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Antioxidants
Special Issues
Natural Products as Agents of Targeted Cancer Therapeutic Action
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Natural Products as Agents of Targeted Cancer Therapeutic Action

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Natural and Synthetic Antioxidants".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 21853

Special Issue Editors

Prof. Dr. Mihalis I. Panagiotidis

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Guest Editor
Department of Cancer Genetics, Therapeutics & Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, Cyprus
Interests: carcinogenesis; disease mechanisms; apoptosis; epigenetics; oxidative stress; natural products; experimental therapeutics; drug development; disease prevention; disease biomarkers
Special Issues, Collections and Topics in MDPI journals
Dr. Ioannis Anestopoulos

E-Mail Website
Guest Editor
Department of Cancer Genetics, Therapeutics & Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, Cyprus
Interests: molecular biology and genetics
Dr. Sotiris Kyriakou

E-Mail Website
Guest Editor
Department of Cancer Genetics, Therapeutics & Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, Cyprus
Interests: cancer; oxidative stress; natural products

Special Issue Information

Dear Colleagues,

Natural products (plant-derived metabolites, etc.) have been widely used, in various experimental cancer models, as potent anticancer agents regardless of their utilization as single agents or in combination with drugs of clinical significance. In any case, there is insufficient understanding of their mode of action and lack of target specificity as they can induce a plethora of biological effects involving various targets in many cellular cascades (apoptosis, autophagy, growth arrest, etc.). The aim of this Special Issue is to outline the state of the art as to how these compounds exert their anticancer properties by elucidating the underlined mechanism(s) of their action, thereby enhancing our understanding of their potential targeted therapeutic utilization in the clinical setting.

Potential authors are invited to contribute research and/or review manuscripts that bring together the latest research findings on this topic. Emphasis is placed on mechanistic studies delineating underlined pathways by which these molecules exert their potential benefit by acting either as single therapeutic agents or in combination with other established clinical therapeutic strategies. Finally, of great importance are manuscripts focusing on the area(s) of using nutrigenomic/nutriepigenomic approaches to identify key targets and/or cellular pathways involved as part of a targeted cancer therapeutic action induced by these compounds.

Prof. Dr. Mihalis I. Panagiotidis
Dr. Ioannis Anestopoulos
Dr. Sotiris Kyriakou
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. Antioxidants 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 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

  • cancer
  • therapeutics
  • natural products
  • plant metabolites
  • precision medicine anti-cancer agents
  • phytochemicals
  • nutrigenomics
  • nuttriepigenomics
  • nutritional therapy

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Published Papers (6 papers)

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Research

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16 pages, 4394 KiB  
Article
Antrodin C Isolated from Antrodia Cinnamomea Induced Apoptosis through ROS/AKT/ERK/P38 Signaling Pathway and Epigenetic Histone Acetylation of TNFα in Colorectal Cancer Cells
by Yung-Yu Hsieh, Ko-Chao Lee, Kung-Chuan Cheng, Kam-Fai Lee, Ya-Ling Yang, Hsin-Tung Chu, Ting-Wei Lin, Chin-Chu Chen, Meng-Chiao Hsieh, Cheng-Yi Huang, Hsing-Chun Kuo and Chih-Chuan Teng
Antioxidants 2023, 12(3), 764; https://doi.org/10.3390/antiox12030764 - 21 Mar 2023
Cited by 3 | Viewed by 3442
Abstract
Background: Antrodin C, a maleimide derivative compound isolated from the ethanol extract of the mycelium of Antrodia cinnamomea, is an endemic fungus of Taiwan and a potential chemoprotective agent. However, the molecular mechanisms underlying the mode of action of antrodin C on [...] Read more.
Background: Antrodin C, a maleimide derivative compound isolated from the ethanol extract of the mycelium of Antrodia cinnamomea, is an endemic fungus of Taiwan and a potential chemoprotective agent. However, the molecular mechanisms underlying the mode of action of antrodin C on cancer cells, especially in human colorectal cancer (CRC), remain unclear. Methods: The cell death and ROS of the antrodin-C-treated HCT-116 cells were measured by annexin V–FITC/propidium iodide staining, DCFDA, and Fluo-3 fluorescence staining assays. Moreover, signaling molecules regulating TNFα cell death pathways and ROS/AKT/ERK/P38 pathways were also detected in cells treated with antrodin C by Western blotting and chromatin immunoprecipitation. The effects of antrodin C were determined in HCT-116 cell xenograft animal models in terms of tumor volumes and histopathological evaluation. Results: Treatment with antrodin C triggered the activation of extrinsic apoptosis pathways (TNFα, Bax, caspase-3, and -9), and also suppressed the expression of anti-apoptotic molecules Bcl-2 in HCT-116 cells in a time-dependent manner. Antrodin C also decreased cell proliferation and growth through the inactivation of cyclin D1/cyclin for the arrest of the cell cycle at the G1 phase. The activation of the ROS/AKT/ERK/P38 pathways was involved in antrodin-C-induced transcriptional activation, which implicates the role of the histone H3K9K14ac (Acetyl Lys9/Lys14) of the TNFα promoters. Immunohistochemical analyses revealed that antrodin C treatment significantly induced TNFα levels, whereas it decreased the levels of PCNA, cyclin D1, cyclin E, and MMP-9 in an in vivo xenograft mouse model. Thus, antrodin C induces cell apoptosis via the activation of the ROS/AKT/ERK/P38 signaling modules, indicating a new mechanism for antrodin C to treat CRC in vitro and in vivo. Full article
(This article belongs to the Special Issue Natural Products as Agents of Targeted Cancer Therapeutic Action)
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17 pages, 3940 KiB  
Article
Licochalcone B Induces ROS-Dependent Apoptosis in Oxaliplatin-Resistant Colorectal Cancer Cells via p38/JNK MAPK Signaling
by Ah-Won Kwak, Woo-Keun Kim, Seung-On Lee, Goo Yoon, Seung-Sik Cho, Ki-Taek Kim, Mee-Hyun Lee, Yung Hyun Choi, Jin-Young Lee, Jin Woo Park and Jung-Hyun Shim
Antioxidants 2023, 12(3), 656; https://doi.org/10.3390/antiox12030656 - 7 Mar 2023
Cited by 15 | Viewed by 2726
Abstract
Licochalcone B (LCB) exhibits anticancer activity in oral cancer, lung cancer, and hepatocellular carcinoma cells. However, little is known about its antitumor mechanisms in human oxaliplatin-sensitive and -resistant colorectal cancer (CRC) cells. The purpose of the present study was to investigate the antitumor [...] Read more.
Licochalcone B (LCB) exhibits anticancer activity in oral cancer, lung cancer, and hepatocellular carcinoma cells. However, little is known about its antitumor mechanisms in human oxaliplatin-sensitive and -resistant colorectal cancer (CRC) cells. The purpose of the present study was to investigate the antitumor potential of LCB against human colorectal cancer in vitro and analyze its molecular mechanism of action. The viability of CRC cell lines was evaluated using the MTT assay. Flow cytometric analyses were performed to investigate the effects of LCB on apoptosis, cell cycle distribution, reactive oxygen species (ROS), mitochondrial membrane potential (MMP) dysfunction, and multi-caspase activity in CRC cells. The results demonstrated that LCB induced a reduction in cell viability, apoptosis, G2/M cell cycle arrest, ROS generation, MMP depolarization, activation of multi-caspase, and JNK/p38 MAPK. However, p38 (SB203580) and JNK (SP600125) inhibitors prevented the LCB-induced reduction in cell viability. The ROS scavenger N-acetylcysteine (NAC) inhibited LCB-induced reduction in cell viability, apoptosis, cell cycle arrest, ROS generation, MMP depolarization, and multi-caspase and JNK/p38 MAPK activities. Taken together, LCB has a potential therapeutic effect against CRC cells through the ROS-mediated JNK/p38 MAPK signaling pathway. Therefore, we expect LCB to have promising potential as an anticancer therapeutic and prophylactic agent. Full article
(This article belongs to the Special Issue Natural Products as Agents of Targeted Cancer Therapeutic Action)
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18 pages, 2426 KiB  
Article
Antioxidant and DNA-Protective Activity of an Extract Originated from Kalamon Olives Debittering
by Maria Kourti, Maria V. Alvanou, Zoi Skaperda, Fotis Tekos, Georgios Papaefstathiou, Panagiotis Stathopoulos and Demetrios Kouretas
Antioxidants 2023, 12(2), 333; https://doi.org/10.3390/antiox12020333 - 31 Jan 2023
Cited by 5 | Viewed by 2314
Abstract
Table olives are a major component of the Mediterranean diet and are associated with many beneficial biological activities, which are mainly related to their phenolic compounds. Olive fruit debittering process defines the quantitative and qualitative composition of table olives in biophenols. The aim [...] Read more.
Table olives are a major component of the Mediterranean diet and are associated with many beneficial biological activities, which are mainly related to their phenolic compounds. Olive fruit debittering process defines the quantitative and qualitative composition of table olives in biophenols. The aim of the present study was to evaluate the in vitro antioxidant capacity and DNA-protective activity of an extract originated from brine samples, according to the Greek style debbitering process of Kalamon olive fruits. The main phenolic components determined in the brine extract were hydroxytyrosol (HT), verbascoside (VERB) and tyrosol (T). The in vitro cell-free assays showed strong radical scavenging capacity from the extract, therefore antioxidant potential. At cellular level, human endothelial cells (EA.hy296) and murine myoblasts (C2C12) were treated with non-cytotoxic concentrations of the brine extract and the redox status was assessed by measuring glutathione (GSH), reactive oxygen species (ROS) and lipid peroxidation levels (TBARS). Our results show cell type specific response, exerting a hormetic reflection at endothelial cells. Finally, in both cell lines, pre-treatment with brine extract protected from H2O2-induced DNA damage. In conclusion, this is the first holistic approach highlighted table olive wastewaters from Kalamon- Greek style debittering process, as valuable source of bioactive compounds, which could have interesting implications for the development of new products in food or other industries. Full article
(This article belongs to the Special Issue Natural Products as Agents of Targeted Cancer Therapeutic Action)
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16 pages, 3633 KiB  
Article
Alpinumisoflavone Impairs Mitochondrial Respiration via Oxidative Stress and MAPK/PI3K Regulation in Hepatocellular Carcinoma Cells
by Hyewon Jang, Jiyeon Ham, Jisoo Song, Gwonhwa Song and Whasun Lim
Antioxidants 2022, 11(10), 1929; https://doi.org/10.3390/antiox11101929 - 28 Sep 2022
Cited by 8 | Viewed by 2521
Abstract
Alpinumisoflavone is a natural prenylated isoflavonoid extracted from the raw fruit of Cudrania tricuspidata. Several studies have reported the beneficial characteristics of alpinumisoflavone, such as its antioxidant, anti-inflammation, anti-bacterial, osteoprotective, and neuroprotective effects. Alpinumisoflavone also has anti-cancer effects on thyroid, renal, and [...] Read more.
Alpinumisoflavone is a natural prenylated isoflavonoid extracted from the raw fruit of Cudrania tricuspidata. Several studies have reported the beneficial characteristics of alpinumisoflavone, such as its antioxidant, anti-inflammation, anti-bacterial, osteoprotective, and neuroprotective effects. Alpinumisoflavone also has anti-cancer effects on thyroid, renal, and ovarian cancers, but its therapeutic effects on hepatocellular carcinoma (HCC) have not yet been demonstrated. We investigated the anti-cancer effects of alpinumisoflavone on HCC using human liver cancer cell lines, Hep3B and Huh7. Our results confirmed that alpinumisoflavone inhibited viability and regulated the MAPK/PI3K pathway in Hep3B and Huh7 cells. We also verified that alpinumisoflavone can depolarize the mitochondrial membrane potential and suppress the mitochondrial respiration in HCC cells. Moreover, we confirmed the dysregulation of the mitochondrial complexes I, III, and V involving mitochondrial oxidative phosphorylation at the mRNA level and the accumulation of calcium ions in the mitochondrial matrix. Lastly, we demonstrated that alpinumisoflavone induced mitochondria-mediated apoptosis via regulation of the Bcl-xL and BAK proteins. This study elucidates the anti-cancer effects of alpinumisoflavone on HCC. Full article
(This article belongs to the Special Issue Natural Products as Agents of Targeted Cancer Therapeutic Action)
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15 pages, 4866 KiB  
Article
Antitumor Potential of Withanolide Glycosides from Ashwagandha (Withania somnifera) on Apoptosis of Human Hepatocellular Carcinoma Cells and Tube Formation in Human Umbilical Vein Endothelial Cells
by Dahae Lee, Jae Sik Yu, Ji Won Ha, Seoung Rak Lee, Bum Soo Lee, Jin-Chul Kim, Jung Kyu Kim, Ki Sung Kang and Ki Hyun Kim
Antioxidants 2022, 11(9), 1761; https://doi.org/10.3390/antiox11091761 - 6 Sep 2022
Cited by 12 | Viewed by 3226
Abstract
Hepatocellular carcinoma (HCC) is the fastest-growing tumor capable of spreading to other organs via blood vessels formed by endothelial cells. Apoptosis and angiogenesis-targeting therapies are attractive for cancer treatment. In this study, we aimed to study the in vitro cytotoxicity of Withania somnifera [...] Read more.
Hepatocellular carcinoma (HCC) is the fastest-growing tumor capable of spreading to other organs via blood vessels formed by endothelial cells. Apoptosis and angiogenesis-targeting therapies are attractive for cancer treatment. In this study, we aimed to study the in vitro cytotoxicity of Withania somnifera against human HCC (HepG2) cells, identify potential antitumoral withanolide glycosides from the active fraction, and elucidate cytotoxic molecular mechanisms of identified bioactive compounds. W. somnifera (Solanaceae), well-known as ‘ashwagandha’, is an Ayurvedic medicinal plant used to promote health and longevity, and the MeOH extract of W. somnifera root exhibited cytotoxicity against HepG2 cells during initial screening. Bioactivity-guided fractionation of the MeOH extract and subsequent phytochemical investigation of the active n-BuOH-soluble fraction resulted in the isolation of five withanolide glycosides (1–5), including one new metabolite, withanoside XIII (1), aided by liquid chromatography–mass spectrometry-based analysis. The new compound structure was determined by 1D and 2D nuclear magnetic resonance spectroscopy, high-resolution electrospray ionization mass spectroscopy, electronic circular dichroism, and enzymatic hydrolysis. In addition, withanoside XIIIa (1a) was identified as the new aglycone (1a) of 1. Isolated withanolide glycosides 1–5 and 1a were cytotoxic toward HepG2 cells; withagenin A diglucoside (WAD) (3) exhibited the most potent cytotoxicity against HepG2 cells, with cell viability less than 50% at 100 μM. WAD cytotoxicity was mediated by both extrinsic and intrinsic apoptosis pathways. Treatment with WAD increased protein expression levels of cleaved caspase-8, cleaved caspase-9, cleaved caspase-3, Bcl-2-associated X protein (Bax), and cleaved poly(ADP-ribose) polymerase (cleaved PARP) but decreased expression levels of B-cell lymphoma 2 (Bcl-2). Moreover, WAD inhibited tubular structure formation in human umbilical vein endothelial cells (HUVECs) by inhibiting the protein expression of vascular endothelial growth factor receptor 2 and its downstream pathways, including extracellular signal-regulated kinase (ERK), phosphoinositide 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR). These effects were also enhanced by co-treatment with ERK and PI3K inhibitors. Overall, these results indicate that WAD (3) induced HepG2 apoptosis and inhibited HUVEC tube formation, suggesting its potential application in treating liver cancers. Full article
(This article belongs to the Special Issue Natural Products as Agents of Targeted Cancer Therapeutic Action)
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Review

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46 pages, 1474 KiB  
Review
The Impact of Oxidative Stress and AKT Pathway on Cancer Cell Functions and Its Application to Natural Products
by Jun-Ping Shiau, Ya-Ting Chuang, Jen-Yang Tang, Kun-Han Yang, Fang-Rong Chang, Ming-Feng Hou, Ching-Yu Yen and Hsueh-Wei Chang
Antioxidants 2022, 11(9), 1845; https://doi.org/10.3390/antiox11091845 - 19 Sep 2022
Cited by 37 | Viewed by 6849
Abstract
Oxidative stress and AKT serine-threonine kinase (AKT) are responsible for regulating several cell functions of cancer cells. Several natural products modulate both oxidative stress and AKT for anticancer effects. However, the impact of natural product-modulating oxidative stress and AKT on cell functions lacks [...] Read more.
Oxidative stress and AKT serine-threonine kinase (AKT) are responsible for regulating several cell functions of cancer cells. Several natural products modulate both oxidative stress and AKT for anticancer effects. However, the impact of natural product-modulating oxidative stress and AKT on cell functions lacks systemic understanding. Notably, the contribution of regulating cell functions by AKT downstream effectors is not yet well integrated. This review explores the role of oxidative stress and AKT pathway (AKT/AKT effectors) on ten cell functions, including apoptosis, autophagy, endoplasmic reticulum stress, mitochondrial morphogenesis, ferroptosis, necroptosis, DNA damage response, senescence, migration, and cell-cycle progression. The impact of oxidative stress and AKT are connected to these cell functions through cell function mediators. Moreover, the AKT effectors related to cell functions are integrated. Based on this rationale, natural products with the modulating abilities for oxidative stress and AKT pathway exhibit the potential to regulate these cell functions, but some were rarely reported, particularly for AKT effectors. This review sheds light on understanding the roles of oxidative stress and AKT pathway in regulating cell functions, providing future directions for natural products in cancer treatment. Full article
(This article belongs to the Special Issue Natural Products as Agents of Targeted Cancer Therapeutic Action)
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