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Molecular and Cellular Studies of Natural Antioxidants as Potential Therapeutics for Cancer

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Natural Products".

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 30196

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Prof. Dr. Hsueh-Wei Chang

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Department of Biomedical Science and Environmental Biology, College of Life Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
Interests: natural product screening for anticancer; oxidative stress, antioxidant, DNA damage, apoptosis, selective killing, flow cytometry
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Chien-Chih Chiu

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Guest Editor

Department of Biotechnology , Kaohsiung Medical University, Kaohsiung, Taiwan
Interests: tumor biology; signal transduction; chemoresistance; programmed cell death; natural products
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

I am inviting you to submit an article for the upcoming Special Issue “Molecular and Cellular Studies of Natural Antioxidants as Potential Therapeutics for Cancer” in Pharmaceuticals.

Mounting evidence demonstrates natural antioxidants’ chemopreventive and antiproliferative effects on cancer cells. For this purpose, many natural products have been rapidly developed, most of which present antioxidant properties but rarely anticancer effects. Moreover, antioxidants may exhibit dual functions for modulating oxidative stress by decreasing or increasing cellular ROS levels in a concentration-dependent manner. Therefore, the antioxidant properties of natural products warrant detailed investigation, especially for their applications in cancer therapy.

This Special Issue will present research and review papers concerning the development of novel pharmaceuticals and therapy strategies with natural antioxidants for anticancer research, which holds great future promise. Areas of interest include, but are not limited to:

Identification of new targets for natural antioxidants in cancer theranostics;
Evaluation of natural products with antioxidant and anticancer properties;
Evaluation of natural products with antioxidant and chemopreventive properties;
Exploring the relationship between oxidative stress and natural antioxidants;
The mechanism of antioxidant signaling in natural products;
Studies of natural antioxidant-derived compound development;
Prospective combination therapy with clinical drugs and natural products;
Prospective combination therapy with radiation and natural products.

Prof. Dr. Hsueh-Wei Chang
Dr. Chien-Chih Chiu
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. Pharmaceuticals 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

antioxidants
natural products
oxidative stress
ROS
mitochondria
DNA damage
apoptosis
ferroptosis
necroptosis
migration
angiogenesis
ER stress
senescence
cell death

Published Papers (9 papers)

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Research

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18 pages, 11544 KiB

Open AccessArticle

Resveratrol Enhances Cytotoxic Effects of Cisplatin by Inducing Cell Cycle Arrest and Apoptosis in Ovarian Adenocarcinoma SKOV-3 Cells through Activating the p38 MAPK and Suppressing AKT

by Phateep Hankittichai, Phatarawat Thaklaewphan, Nitwara Wikan, Jirapak Ruttanapattanakul, Saranyapin Potikanond, Duncan R. Smith and Wutigri Nimlamool

Pharmaceuticals 2023, 16(5), 755; https://doi.org/10.3390/ph16050755 - 17 May 2023

Cited by 3 | Viewed by 2068

Abstract

In the current study, we identified a mechanism of resveratrol (RES) underlying its anti-cancer properties against human ovarian adenocarcinoma SKOV-3 cells. We investigated its anti-proliferative and apoptosis-inducing effects in combination with cisplatin, using cell viability assay, flow cytometry, immunofluorescence study and Western blot analysis. We discovered that RES suppressed cancer cell proliferation and stimulated apoptosis, especially when combined with cisplatin. This compound also inhibited SKOV-3 cell survival, which may partly be due to its potential to inhibit protein kinase B (AKT) phosphorylation and induce the S-phase cell cycle arrest. RES in combination with cisplatin strongly induced cancer cell apoptosis through activating the caspase-dependent cascade, which was associated with its ability to stimulate nuclear phosphorylation of p38 mitogen-activated protein kinase (MAPK), well recognized to be involved in transducing environmental stress signals. RES-induced p38 phosphorylation was very specific, and the activation status of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) was not mainly affected. Taken together, our study provides accumulated evidence that RES represses proliferation and promotes apoptosis in SKOV-3 ovarian cancer cells through activating the p38 MAPK pathway. It is interesting that this active compound may be used as an effective agent to sensitize ovarian cancer to apoptosis induced by standard chemotherapies. Full article

(This article belongs to the Special Issue Molecular and Cellular Studies of Natural Antioxidants as Potential Therapeutics for Cancer)

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19 pages, 7187 KiB

Open AccessArticle

Marine Sponge Aaptos suberitoides Extract Improves Antiproliferation and Apoptosis of Breast Cancer Cells without Cytotoxicity to Normal Cells In Vitro

by Jun-Ping Shiau, Min-Yu Lee, Jen-Yang Tang, Hsin Huang, Zheng-Yu Lin, Jui-Hsin Su, Ming-Feng Hou, Yuan-Bin Cheng and Hsueh-Wei Chang

Pharmaceuticals 2022, 15(12), 1575; https://doi.org/10.3390/ph15121575 - 16 Dec 2022

Cited by 3 | Viewed by 1708

Abstract

The anticancer effects and mechanisms of marine sponge Aaptos suberitoides were rarely assessed, especially for methanol extract of A. suberitoides (MEAS) to breast cancer cells. This study evaluated the differential suppression effects of proliferation by MEAS between breast cancer and normal cells. MEAS demonstrated more antiproliferation impact on breast cancer cells than normal cells, indicating oxidative stress-dependent preferential antiproliferation effects on breast cancer cells but not for normal cells. Several oxidative stress-associated responses were highly induced by MEAS in breast cancer cells but not normal cells, including the generations of cellular and mitochondrial oxidative stress as well as the depletion of mitochondrial membrane potential. MEAS downregulated cellular antioxidants such as glutathione, partly contributing to the upregulation of oxidative stress in breast cancer cells. This preferential oxidative stress generation is accompanied by more DNA damage (γH2AX and 8-hydroxy-2-deoxyguanosine) in breast cancer cells than in normal cells. N-acetylcysteine reverted these MEAS-triggered responses. In conclusion, MEAS is a potential natural product for treating breast cancer cells with the characteristics of preferential antiproliferation function without cytotoxicity to normal cells in vitro. Full article

(This article belongs to the Special Issue Molecular and Cellular Studies of Natural Antioxidants as Potential Therapeutics for Cancer)

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11 pages, 1354 KiB

Open AccessArticle

Components with Anti-Diabetic Activity Isolated from the Leaves and Twigs of Glycosmis pentaphylla Collected in Vietnam

by Minh Tuyet Thi Nguyen, I-Chi Hsu, Hui-Kang Liu, Yu-Chi Lin, Shu-Rong Chen, Fang-Rong Chang and Yuan-Bin Cheng

Pharmaceuticals 2022, 15(12), 1543; https://doi.org/10.3390/ph15121543 - 12 Dec 2022

Viewed by 1445

Abstract

A phytochemical investigation of the leaves and twigs of Glycosmis pentaphylla (Rutaceae), collected in Vietnam, yielded three new compounds named glyfuran (1), glyphyllamide (2), and glyphyllazole (3), along with twenty-five known compounds (4–28). The structures of isolates were determined by IR, MS, NMR, and UV data analyses. In the anti-diabetic activity screening, (+)-isoaltholacton (4), glycoborinine (17), 2′,4′-dihydroxy-4,6′-dimethoxychalcone (24), and flavokawain A (25) simultaneously exhibited inhibition of dipeptidyl peptidase-4 (DPP4) and stimulation of the glucagon-like peptide-1 (GLP-1) secretion on the murine intestinal secretin tumor cell line (STC-1). Full article

(This article belongs to the Special Issue Molecular and Cellular Studies of Natural Antioxidants as Potential Therapeutics for Cancer)

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15 pages, 3576 KiB

Open AccessArticle

Cucurbitacin-B Exerts Anticancer Effects through Instigation of Apoptosis and Cell Cycle Arrest within Human Prostate Cancer PC3 Cells via Downregulating JAK/STAT Signaling Cascade

by Ahmed Alafnan, Abdulwahab Alamri, Talib Hussain and Syed Mohd Danish Rizvi

Pharmaceuticals 2022, 15(10), 1229; https://doi.org/10.3390/ph15101229 - 06 Oct 2022

Cited by 8 | Viewed by 1684

Abstract

Cucurbitacin-B (Cur-B) is an analogue triterpenoid belonging to the Cucurbitaceae family. Previous reports have explicitly outlined various biological activities of Cucurbitaceae family members, including the anticancer activity of Cur-B. In the present study, we tried to elucidate the anticancer efficacy of Cur-B against prostate cancer PC3 cells. PC3 cells were exposed to purified Cur-B at 5, 10, 15, 20 and 25 µM for 24. Cur-B exposure reduced cell viability of PC3 cells at 5 µM (p < 0.05), with further reduction with increased Cur-B concentration (15 µM, p < 0.01 and 25 µM, p < 0.001). Cur-B also succeeded in instigating nuclear fragmentation and condensation, followed by activation of caspase-8, -9 and -3 proportionally with increasing concentrations of Cur-B. Treatment with Cur-B also instigated ROS-mediated oxidative stress both qualitatively and quantitatively at 5 µM, p < 0.05; 15 µM, p < 0.01 and 25 µM, p < 0.001. Increased ROS after Cur-B treatment also led to dissipation of mitochondrial membrane potential, thereby resulting in considerable apoptosis (p < 0.001), which, again, was proportionally dependent on Cur-B concentration. Cur-B exposure to PC3 cells was concomitantly followed by reduced cyclin D1, cyclin-dependent kinase 4 (CDK4) expression and augmented mRNA expression of CDK inhibitor p21^Cip1. Intriguingly, Cur-B exposure also led to considerable downregulation of the JAK/STAT signaling cascade, which may be the reason behind Cur-B-mediated apoptosis and cell cycle arrest within PC3 cells. Therefore, these observations explicitly establish that Cur-B could serve in the prevention of prostate cancer. Full article

(This article belongs to the Special Issue Molecular and Cellular Studies of Natural Antioxidants as Potential Therapeutics for Cancer)

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16 pages, 3809 KiB

Open AccessArticle

Quercetin-Rich Extracts from Onions (Allium cepa) Play Potent Cytotoxicity on Adrenocortical Carcinoma Cell Lines, and Quercetin Induces Important Anticancer Properties

by Alan A. Veiga, Ana Carolina Irioda, Bassam F. Mogharbel, Sandro J. R. Bonatto and Lauro M. Souza

Pharmaceuticals 2022, 15(6), 754; https://doi.org/10.3390/ph15060754 - 16 Jun 2022

Cited by 4 | Viewed by 2273

Abstract

Adrenocortical carcinoma (ACC) is a rare subtype of cancer, with a poor prognosis in children and adults. Mitotane is the only approved adrenolytic drug for the treatment of ACC, which has controversies regarding its efficacy and side effects on patients. Onion (Allium cepa), a worldwide consumed food, is associated with many health benefits. Along with its glycosides, the flavonoid quercetin is abundant in onions. After evaluating the cytotoxicity of A. cepa extracts on adrenocortical carcinoma cell line (H295R), the rich quercetin fractions had better results. Then, we aimed to compare the quercetin vs. mitotane effectiveness, using adrenocortical carcinoma cell lines H295R and SW-13. Quercetin showed a higher cytotoxicity response on both cancerous cell lines after 10 µM concentration, while mitotane only after 30 µM. Cell cycle dynamics were altered upon quercetin treatments, with G2 phase increase with 30 µM of quercetin on H295R cell line and G1 arrest on SW-13 cell line with 15 µM. Early and late apoptosis, alongside intracellular calcium, were increased on SW-13 treated with 30 µM of quercetin, and ROS rates were reduced by quercetin on H295R. Therefore, quercetin-rich onions have the potential to be a natural source of anticancer agents for adrenocortical carcinoma. Full article

(This article belongs to the Special Issue Molecular and Cellular Studies of Natural Antioxidants as Potential Therapeutics for Cancer)

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Review

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38 pages, 7648 KiB

Open AccessReview

Innovative Delivery and Release Systems for Antioxidants and Other Active Substances in the Treatment of Cancer

by Zerrin Sezgin-Bayindir, Sonia Losada-Barreiro, Sofía Fernández-Bravo and Carlos Bravo-Díaz

Pharmaceuticals 2023, 16(7), 1038; https://doi.org/10.3390/ph16071038 - 21 Jul 2023

Cited by 3 | Viewed by 1404

Abstract

Cancer is one of the major diseases leading to death worldwide, and the fight against the disease is still challenging. Cancer diseases are usually associated with increased oxidative stress and the accumulation of reactive oxygen and nitrogen species as a result of metabolic alterations or signaling aberrations. While numerous antioxidants exhibit potential therapeutic properties, their clinical efficiency against cancer is limited and even unproven. Conventional anticancer antioxidants and drugs have, among others, the great disadvantage of low bioavailability, poor targeting efficiency, and serious side effects, constraining their use in the fight against diseases. Here, we review the rationale for and recent advances in potential delivery systems that could eventually be employed in clinical research on antioxidant therapy in cancer. We also review some of the various strategies aimed at enhancing the solubility of poorly water-soluble active drugs, including engineered delivery systems such as lipid-based, polymeric, and inorganic formulations. The use of cyclodextrins, micro- and nanoemulsions, and thermosensitive smart liposomes as useful systems for the delivery and release of poorly aqueous-soluble drugs, improving their bioactivity and stability, is also addressed. We also provide some details on their formulation processes and their use in a variety of medical applications. Finally, we briefly cover a case study specifically focused on the use of delivery systems to minimize oral cancer and associated dental problems. Full article

(This article belongs to the Special Issue Molecular and Cellular Studies of Natural Antioxidants as Potential Therapeutics for Cancer)

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17 pages, 1307 KiB

Open AccessReview

Antioxidants in Traditional Mexican Medicine and Their Applications as Antitumor Treatments

by Karen M. Soto, José de Jesús Pérez Bueno, Maria Luisa Mendoza López, Miguel Apátiga-Castro, José M. López-Romero, Sandra Mendoza and Alejandro Manzano-Ramírez

Pharmaceuticals 2023, 16(4), 482; https://doi.org/10.3390/ph16040482 - 23 Mar 2023

Cited by 5 | Viewed by 2993

Abstract

Traditional medicine in Latin America and mainly in Mexico represents an essential alternative for treating different diseases. The use of plants as medicine is the product of a rich cultural tradition of the indigenous peoples, in which a great variety of species are used for the treatment of gastrointestinal, respiratory, and mental diseases and some other sicknesses; the therapeutic efficacy that they possess is due to the properties that derive from the active ingredients of plants principally antioxidants, such as phenolic compounds, flavonoids, terpenes, and tannins. An antioxidant is a substance that, at low concentrations, delays or prevents substrate oxidation through the exchange of electrons. Different methods are used to determine the antioxidant activity and the most commonly used are described in the review. Cancer is a disease in which some cells multiply uncontrollably and spread to other parts of the body, a process known as metastasis. These cells can lead to the formation of tumors, which are lumps of tissue that can be cancerous (malignant) or noncancerous (benign). Generally, the treatment of this disease consists of surgery, radiotherapy, or chemotherapy, which have side effects that decrease the quality of life of patients, so new treatments, focusing on natural resources such as plants, can be developed. This review aims to gather scientific evidence on the antioxidant compounds present in plants used in traditional Mexican medicine, specifically as antitumor treatment in the most common cancer types worldwide (e.g., breast, liver, and colorectal cancer). Full article

(This article belongs to the Special Issue Molecular and Cellular Studies of Natural Antioxidants as Potential Therapeutics for Cancer)

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28 pages, 2106 KiB

Open AccessReview

Propolis: A Detailed Insight of Its Anticancer Molecular Mechanisms

by Suhib Altabbal, Khawla Athamnah, Aaesha Rahma, Adil Farooq Wali, Ali H. Eid, Rabah Iratni and Yusra Al Dhaheri

Pharmaceuticals 2023, 16(3), 450; https://doi.org/10.3390/ph16030450 - 16 Mar 2023

Cited by 7 | Viewed by 8219

Abstract

Cancer is the second most life-threatening disease and has become a global health and economic problem worldwide. Due to the multifactorial nature of cancer, its pathophysiology is not completely understood so far, which makes it hard to treat. The current therapeutic strategies for cancer lack the efficacy due to the emergence of drug resistance and the toxic side effects associated with the treatment. Therefore, the search for more efficient and less toxic cancer treatment strategies is still at the forefront of current research. Propolis is a mixture of resinous compounds containing beeswax and partially digested exudates from plants leaves and buds. Its chemical composition varies widely depending on the bee species, geographic location, plant species, and weather conditions. Since ancient times, propolis has been used in many conditions and aliments for its healing properties. Propolis has well-known therapeutic actions including antioxidative, antimicrobial, anti-inflammatory, and anticancer properties. In recent years, extensive in vitro and in vivo studies have suggested that propolis possesses properties against several types of cancers. The present review highlights the recent progress made on the molecular targets and signaling pathways involved in the anticancer activities of propolis. Propolis exerts anticancer effects primarily by inhibiting cancer cell proliferation, inducing apoptosis through regulating various signaling pathways and arresting the tumor cell cycle, inducing autophagy, epigenetic modulations, and further inhibiting the invasion and metastasis of tumors. Propolis targets numerous signaling pathways associated with cancer therapy, including pathways mediated by p53, β-catenin, ERK1/2, MAPK, and NF-κB. Possible synergistic actions of a combination therapy of propolis with existing chemotherapies are also discussed in this review. Overall, propolis, by acting on diverse mechanisms simultaneously, can be considered to be a promising, multi-targeting, multi-pathways anticancer agent for the treatment of various types of cancers. Full article

(This article belongs to the Special Issue Molecular and Cellular Studies of Natural Antioxidants as Potential Therapeutics for Cancer)

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33 pages, 2264 KiB

Open AccessReview

High-Dose Vitamin C for Cancer Therapy

by Ali Mussa, Ros Akmal Mohd Idris, Naveed Ahmed, Suhana Ahmad, Ahmad Hafiz Murtadha, Tengku Ahmad Damitri Al Astani Tengku Din, Chan Yean Yean, Wan Faiziah Wan Abdul Rahman, Norhafiza Mat Lazim, Vuk Uskoković, Khalid Hajissa, Noor Fatmawati Mokhtar, Rohimah Mohamud and Rosline Hassan

Pharmaceuticals 2022, 15(6), 711; https://doi.org/10.3390/ph15060711 - 03 Jun 2022

Cited by 21 | Viewed by 7402

Abstract

In recent years, the idea that Vitamin C (Vit-C) could be utilized as a form of anti-cancer therapy has generated many contradictory arguments. Recent insights into the physiological characteristics of Vit-C, its pharmacokinetics, and results from preclinical reports, however, suggest that high-dose Vit-C could be effectively utilized in the management of various tumor types. Studies have shown that the pharmacological action of Vit-C can attack various processes that cancerous cells use for their growth and development. Here, we discuss the anti-cancer functions of Vit-C, but also the potential for the use of Vit-C as an epigenetic regulator and immunotherapy enhancer. We also provide a short overview of the current state of systems for scavenging reactive oxygen species (ROS), especially in the context of their influencing high-dose Vit-C toxicity for the inhibition of cancer growth. Even though the mechanisms of Vit-C action are promising, they need to be supported with robust randomized and controlled clinical trials. Moreover, upcoming studies should focus on how to define the most suitable cancer patient populations for high-dose Vit-C treatments and develop effective strategies that combine Vit-C with various concurrent cancer treatment regimens. Full article

(This article belongs to the Special Issue Molecular and Cellular Studies of Natural Antioxidants as Potential Therapeutics for Cancer)

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