi-Tai Yeh and Ming-Yao Chen

Int. J. Mol. Sci. 2021, 22(14), 7508; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147508 - 14 Jul 2021

Cited by 8 | Viewed by 3192

Abstract

The KRAS mutation is one of the leading driver mutations in colorectal cancer (CRC), and it is usually associated with poor prognosis and drug resistance. Therapies targeting the epidermal growth factor receptor (EFGR) are widely used for end-stage CRC. However, patients with KRAS mutant genes cannot benefit from this therapy because of Ras signaling activation by KRAS mutant genes. Our previous study revealed the anti-proliferative effect of 4-acetyl-antroquinonol B (4-AAQB) on CRC cells, but whether the drug is effective in KRAS-mutant CRC remains unknown. We screened CRC cell lines harboring the KRAS mutation, namely G12A, G12C, G12V and G13D, with one wild type cell line as the control; SW1463 and Caco-2 cell lines were used for further experiments. Sulforhodamine B assays, together with the clonogenicity and invasion assay, revealed that KRAS-mutant SW1463 cells were resistant to cetuximab; however, 4-AAQB treatment effectively resensitized CRC cells to cetuximab through the reduction of colony formation, invasion, and tumorsphere generation and of oncogenic KRAS signaling cascade of CRC cells. Thus, inducing cells with 4-AAQB before cetuximab therapy could resensitize KRAS-mutant, but not wild-type, cells to cetuximab. Therefore, we hypothesized that 4-AAQB can inhibit KRAS. In silico analysis of the publicly available GEO (GSE66548) dataset of KRAS-mutated versus KRAS wild-type CRC patients confirmed that miR-193a-3p was significantly downregulated in the former compared with the latter patient population. Overexpression of miR-193a-3p considerably reduced the oncogenicity of both CRC cells. Furthermore, KRAS is a key target of miR-193a-3p. In vivo treatment with the combination of 4-AAQB and cetuximab significantly reduced the tumor burden of a xenograft mice model through the reduction of the expression of oncogenic markers (EGFR) and p-MEK, p-ERK, and c-RAF/p-c-RAF signaling, with the simultaneous induction of miR-193a-3p expression in the plasma. In summary, our findings provide strong evidence regarding the therapeutic effect of 4-AAQB on KRAS-mutant CRC cells. Furthermore, 4-AAQB effectively inhibits Ras singling in CRC cells, through which KRAS-mutant CRC can be resensitized to cetuximab. Full article

(This article belongs to the Special Issue Plant-Based Cancer Drug Discovery: Natural Products with Anti-Cancer Activity)

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18 pages, 6823 KiB

Open AccessArticle

Pancracine, a Montanine-Type Amaryllidaceae Alkaloid, Inhibits Proliferation of A549 Lung Adenocarcinoma Cells and Induces Apoptotic Cell Death in MOLT-4 Leukemic Cells

by Darja Koutová, Radim Havelek, Eva Peterová, Darina Muthná, Karel Královec, Kateřina Breiterová, Lucie Cahlíková and Martina Řezáčová

Int. J. Mol. Sci. 2021, 22(13), 7014; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22137014 - 29 Jun 2021

Cited by 7 | Viewed by 2144

Abstract

Pancracine, a montanine-type Amaryllidaceae alkaloid (AA), is one of the most potent compounds among natural isoquinolines. In previous studies, pancracine exhibited cytotoxic activity against diverse human cancer cell lines in vitro. However, further insight into the molecular mechanisms that underlie the cytotoxic effect of pancracine have not been reported and remain unknown. To fill this void, the cell proliferation and viability of cancer cells was explored using the Trypan Blue assay or by using the xCELLigence system. The impact on the cell cycle was determined by flow cytometry. Apoptosis was evaluated by Annexin V/PI and by quantifying the activity of caspases (-3/7, -8, and -9). Proteins triggering growth arrest or apoptosis were detected by Western blotting. Pancracine has strong antiproliferative activity on A549 cells, lasting up to 96 h, and antiproliferative and cytotoxic effects on MOLT-4 cells. The apoptosis-inducing activity of pancracine in MOLT-4 cells was evidenced by the significantly higher activity of caspases. This was transmitted through the upregulation of p53 phosphorylated on Ser392, p38 MAPK phosphorylated on Thr180/Tyr182, and upregulation of p27. The pancracine treatment negatively altered the proliferation of A549 cells as a consequence of an increase in G1-phase accumulation, associated with the downregulation of Rb phosphorylated on Ser807/811 and with the concomitant upregulation of p27 and downregulation of Akt phosphorylated on Thr308. This was the first study to glean a deeper mechanistic understanding of pancracine activity in vitro. Perturbation of the cell cycle and induction of apoptotic cell death were considered key mechanisms of pancracine action. Full article

(This article belongs to the Special Issue Plant-Based Cancer Drug Discovery: Natural Products with Anti-Cancer Activity)

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Review

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33 pages, 2257 KiB

Open AccessReview

Current Advancements of Plant-Derived Agents for Triple-Negative Breast Cancer Therapy through Deregulating Cancer Cell Functions and Reprogramming Tumor Microenvironment

by Tai-Na Wu, Hui-Ming Chen and Lie-Fen Shyur

Int. J. Mol. Sci. 2021, 22(24), 13571; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413571 - 17 Dec 2021

Cited by 10 | Viewed by 5080

Abstract

Triple-negative breast cancer (TNBC) is defined based on the absence of estrogen, progesterone, and human epidermal growth factor receptor 2 receptors. Currently, chemotherapy is the major therapeutic approach for TNBC patients; however, poor prognosis after a standard chemotherapy regimen is still commonplace due to drug resistance. Abnormal tumor metabolism and infiltrated immune or stromal cells in the tumor microenvironment (TME) may orchestrate mammary tumor growth and metastasis or give rise to new subsets of cancer cells resistant to drug treatment. The immunosuppressive mechanisms established in the TME make cancer cell clones invulnerable to immune recognition and killing, and turn immune cells into tumor-supporting cells, hence allowing cancer growth and dissemination. Phytochemicals with the potential to change the tumor metabolism or reprogram the TME may provide opportunities to suppress cancer metastasis and/or overcome chemoresistance. Furthermore, phytochemical intervention that reprograms the TME away from favoring immunoevasion and instead towards immunosurveillance may prevent TNBC metastasis and help improve the efficacy of combination therapies as phyto-adjuvants to combat drug-resistant TNBC. In this review, we summarize current findings on selected bioactive plant-derived natural products in preclinical mouse models and/or clinical trials with focus on their immunomodulatory mechanisms in the TME and their roles in regulating tumor metabolism for TNBC prevention or therapy. Full article

(This article belongs to the Special Issue Plant-Based Cancer Drug Discovery: Natural Products with Anti-Cancer Activity)

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23 pages, 5640 KiB

Open AccessReview

Natural Products Targeting Cancer Stem Cells for Augmenting Cancer Therapeutics

by Ari Meerson, Soliman Khatib and Jamal Mahajna

Int. J. Mol. Sci. 2021, 22(23), 13044; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222313044 - 02 Dec 2021

Cited by 16 | Viewed by 9962

Abstract

Cancer stem cells (CSC) have been identified in several types of solid tumors. In some cases, CSC may be the source of all the tumor cells, the cause of the tumor’s resistance to chemotherapeutic agents, and the source of metastatic cells. Thus, a combination therapy targeting non-CSC tumor cells as well as specifically targeting CSCs holds the potential to be highly effective. Natural products (NPs) have been a historically rich source of biologically active compounds and are known for their ability to influence multiple signaling pathways simultaneously with negligible side effects. In this review, we discuss the potential of NPs in targeting multiple signaling pathways in CSC and their potential to augment the efficacy of standard cancer therapy. Specifically, we focus on the anti-CSC activities of flavonoids, FDA-approved drugs originating from natural sources. Additionally, we emphasize the potential of NPs in targeting microRNA-mediated signaling, given the roles of microRNA in the maintenance of the CSC phenotype. Full article

(This article belongs to the Special Issue Plant-Based Cancer Drug Discovery: Natural Products with Anti-Cancer Activity)

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30 pages, 7664 KiB

Open AccessReview

Natural Products Counteracting Cardiotoxicity during Cancer Chemotherapy: The Special Case of Doxorubicin, a Comprehensive Review

by Izabela Koss-Mikołajczyk, Vanja Todorovic, Sladjana Sobajic, Jamal Mahajna, Marko Gerić, Josep A. Tur and Agnieszka Bartoszek

Int. J. Mol. Sci. 2021, 22(18), 10037; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221810037 - 17 Sep 2021

Cited by 14 | Viewed by 4008

Abstract

Cardiotoxicity is a frequent undesirable phenomenon observed during oncological treatment that limits the therapeutic dose of antitumor drugs and thus may decrease the effectiveness of cancer eradication. Almost all antitumor drugs exhibit toxic properties towards cardiac muscle. One of the underlying causes of cardiotoxicity is the stimulation of oxidative stress by chemotherapy. This suggests that an appropriately designed diet or dietary supplements based on edible plants rich in antioxidants could decrease the toxicity of antitumor drugs and diminish the risk of cardiac failure. This comprehensive review compares the cardioprotective efficacy of edible plant extracts and foodborne phytochemicals whose beneficial activity was demonstrated in various models in vivo and in vitro. The studies selected for this review concentrated on a therapy frequently applied in cancer, anthracycline antibiotic—doxorubicin—as the oxidative stress- and cardiotoxicity-inducing agent. Full article

(This article belongs to the Special Issue Plant-Based Cancer Drug Discovery: Natural Products with Anti-Cancer Activity)

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18 pages, 5059 KiB

Open AccessReview

Phytochemicals in Malignant Pleural Mesothelioma Treatment—Review on the Current Trends of Therapies

by Malgorzata Chmielewska-Kassassir and Lucyna A. Wozniak

Int. J. Mol. Sci. 2021, 22(15), 8279; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158279 - 31 Jul 2021

Cited by 3 | Viewed by 2769

Abstract

Malignant pleural mesothelioma (MPM) is a rare but highly aggressive tumor of pleura arising in response to asbestos fibers exposure. MPM is frequently diagnosed in the advanced stage of the disease and causes poor prognostic outcomes. From the clinical perspective, MPM is resistant to conventional treatment, thus challenging the therapeutic options. There is still demand for improvement and sensitization of MPM cells to therapy in light of intensive clinical studies on chemotherapeutic drugs, including immuno-modulatory and targeted therapies. One way is looking for natural sources, whole plants, and extracts whose ingredients, especially polyphenols, have potential anticancer properties. This comprehensive review summarizes the current studies on natural compounds and plant extracts in developing new treatment strategies for MPM. Full article

(This article belongs to the Special Issue Plant-Based Cancer Drug Discovery: Natural Products with Anti-Cancer Activity)

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