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Plant-Derived Natural Compounds in the Management of Cancer: Significance and...
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Plant-Derived Natural Compounds in the Management of Cancer: Significance and Challenges

A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 129177

Special Issue Editors

Prof. Dr. Dietrich Büsselberg

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Guest Editor
Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar (Medbay), Qatar Foundation, Education City, Doha P.O. Box 24144, Qatar
Interests: tumor biology; metal toxicity; cellular pain modulation; anti-cancer drugs; natural compounds; phytochemicals
Special Issues, Collections and Topics in MDPI journals
Dr. Samson Mathews Samuel

E-Mail Website
Guest Editor
Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar (Medbay), Qatar Foundation, Education City, Doha P.O. Box 24144, Qatar
Interests: angiogenesis; autophagy; breast cancer; cancer (glucose) metabolism; cancer stem cells; diabetes; epithelial-mesenchymal-epithelial transition (EMT/MET); endoplasmic reticulum (ER) stress; metformin; therapeutic resistance; tumor microenvironment
Special Issues, Collections and Topics in MDPI journals
Dr. Peter Kubatka

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Guest Editor
Comenius University in Bratislava, Jesseniuss Faculty of Medicine, Department of Medical Biology, Martin, Slovakia
Interests: experimental mammary carcinogenesis, chemoprevention, therapy, animal models, plant-derived funtional foods, cancer cell signaling
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer is a major disease worldwide, contributing significantly to the social and economic burden. Therefore, there is an unmet need to develop cancer prevention strategies for those at risk and improve treatment strategies for the benefit of those that are already affected. Although several mechanisms have been proposed for the development and progression of various cancers, there remain areas that need to be explored and an urgency to tackle these processes (using anti-cancer drugs) to reduce the development and progression of cancers and improve the efficacy of cancer treatments.

Cancers often develop over years or even decades, triggered by different processes involving DNA damage, chronic inflammation, comprehensive interaction between relevant molecular pathways, and cellular cross-talk with the neighboring tissues. Only a minor part of cancers are caused by inborn pre-disposition. The absolute majority carry a sporadic character based on modifiable risk factors which play a central role in cancer prevention. Numerous studies have documented that dietary natural plant products (both whole products as well as their isolated active compounds) are able to affect the initiation, promotion, and progression of cancers. The long-term administration of multi-target phytochemicals with a plethora of biological activities can thus be the most rational and effective strategy used in medical practice in this regard.

This Special Issue focusses on the effects of plant-derived dietary factors on carcinogenesis and effective cancer treatment. It includes in-vitro- and in-vivo-based cancer models evaluating the mechanisms of action of phytochemicals on cancer; clinical investigations on the role of the plant compounds on cancer risk, treatment, and survival; novel methodological approaches to enhance the bioavailability of phytochemicals; and novel strategies for the extraction, purification, and characterization natural compounds with anticancer activity. For this Special Issue, we invite original research articles and reviews related to the role of plant-derived natural compounds on cancers.

Dr. Dietrich Büsselberg
Dr. Samson Mathews Samuel
Dr. Peter Kubatka
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. Biomolecules is an international peer-reviewed open access monthly 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

  • angiogenesis
  • antioxidants
  • apoptosis
  • cancer cells
  • cancer chemoprevention
  • cancer stem cells
  • cancer treatment
  • cell cycle regulation
  • epigenetic modulators
  • geno-protective effects
  • natural bioactive compounds
  • nutraceuticals
  • nutrition
  • oxidative stress
  • phytochemicals
  • plant functional foods
  • polyphenols
  • terpenoids

Published Papers (19 papers)

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Editorial

Jump to: Research, Review

7 pages, 929 KiB  
Editorial
Treating Cancers Using Nature’s Medicine: Significance and Challenges
by Samson Mathews Samuel, Peter Kubatka and Dietrich Büsselberg
Biomolecules 2021, 11(11), 1698; https://doi.org/10.3390/biom11111698 - 15 Nov 2021
Cited by 4 | Viewed by 2101
Abstract
There was a time when plant-derived natural formulations were the cornerstone of ancient therapeutic approaches for treating many illnesses [...] Full article
(This article belongs to the Special Issue Plant-Derived Natural Compounds in the Management of Cancer: Significance and Challenges)
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Research

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19 pages, 3846 KiB  
Article
Antiproliferative Effect of Acridine Chalcone Is Mediated by Induction of Oxidative Stress
by Peter Takac, Martin Kello, Maria Vilkova, Janka Vaskova, Radka Michalkova, Gabriela Mojzisova and Jan Mojzis
Biomolecules 2020, 10(2), 345; https://doi.org/10.3390/biom10020345 - 22 Feb 2020
Cited by 33 | Viewed by 3731
Abstract
Chalcones are naturally occurring phytochemicals with diverse biological activities including antioxidant, antiproliferative, and anticancer effects. Some studies indicate that the antiproliferative effect of chalcones may be associated with their pro-oxidant effect. In the present study, we evaluated contribution of oxidative stress in the [...] Read more.
Chalcones are naturally occurring phytochemicals with diverse biological activities including antioxidant, antiproliferative, and anticancer effects. Some studies indicate that the antiproliferative effect of chalcones may be associated with their pro-oxidant effect. In the present study, we evaluated contribution of oxidative stress in the antiproliferative effect of acridine chalcone 1C ((2 E)-3-(acridin-9-yl)-1-(2,6-dimethoxyphenyl)prop-2-en-1-one) in human colorectal HCT116 cells. We demonstrated that chalcone 1C induced oxidative stress via increased reactive oxygen/nitrogen species (ROS/RNS) and superoxide production with a simultaneous weak adaptive activation of the cellular antioxidant defence mechanism. Furthermore, we also showed chalcone-induced mitochondrial dysfunction, DNA damage, and apoptosis induction. Moreover, activation of mitogen activated phosphokinase (MAPK) signalling pathway in 1C-treated cancer cells was also observed. On the other hand, co-treatment of cells with strong antioxidant, N-acetyl cysteine (NAC), significantly attenuated all of the above-mentioned effects of chalcone 1C, that is, decreased oxidant production, prevent mitochondrial dysfunction, DNA damage, and induction of apoptosis, as well as partially preventing the activation of MAPK signalling. Taken together, we documented the role of ROS in the antiproliferative/pro-apoptotic effects of acridine chalcone 1C. Moreover, these data suggest that this chalcone may be useful as a promising anti-cancer agent for treating colon cancer. Full article
(This article belongs to the Special Issue Plant-Derived Natural Compounds in the Management of Cancer: Significance and Challenges)
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9 pages, 825 KiB  
Article
Efficacy of Jackfruit365™ Green Jackfruit Flour Fortified Diet on Pegfilgrastim to Prevent Chemotherapy-Induced Leukopenia, Irrespective of Tumor Type or Drugs Used—A Retrospective Study
by Thomas Varughese, James Joseph and Rejeesh Menon
Biomolecules 2020, 10(2), 218; https://doi.org/10.3390/biom10020218 - 2 Feb 2020
Cited by 5 | Viewed by 6501
Abstract
Chemotherapy-Induced Leukopenia (CIL) is associated with increased mortality and economic burden on patients. This study was conducted to evaluate whether inclusion of green jackfruit flour in regular diet of those patients receiving chemotherapy, could prevent CIL. This was a retrospective study conducted among [...] Read more.
Chemotherapy-Induced Leukopenia (CIL) is associated with increased mortality and economic burden on patients. This study was conducted to evaluate whether inclusion of green jackfruit flour in regular diet of those patients receiving chemotherapy, could prevent CIL. This was a retrospective study conducted among a group of patients undergoing chemotherapy for solid tumors at Renai Medicity Hospital, Palarivattom, Cochin, Kerala, India, since June 2018. The study group comprised of 50 consecutive subjects, who were supplemented with green jackfruit flour diet in their regular diet and further followed up prospectively. The control group was retrospective with 50 subjects prior to June 2018, with no diet supplements. Those who received less than three cycles were excluded from either arm. The mean age of the participants in study group and control group were 53.16 ± 11.06 and 56.96 ± 12.16 years respectively. In the study group, six patients out of 37, and 20 patients out of 50 in the control group, developed CIL. They received 38 and 105 vials of filgrastim respectively. After excluding those cycles in study group patients, where green jackfruit flour was not taken, the mean number of cycles in which CIL developed (p = 0.00) and number of vials of filgrastim taken per cycle (p = 0.00) were significantly different from control group and no patient in the study group developed CIL. Inclusion of green jackfruit flour as a dietary intervention prevents chemotherapy-induced leukopenia in patients undergoing chemotherapy along with pegfilgrastim. Full article
(This article belongs to the Special Issue Plant-Derived Natural Compounds in the Management of Cancer: Significance and Challenges)
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16 pages, 2315 KiB  
Article
Multiple Targets Directed Multiple Ligands: An In Silico and In Vitro Approach to Evaluating the Effect of Triphala on Angiogenesis
by Chandran S. Abhinand, Prabhakaran A. Athira, Sasikumar J. Soumya and Perumana R. Sudhakaran
Biomolecules 2020, 10(2), 177; https://doi.org/10.3390/biom10020177 - 23 Jan 2020
Cited by 11 | Viewed by 3205
Abstract
Angiogenesis is critical in both physiological and pathological conditions and targeting angiogenesis is a promising strategy for the development of therapies against cancer; however, cells develop resistance to anti-angiogenic therapy, necessitating a more effective strategy. Natural medicines have been used in anti-cancer therapy [...] Read more.
Angiogenesis is critical in both physiological and pathological conditions and targeting angiogenesis is a promising strategy for the development of therapies against cancer; however, cells develop resistance to anti-angiogenic therapy, necessitating a more effective strategy. Natural medicines have been used in anti-cancer therapy for many years, but the mechanisms behind these have not generally been explored. Triphala churna (THL), an Indian ayurvedic herbal formulation made from the dried fruits of three medicinal plants, is used as a herbal drug for the treatment of various diseases, including cancer. THL contains over fifteen phytochemicals with different pharmacological effects, especially inhibition of tumor progression. In this study, we examined the effect of these compounds against different targets using docking and in vitro studies. Results showed that THL has a prediction efficacy of (−)436.7, and it inhibited angiogenesis by blocking multiple components of the VEGF/VEGFR2 signaling pathway. The anti-angiogenic effect was mediated by the combined effect of the two top ranked phytochemicals, punicalagin (−424.8) and chebulagic acid (−414.8). The new approach developed in this study to determine the potential efficacy of herbal formulation could be a useful strategy to assess the efficacy of different herbal formulations. Full article
(This article belongs to the Special Issue Plant-Derived Natural Compounds in the Management of Cancer: Significance and Challenges)
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15 pages, 2893 KiB  
Article
Oxidative Stress-Induced DNA Damage and Apoptosis in Clove Buds-Treated MCF-7 Cells
by Martin Kello, Peter Takac, Peter Kubatka, Tomas Kuruc, Klaudia Petrova and Jan Mojzis
Biomolecules 2020, 10(1), 139; https://doi.org/10.3390/biom10010139 - 14 Jan 2020
Cited by 25 | Viewed by 4116
Abstract
In recent decades, several spices have been studied for their potential in the prevention and treatment of cancer. It is documented that spices have antioxidant, anti-inflammatory, immunomodulatory, and anticancer effects. The main mechanisms of spices action included apoptosis induction, proliferation, migration and invasion [...] Read more.
In recent decades, several spices have been studied for their potential in the prevention and treatment of cancer. It is documented that spices have antioxidant, anti-inflammatory, immunomodulatory, and anticancer effects. The main mechanisms of spices action included apoptosis induction, proliferation, migration and invasion of tumour inhibition, and sensitization of tumours to radiotherapy and chemotherapy. In this study, the ability of clove buds extract (CBE) to induce oxidative stress, DNA damage, and stress/survival/apoptotic pathways modulation were analysed in MCF-7 cells. We demonstrated that CBE treatment induced intrinsic caspase-dependent cell death associated with increased oxidative stress mediated by oxygen and nitrogen radicals. We showed also the CBE-mediated release of mitochondrial pro-apoptotic factors, signalling of oxidative stress-mediated DNA damage with modulation of cell antioxidant SOD (superoxide dismutase) system, and modulation activity of the Akt, p38 MAPK, JNK and Erk 1/2 pathways. Full article
(This article belongs to the Special Issue Plant-Derived Natural Compounds in the Management of Cancer: Significance and Challenges)
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15 pages, 1937 KiB  
Article
Benzyl Isothiocyanate Induces Apoptosis via Reactive Oxygen Species-Initiated Mitochondrial Dysfunction and DR4 and DR5 Death Receptor Activation in Gastric Adenocarcinoma Cells
by Khin Wah Wah Han, Wah Wah Po, Uy Dong Sohn and Hyun-Jung Kim
Biomolecules 2019, 9(12), 839; https://doi.org/10.3390/biom9120839 - 6 Dec 2019
Cited by 24 | Viewed by 3483
Abstract
Benzyl isothiocyanate (BITC) is known to inhibit the metastasis of gastric cancer cells but further studies are needed to confirm its chemotherapeutic potential against gastric cancer. In this study, we observed cell shrinkage and morphological changes in one of the gastric adenocarcinoma cell [...] Read more.
Benzyl isothiocyanate (BITC) is known to inhibit the metastasis of gastric cancer cells but further studies are needed to confirm its chemotherapeutic potential against gastric cancer. In this study, we observed cell shrinkage and morphological changes in one of the gastric adenocarcinoma cell lines, the AGS cells, after BITC treatment. We performed 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, a cell viability assay, and found that BITC decreased AGS cell viability. Reactive oxygen species (ROS) analyses using 2′,7′-dichlorofluorescin diacetate (DCFDA) revealed that BITC-induced cell death involved intracellular ROS production, which resulted in mitochondrial dysfunction. Additionally, cell viability was partially restored when BITC-treated AGS cells were preincubated with glutathione (GSH). Western blotting indicated that BITC regulated the expressions of the mitochondria-mediated apoptosis signaling molecules, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), and cytochrome c (Cyt c). In addition, BITC increased death receptor DR5 expression, and activated the cysteine-aspartic proteases (caspases) cascade. Overall, our results showed that BITC triggers apoptosis in AGS cells via the apoptotic pathways involved in ROS-promoted mitochondrial dysfunction and death receptor activation. Full article
(This article belongs to the Special Issue Plant-Derived Natural Compounds in the Management of Cancer: Significance and Challenges)
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14 pages, 3458 KiB  
Article
Honokiol Enhances TRAIL-Mediated Apoptosis through STAMBPL1-Induced Survivin and c-FLIP Degradation
by Seon Min Woo, Seung Un Seo, Peter Kubatka, Kyoung-jin Min and Taeg Kyu Kwon
Biomolecules 2019, 9(12), 838; https://doi.org/10.3390/biom9120838 - 6 Dec 2019
Cited by 25 | Viewed by 3483
Abstract
Honokiol is a natural biphenolic compound extracted from traditional Chinese medicine Magnolia species, which have been known to display various biological effects including anti-cancer, anti-proliferative, anti-angiogenic, and anti-metastatic activities in cancer cells. Here, we found that honokiol sensitizes cancer cells to tumor necrosis [...] Read more.
Honokiol is a natural biphenolic compound extracted from traditional Chinese medicine Magnolia species, which have been known to display various biological effects including anti-cancer, anti-proliferative, anti-angiogenic, and anti-metastatic activities in cancer cells. Here, we found that honokiol sensitizes cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through downregulation of anti-apoptotic proteins survivin and c-FLIP. Ectopic expression of survivin and c-FLIP markedly abolished honokiol and TRAIL-induced apoptosis. Mechanistically, honokiol induced protein degradation of c-FLIP and survivin through STAMBPL1, a deubiquitinase. STAMBPL1 interacted with survivin and c-FLIP, resulted in reduction of ubiquitination. Knockdown of STAMBPL1 reduced survivin and c-FLIP protein levels, while overexpression of STAMBPL1 inhibited honokinol-induced survivin and c-FLIP degradation. Our findings provided that honokiol could overcome TRAIL resistance through survivin and c-FLIP degradation induced by inhibition of STAMBPL1 expression. Full article
(This article belongs to the Special Issue Plant-Derived Natural Compounds in the Management of Cancer: Significance and Challenges)
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16 pages, 4362 KiB  
Article
Wasabi Compound 6-(Methylsulfinyl) Hexyl Isothiocyanate Induces Cell Death with Coexisting Mitotic Arrest and Autophagy in Human Chronic Myelogenous Leukemia K562 Cells
by Kun-Ming Wu, Hui-Fen Liao, Chih-Wen Chi, Yu Ru Kou and Yu-Jen Chen
Biomolecules 2019, 9(12), 774; https://doi.org/10.3390/biom9120774 - 23 Nov 2019
Cited by 8 | Viewed by 3482
Abstract
A natural compound from Wasabia japonica, 6-(methylsulfinyl) hexyl isothiocyanate (6-MITC) was investigated for its anti-leukemia activity and mechanism of action. It was found that 6-MITC inhibited the viability of human chronic myelogenous leukemia K562 cells along with extensive mitotic arrest, spindle multipolarity, [...] Read more.
A natural compound from Wasabia japonica, 6-(methylsulfinyl) hexyl isothiocyanate (6-MITC) was investigated for its anti-leukemia activity and mechanism of action. It was found that 6-MITC inhibited the viability of human chronic myelogenous leukemia K562 cells along with extensive mitotic arrest, spindle multipolarity, and cytoplasmic vacuole accumulation. The evidence of autophagy included the validation of autophagosomes with double-layered membranes under transmission electron microscopy, LC3I/II conversion, and the induction of G2/M phase arrest observed with acridine orange staining of treated cells, as well as the elevation of phosphorylated-histone H3 expression at the M phase. With regard to the expression of proteins related to mitosis, the down regulation of p-CHK1, p-CHK2, p-cdc25c, and p-cdc2, as well as the upregulation of cyclin B1, p-cdc20, cdc23, BubR1, Mad2, and p-plk-1 was observed. The knockdown of cdc20 was unable to block the effect of 6-MITC. The differentiation of k562 cells into monocytes, granulocytes, and megakaryocytes was not affected by 6-MITC. The 6-MITC-induced unique mode of cell death through the concurrent induction of mitosis and autophagy may have therapeutic potential. Further studies are required to elucidate the pathways associated with the counteracting occurrence of mitosis and autophagy. Full article
(This article belongs to the Special Issue Plant-Derived Natural Compounds in the Management of Cancer: Significance and Challenges)
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16 pages, 2768 KiB  
Article
Antioxidant Activity of Selected Stilbenoid Derivatives in a Cellular Model System
by Jakub Treml, Veronika Leláková, Karel Šmejkal, Tereza Paulíčková, Šimon Labuda, Sebastian Granica, Jaroslav Havlík, Dagmar Jankovská, Tereza Padrtová and Jan Hošek
Biomolecules 2019, 9(9), 468; https://doi.org/10.3390/biom9090468 - 9 Sep 2019
Cited by 13 | Viewed by 3530
Abstract
The stilbenoids, a group of naturally occurring phenolic compounds, are found in a variety of plants, including some berries that are used as food or for medicinal purposes. They are known to be beneficial for human health as anti-inflammatory, chemopreventive, and antioxidative agents. [...] Read more.
The stilbenoids, a group of naturally occurring phenolic compounds, are found in a variety of plants, including some berries that are used as food or for medicinal purposes. They are known to be beneficial for human health as anti-inflammatory, chemopreventive, and antioxidative agents. We have investigated a group of 19 stilbenoid substances in vitro using a cellular model of THP-1 macrophage-like cells and pyocyanin-induced oxidative stress to evaluate their antioxidant or pro-oxidant properties. Then we have determined any effects that they might have on the expression of the enzymes catalase, glutathione peroxidase, and heme oxygenase-1, and their effects on the activation of Nrf2. The experimental results showed that these stilbenoids could affect the formation of reactive oxygen species in a cellular model, producing either an antioxidative or pro-oxidative effect, depending on the structure pinostilbene (2) worked as a pro-oxidant and also decreased expression of catalase in the cell culture. Piceatannol (4) had shown reactive oxygen species (ROS) scavenging activity, whereas isorhapontigenin (18) had a mild direct antioxidant effect and activated Nrf2-antioxidant response element (ARE) system and elevated expression of Nrf2 and catalase. Their effects shown on cells in vitro warrant their further study in vivo. Full article
(This article belongs to the Special Issue Plant-Derived Natural Compounds in the Management of Cancer: Significance and Challenges)
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Review

Jump to: Editorial, Research

23 pages, 1406 KiB  
Review
Therapeutic Potential of Plant Phenolic Acids in the Treatment of Cancer
by Mariam Abotaleb, Alena Liskova, Peter Kubatka and Dietrich Büsselberg
Biomolecules 2020, 10(2), 221; https://doi.org/10.3390/biom10020221 - 3 Feb 2020
Cited by 216 | Viewed by 10775
Abstract
Globally, cancer is the second leading cause of death. Different conventional approaches to treat cancer include chemotherapy or radiotherapy. However, these are usually associated with various deleterious effects and numerous disadvantages in clinical practice. In addition, there are increasing concerns about drug resistance. [...] Read more.
Globally, cancer is the second leading cause of death. Different conventional approaches to treat cancer include chemotherapy or radiotherapy. However, these are usually associated with various deleterious effects and numerous disadvantages in clinical practice. In addition, there are increasing concerns about drug resistance. In the continuous search for safer and more effective treatments, plant-derived natural compounds are of major interest. Plant phenolics are secondary metabolites that have gained importance as potential anti-cancer compounds. Phenolics display a great prospective as cytotoxic anti-cancer agents promoting apoptosis, reducing proliferation, and targeting various aspects of cancer (angiogenesis, growth and differentiation, and metastasis). Phenolic acids are a subclass of plant phenolics, furtherly divided into benzoic and cinnamic acids, that are associated with potent anticancer abilities in various in vitro and in vivo studies. Moreover, the therapeutic activities of phenolic acids are reinforced by their role as epigenetic regulators as well as supporters of adverse events or resistance associated with conventional anticancer therapy. Encapsulation of phyto-substances into nanocarrier systems is a challenging aspect concerning the efficiency of natural substances used in cancer treatment. A summary of phenolic acids and their effectiveness as well as phenolic-associated advances in cancer treatment will be discussed in this review. Full article
(This article belongs to the Special Issue Plant-Derived Natural Compounds in the Management of Cancer: Significance and Challenges)
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28 pages, 1029 KiB  
Review
Anti-Angiogenic Effects of Phytochemicals on miRNA Regulating Breast Cancer Progression
by Elizabeth Varghese, Alena Liskova, Peter Kubatka, Samson Mathews Samuel and Dietrich Büsselberg
Biomolecules 2020, 10(2), 191; https://doi.org/10.3390/biom10020191 - 27 Jan 2020
Cited by 53 | Viewed by 6732
Abstract
Several phytochemicals have been identified for their role in modifying miRNA regulating tumor progression. miRNAs modulate the expression of several oncogenes and tumor suppressor genes including the genes that regulate tumor angiogenesis. Hypoxia inducible factor-1 alpha (HIF-1α) signaling is a central axis that [...] Read more.
Several phytochemicals have been identified for their role in modifying miRNA regulating tumor progression. miRNAs modulate the expression of several oncogenes and tumor suppressor genes including the genes that regulate tumor angiogenesis. Hypoxia inducible factor-1 alpha (HIF-1α) signaling is a central axis that activates oncogenic signaling and acts as a metabolic switch in endothelial cell (EC) driven tumor angiogenesis. Tumor angiogenesis driven by metabolic reprogramming of EC is crucial for tumor progression and metastasis in many different cancers, including breast cancers, and has been linked to aberrant miRNA expression profiles. In the current article, we identify different miRNAs that regulate tumor angiogenesis in the context of oncogenic signaling and metabolic reprogramming in ECs and review how selected phytochemicals could modulate miRNA levels to induce an anti-angiogenic action in breast cancer. Studies involving genistein, epigallocatechin gallate (EGCG) and resveratrol demonstrate the regulation of miRNA-21, miRNA-221/222 and miRNA-27, which are prognostic markers in triple negative breast cancers (TNBCs). Modulating the metabolic pathway is a novel strategy for controlling tumor angiogenesis and tumor growth. Cardamonin, curcumin and resveratrol exhibit their anti-angiogenic property by targeting the miRNAs that regulate EC metabolism. Here we suggest that using phytochemicals to target miRNAs, which in turn suppresses tumor angiogenesis, should have the potential to inhibit tumor growth, progression, invasion and metastasis and may be developed into an effective therapeutic strategy for the treatment of many different cancers where tumor angiogenesis plays a significant role in tumor growth and progression. Full article
(This article belongs to the Special Issue Plant-Derived Natural Compounds in the Management of Cancer: Significance and Challenges)
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19 pages, 790 KiB  
Review
The Plant-Derived Compound Resveratrol in Brain Cancer: A Review
by Terezia Kiskova, Peter Kubatka, Dietrich Büsselberg and Monika Kassayova
Biomolecules 2020, 10(1), 161; https://doi.org/10.3390/biom10010161 - 19 Jan 2020
Cited by 64 | Viewed by 7023
Abstract
Despite intensive research, malignant brain tumors are among the most difficult to treat due to high resistance to conventional therapeutic approaches. High-grade malignant gliomas, including glioblastoma and anaplastic astrocytoma, are among the most devastating and rapidly growing cancers. Despite the ability of standard [...] Read more.
Despite intensive research, malignant brain tumors are among the most difficult to treat due to high resistance to conventional therapeutic approaches. High-grade malignant gliomas, including glioblastoma and anaplastic astrocytoma, are among the most devastating and rapidly growing cancers. Despite the ability of standard treatment agents to achieve therapeutic concentrations in the brain, malignant gliomas are often resistant to alkylating agents. Resveratrol is a plant polyphenol occurring in nuts, berries, grapes, and red wine. Resveratrol crosses the blood‒brain barrier and may influence the central nervous system. Moreover, it influences the enzyme isocitrate dehydrogenase and, more importantly, the resistance to standard treatment via various mechanisms, such as O6-methylguanine methyltransferase. This review summarizes the anticancer effects of resveratrol in various types of brain cancer. Several in vitro and in vivo studies have presented promising results; however, further clinical research is necessary to prove the therapeutic efficacy of resveratrol in brain cancer treatment. Full article
(This article belongs to the Special Issue Plant-Derived Natural Compounds in the Management of Cancer: Significance and Challenges)
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30 pages, 3199 KiB  
Review
Phytochemicals and Gastrointestinal Cancer: Cellular Mechanisms and Effects to Change Cancer Progression
by Raghad Khalid AL-Ishaq, Anthony J. Overy and Dietrich Büsselberg
Biomolecules 2020, 10(1), 105; https://doi.org/10.3390/biom10010105 - 8 Jan 2020
Cited by 85 | Viewed by 10689
Abstract
Gastrointestinal (GI) cancer is a prevailing global health disease with a high incidence rate which varies by region. It is a huge economic burden on health care providers. GI cancer affects different organs in the body such as the gastric organs, colon, esophagus, [...] Read more.
Gastrointestinal (GI) cancer is a prevailing global health disease with a high incidence rate which varies by region. It is a huge economic burden on health care providers. GI cancer affects different organs in the body such as the gastric organs, colon, esophagus, intestine, and pancreas. Internal and external factors like smoking, obesity, urbanization, genetic mutations, and prevalence of Helicobacter pylori and Hepatitis B and Hepatitis C viral infections could increase the risk of GI cancer. Phytochemicals are non-nutritive bioactive secondary compounds abundantly found in fruits, grains, and vegetables. Consumption of phytochemicals may protect against chronic diseases like cardiovascular disease, neurodegenerative disease, and cancer. Multiple studies have assessed the chemoprotective effect of selected phytochemicals in GI cancer, offering support to their potential towards reducing the pathogenesis of the disease. The aim of this review was to summarize the current knowledge addressing the anti-cancerous effects of selected dietary phytochemicals on GI cancer and their molecular activities on selected mechanisms, i.e., nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), detoxification enzymes, adenosine monophosphate activated protein kinase (AMPK), wingless-related integration site/β-catenin (wingless-related integration site (Wnt) β-catenin, cell apoptosis, phosphoinositide 3-kinases (PI3K)/ protein kinase B AKT/ mammalian target of rapamycin (mTOR), and mitogen-activated protein kinase (MAPK). In this review phytochemicals were classified into four main categories: (i) carotenoids, including lutein, lycopene, and β-carotene; (ii) proanthocyanidins, including quercetin and ellagic acid; (iii) organosulfur compounds, including allicin, allyl propyl disulphide, asparagusic acid, and sulforaphane; and (iv) other phytochemicals including pectin, curcumins, p-coumaric acid and ferulic acid. Overall, phytochemicals improve cancer prognosis through the downregulation of β-catenin phosphorylation, therefore enhancing apoptosis, and upregulation of the AMPK pathway, which supports cellular homeostasis. Nevertheless, more studies are needed to provide a better understanding of the mechanism of cancer treatment using phytochemicals and possible side effects associated with this approach. Full article
(This article belongs to the Special Issue Plant-Derived Natural Compounds in the Management of Cancer: Significance and Challenges)
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31 pages, 4165 KiB  
Review
Anticancer Potential of Lichens’ Secondary Metabolites
by Zuzana Solárová, Alena Liskova, Marek Samec, Peter Kubatka, Dietrich Büsselberg and Peter Solár
Biomolecules 2020, 10(1), 87; https://doi.org/10.3390/biom10010087 - 5 Jan 2020
Cited by 78 | Viewed by 9279
Abstract
Lichens produce different classes of phenolic compounds, including anthraquinones, xanthones, dibenzofuranes, depsides and depsidones. Many of them have revealed effective biological activities such as antioxidant, antiviral, antibiotics, antifungal, and anticancer. Although no clinical study has been conducted yet, there are number of in [...] Read more.
Lichens produce different classes of phenolic compounds, including anthraquinones, xanthones, dibenzofuranes, depsides and depsidones. Many of them have revealed effective biological activities such as antioxidant, antiviral, antibiotics, antifungal, and anticancer. Although no clinical study has been conducted yet, there are number of in vitro and in vivo studies demonstrating anticancer effects of lichen metabolites. The main goal of our work was to review most recent published papers dealing with anticancer activities of secondary metabolites of lichens and point out to their perspective clinical use in cancer management. Full article
(This article belongs to the Special Issue Plant-Derived Natural Compounds in the Management of Cancer: Significance and Challenges)
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20 pages, 6183 KiB  
Review
Combination Therapy with Vitamin C Could Eradicate Cancer Stem Cells
by Noothan Jyothi Satheesh, Samson Mathews Samuel and Dietrich Büsselberg
Biomolecules 2020, 10(1), 79; https://doi.org/10.3390/biom10010079 - 3 Jan 2020
Cited by 32 | Viewed by 12195
Abstract
Cancer remains one of the most feared and dreaded diseases in this era of modern medicine, claiming the lives of many, and affecting the quality of life of several others around the globe despite major advances in the diagnosis, treatment, palliative care and [...] Read more.
Cancer remains one of the most feared and dreaded diseases in this era of modern medicine, claiming the lives of many, and affecting the quality of life of several others around the globe despite major advances in the diagnosis, treatment, palliative care and the immense resources invested into cancer research. While research in cancer has largely focused on the neoplasm/tumor and the cancerous cells that make up the tumor, more recently, the existence, proliferation, differentiation, migration and invasion of cancer stem cells (CSCs) and the role that CSCs play in tumor initiation, progression, metastasis, drug resistance and relapse/recurrence of the disease has gained widespread interest in cancer research. Although the conventional therapeutic approaches such as surgery, chemotherapy and radiation therapy are effective cancer treatments, very often these treatment modalities fail to target the CSCs, which then later become the source of disease recurrence. A majority of the anti-cancer agents target rapidly dividing cancer cells and normal cells and hence, have side effects that are not expected. Targeting CSCs remains a challenge due to their deviant nature with a low proliferation rate and increased drug resistance mechanism. Ascorbic acid/Vitamin C (Vit.C), a potent antioxidant, is a cofactor for several biosynthetic and gene regulatory enzymes and a vital contributor to immune defense of the body, and was found to be deficient in patients with advanced stages of cancer. Vit.C has gained importance in the treatment of cancer due to its ability to modulate the redox status of the cell and influence epigenetic modifications and significant roles in HIF1α signaling. Studies have reported that intravenous administration of Vit.C at pharmacological doses selectively kills tumor cells and targets CSCs when administered along with chemotherapeutic drugs. In the current article, we provide an in-depth review of how Vit.C plays an important role in targeting CSCs and its possible use as an adjuvant, neoadjuvant or co-treatment in the treatment of cancers. Full article
(This article belongs to the Special Issue Plant-Derived Natural Compounds in the Management of Cancer: Significance and Challenges)
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33 pages, 1639 KiB  
Review
Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer
by Samson Mathews Samuel, Elizabeth Varghese, Peter Kubatka, Chris R. Triggle and Dietrich Büsselberg
Biomolecules 2019, 9(12), 846; https://doi.org/10.3390/biom9120846 - 9 Dec 2019
Cited by 58 | Viewed by 8173
Abstract
Interest has grown in studying the possible use of well-known anti-diabetic drugs as anti-cancer agents individually or in combination with, frequently used, chemotherapeutic agents and/or radiation, owing to the fact that diabetes heightens the risk, incidence, and rapid progression of cancers, including breast [...] Read more.
Interest has grown in studying the possible use of well-known anti-diabetic drugs as anti-cancer agents individually or in combination with, frequently used, chemotherapeutic agents and/or radiation, owing to the fact that diabetes heightens the risk, incidence, and rapid progression of cancers, including breast cancer, in an individual. In this regard, metformin (1, 1-dimethylbiguanide), well known as ‘Glucophage’ among diabetics, was reported to be cancer preventive while also being a potent anti-proliferative and anti-cancer agent. While meta-analysis studies reported a lower risk and incidence of breast cancer among diabetic individuals on a metformin treatment regimen, several in vitro, pre-clinical, and clinical studies reported the efficacy of using metformin individually as an anti-cancer/anti-tumor agent or in combination with chemotherapeutic drugs or radiation in the treatment of different forms of breast cancer. However, unanswered questions remain with regards to areas such as cancer treatment specific therapeutic dosing of metformin, specificity to cancer cells at high concentrations, resistance to metformin therapy, efficacy of combinatory therapeutic approaches, post-therapeutic relapse of the disease, and efficacy in cancer prevention in non-diabetic individuals. In the current article, we discuss the biology of metformin and its molecular mechanism of action, the existing cellular, pre-clinical, and clinical studies that have tested the anti-tumor potential of metformin as a potential anti-cancer/anti-tumor agent in breast cancer therapy, and outline the future prospects and directions for a better understanding and re-purposing of metformin as an anti-cancer drug in the treatment of breast cancer. Full article
(This article belongs to the Special Issue Plant-Derived Natural Compounds in the Management of Cancer: Significance and Challenges)
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27 pages, 2320 KiB  
Review
Fluctuations of Histone Chemical Modifications in Breast, Prostate, and Colorectal Cancer: An Implication of Phytochemicals as Defenders of Chromatin Equilibrium
by Marek Samec, Alena Liskova, Lenka Koklesova, Veronika Mestanova, Maria Franekova, Monika Kassayova, Bianka Bojkova, Sona Uramova, Pavol Zubor, Katarina Janikova, Jan Danko, Samson Mathews Samuel, Dietrich Büsselberg and Peter Kubatka
Biomolecules 2019, 9(12), 829; https://doi.org/10.3390/biom9120829 - 5 Dec 2019
Cited by 20 | Viewed by 5787
Abstract
Natural substances of plant origin exert health beneficiary efficacy due to the content of various phytochemicals. Significant anticancer abilities of natural compounds are mediated via various processes such as regulation of a cell’s epigenome. The potential antineoplastic activity of plant natural substances mediated [...] Read more.
Natural substances of plant origin exert health beneficiary efficacy due to the content of various phytochemicals. Significant anticancer abilities of natural compounds are mediated via various processes such as regulation of a cell’s epigenome. The potential antineoplastic activity of plant natural substances mediated by their action on posttranslational histone modifications (PHMs) is currently a highly evaluated area of cancer research. PHMs play an important role in maintaining chromatin structure and regulating gene expression. Aberrations in PHMs are directly linked to the process of carcinogenesis in cancer such as breast (BC), prostate (PC), and colorectal (CRC) cancer, common malignant diseases in terms of incidence and mortality among both men and women. This review summarizes the effects of plant phytochemicals (isolated or mixtures) on cancer-associated PHMs (mainly modulation of acetylation and methylation) resulting in alterations of chromatin structure that are related to the regulation of transcription activity of specific oncogenes, which are crucial in the development of BC, PC, and CRC. Significant effectiveness of natural compounds in the modulation of aberrant PHMs were confirmed by a number of in vitro or in vivo studies in preclinical cancer research. However, evidence concerning PHMs-modulating abilities of plant-based natural substances in clinical trials is insufficient. Full article
(This article belongs to the Special Issue Plant-Derived Natural Compounds in the Management of Cancer: Significance and Challenges)
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22 pages, 969 KiB  
Review
Paclitaxel’s Mechanistic and Clinical Effects on Breast Cancer
by Tala M. Abu Samaan, Marek Samec, Alena Liskova, Peter Kubatka and Dietrich Büsselberg
Biomolecules 2019, 9(12), 789; https://doi.org/10.3390/biom9120789 - 27 Nov 2019
Cited by 299 | Viewed by 15636
Abstract
Paclitaxel (PTX), the most widely used anticancer drug, is applied for the treatment of various types of malignant diseases. Mechanisms of PTX action represent several ways in which PTX affects cellular processes resulting in programmed cell death. PTX is frequently used as the [...] Read more.
Paclitaxel (PTX), the most widely used anticancer drug, is applied for the treatment of various types of malignant diseases. Mechanisms of PTX action represent several ways in which PTX affects cellular processes resulting in programmed cell death. PTX is frequently used as the first-line treatment drug in breast cancer (BC). Unfortunately, the resistance of BC to PTX treatment is a great obstacle in clinical applications and one of the major causes of death associated with treatment failure. Factors contributing to PTX resistance, such as ABC transporters, microRNAs (miRNAs), or mutations in certain genes, along with side effects of PTX including peripheral neuropathy or hypersensitivity associated with the vehicle used to overcome its poor solubility, are responsible for intensive research concerning the use of PTX in preclinical and clinical studies. Novelties such as albumin-bound PTX (nab-PTX) demonstrate a progressive approach leading to higher efficiency and decreased risk of side effects after drug administration. Moreover, PTX nanoparticles for targeted treatment of BC promise a stable and efficient therapeutic intervention. Here, we summarize current research focused on PTX, its evaluations in preclinical research and application clinical practice as well as the perspective of the drug for future implication in BC therapy. Full article
(This article belongs to the Special Issue Plant-Derived Natural Compounds in the Management of Cancer: Significance and Challenges)
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19 pages, 656 KiB  
Review
DNA Methylation Status in Cancer Disease: Modulations by Plant-Derived Natural Compounds and Dietary Interventions
by Karin Jasek, Peter Kubatka, Marek Samec, Alena Liskova, Karel Smejkal, Desanka Vybohova, Ondrej Bugos, Kristina Biskupska-Bodova, Tibor Bielik, Pavol Zubor, Jan Danko, Marian Adamkov, Taeg Kyu Kwon and Dietrich Büsselberg
Biomolecules 2019, 9(7), 289; https://doi.org/10.3390/biom9070289 - 18 Jul 2019
Cited by 45 | Viewed by 7582
Abstract
The modulation of the activity of DNA methyltransferases (DNMTs) represents a crucial epigenetic mechanism affecting gene expressions or DNA repair mechanisms in the cells. Aberrant modifications in the function of DNMTs are a fundamental event and part of the pathogenesis of human cancer. [...] Read more.
The modulation of the activity of DNA methyltransferases (DNMTs) represents a crucial epigenetic mechanism affecting gene expressions or DNA repair mechanisms in the cells. Aberrant modifications in the function of DNMTs are a fundamental event and part of the pathogenesis of human cancer. Phytochemicals, which are biosynthesized in plants in the form of secondary metabolites, represent an important source of biomolecules with pleiotropic effects and thus provide a wide range of possible clinical applications. It is well documented that phytochemicals demonstrate significant anticancer properties, and in this regard, rapid development within preclinical research is encouraging. Phytochemicals affect several epigenetic molecular mechanisms, including DNA methylation patterns such as the hypermethylation of tumor-suppressor genes and the global hypomethylation of oncogenes, that are specific cellular signs of cancer development and progression. This review will focus on the latest achievements in using plant-derived compounds and plant-based diets targeting epigenetic regulators and modulators of gene transcription in preclinical and clinical research in order to generate novel anticancer drugs as sensitizers for conventional therapy or compounds suitable for the chemoprevention clinical setting in at-risk individuals. In conclusion, indisputable anticancer activities of dietary phytochemicals linked with proper regulation of DNA methylation status have been described. However, precisely designed and well-controlled clinical studies are needed to confirm their beneficial epigenetic effects after long-term consumption in humans. Full article
(This article belongs to the Special Issue Plant-Derived Natural Compounds in the Management of Cancer: Significance and Challenges)
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