Antioxidants for Breast Cancer

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (15 July 2021) | Viewed by 31642

Special Issue Editor


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Guest Editor
Department of Medical Oncology, University Hospital of Jaen, Jaen, Spain
Interests: breast cancer; natural compounds; polyphenols; antioxidants; chemoprevention; cancer stem cells; chemotherapy; tumor resistance; metastasis; targeted therapy
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Special Issue Information

Dear Colleagues,

Breast cancer is one of the most frequent cancer, and one of the leading causes of death among women worldwide, although the frequency of disease varies between regions. Advances in early detection methods, low physical activity, smoking, diet and nutrition, obesity, stress, hormone therapy, reproductive events (early menarche or late menopause), or exposure to ionizing radiation are known factors that influence the rising incidence rates of breast cancer. Importantly, overall survival has improved, mainly due to better medical care, early detection, and important progress of treatments (surgery, targeted therapies, immunotherapy, and tailored treatments, among others).

In breast cancer, amid other malignances, tumorigenesis, progression, resistance to therapies, or relapse are highly influenced by important molecular events, such as genetic aberrations, activation of multiple signaling pathways (TGFβ, PI3K/AKT/mTOR, integrated stress response, etc.) or metabolic rewiring, which invariably promote tumor cell survival, proliferation, metastasis, tumor cell heterogeneity, or adaptation to adverse microenvironmental conditions. Generation of oxidative stress is a common consequence of these episodes, which is deftly balanced by cancer cells to avoid any detriment to their viability. The tight regulation of redox homeostasis by tumor cells can maintain low levels of oxidative stress, indicing a plethora of protective mechanisms aimed at preserving tumor progression and aggressiveness (expression of detoxifying enzymes, inflammation, angiogenesis, proliferation, or viability). On this basis, inhibition or amelioration of oxidative stress by antioxidants has been extensively investigated as a plausible strategy to counteract tumor aggressiveness and progression, not only for breast cancer prevention but also as putative adjuvants in cancer treatment.

Investigations showed that dietary antioxidants, such as hydroxytyrosol, resveratrol, sulforaphane, epigallocatechin gallate, or curcumin, exhibit anti-breast cancer effects as they not only inhibit tumor cell proliferation and viability, but also aggressiveness by targeting tumor initiating cells, epithelial to mesenchymal plasticity, migration, and invasion. This evidence should be addressed with caution because, first, some of these properties could not directly be attributed to the antioxidant capacity of these compounds and, second, contradictory reports noted absence of a beneficial impact of antioxidants on breast cancer patient prognosis.

This special issue of Antioxidants is focused on addressing the latest research on the beneficial and/or negative roles of antioxidants, from either natural or synthetic origins, on breast cancer, including prevention, onset, and progression, as well as their potential as adjuvant therapies at different levels, with special attention on immunotherapy, targeted therapies, chemo and radiation therapy, surgery, or resistance to treatment, as well as on patient prognosis.

Dr. Sergio Granados-Principal
Guest Editor

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Keywords

  • Chemoprevention
  • Adjuvant treatment
  • Immunotherapy
  • Targeted therapy
  • Patient prognosis
  • Translational oncology
  • Clinical oncology
  • Dietary antioxidants
  • Synthetic antioxidants
  • Therapy resistance

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Published Papers (6 papers)

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Research

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14 pages, 5490 KiB  
Article
Antitumor Potential of Lippia citriodora Essential Oil in Breast Tumor-Bearing Mice
by Katerina Spyridopoulou, Tamara Aravidou, Evangeli Lampri, Eleni Effraimidou, Aglaia Pappa and Katerina Chlichlia
Antioxidants 2021, 10(6), 875; https://doi.org/10.3390/antiox10060875 - 30 May 2021
Cited by 11 | Viewed by 3827
Abstract
Lippia citriodora is a flowering plant cultivated for its lemon-scented leaves and used in folk medicine for the preparation of tea for the alleviation of symptoms of gastrointestinal disorders, cold, and asthma. The oil extracted from the plant leaves was shown to possess [...] Read more.
Lippia citriodora is a flowering plant cultivated for its lemon-scented leaves and used in folk medicine for the preparation of tea for the alleviation of symptoms of gastrointestinal disorders, cold, and asthma. The oil extracted from the plant leaves was shown to possess antioxidant potential and to exert antiproliferative activity against breast cancer. The aim of this study was to further investigate potential antitumor effects of L. citriodora oil (LCO) on breast cancer. The in vitro antiproliferative activity of LCO was examined against murine DA3 breast cancer cells by the sulforhodamine B assay. We further explored the LCO’s pro-apoptotic potential with the Annexin-PI method. The LCO’s anti-migratory effect was assessed by the wound-healing assay. LCO was found to inhibit the growth of DA3 cells in vitro, attenuate their migration, and induce apoptosis. Finally, oral administration of LCO for 14 days in mice inhibited by 55% the size of developing tumors in the DA3 murine tumor model. Noteworthy, in the tumor tissue of LCO-treated mice the apoptotic marker cleaved caspase-3 was elevated, while a reduced protein expression of survivin was observed. These results indicate that LCO, as a source of bioactive compounds, has a very interesting nutraceutical potential. Full article
(This article belongs to the Special Issue Antioxidants for Breast Cancer)
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15 pages, 26035 KiB  
Article
New Amides and Phosphoramidates Containing Selenium: Studies on Their Cytotoxicity and Antioxidant Activities in Breast Cancer
by Mikel Etxebeste-Mitxeltorena, Daniel Plano, Nora Astrain-Redín, Cristina Morán-Serradilla, Carlos Aydillo, Ignacio Encío, Esther Moreno, Socorro Espuelas and Carmen Sanmartín
Antioxidants 2021, 10(4), 590; https://doi.org/10.3390/antiox10040590 - 11 Apr 2021
Cited by 6 | Viewed by 3262
Abstract
Breast cancer is a multifactor disease, and many drug combination therapies are applied for its treatment. Selenium derivatives represent a promising potential anti-breast cancer treatment. This study reports the cytotoxic activity of forty-one amides and phosphoramidates containing selenium against five cancer cell lines [...] Read more.
Breast cancer is a multifactor disease, and many drug combination therapies are applied for its treatment. Selenium derivatives represent a promising potential anti-breast cancer treatment. This study reports the cytotoxic activity of forty-one amides and phosphoramidates containing selenium against five cancer cell lines (MCF-7, CCRF-CEM, HT-29, HTB-54 and PC-3) and two nonmalignant cell lines (184B5 and BEAS-2B). MCF-7 cells were the most sensitive and the selenoamides I.1f and I.2f and the selenium phosphoramidate II.2d, with GI50 values ranging from 0.08 to 0.93 µM, were chosen for further studies. Additionally, radical scavenging activity for all the compounds was determined using DPPH and ABTS colorimetric assays. Phosphoramidates turned out to be inactive as radical scavengers. No correlation was observed for the antioxidant activity and the cytotoxic effect, except for compounds I.1e and I.2f, which showed dual antioxidant and antitumor activity. The type of programmed cell death and cell cycle arrest were determined, and the results provided evidence that I.1f and I.2f induced cell death via autophagy, while the derivative II.2d provoked apoptosis. In addition, Western blot analysis corroborated these mechanisms with an increase in Beclin1 and LC3-IIB and reduced SQSTM1/p62 levels for I.1f and I.2f, as well as an increase in BAX, p21 and p53 accompanied by a decrease in BCL-2 levels for derivative II.2d. Full article
(This article belongs to the Special Issue Antioxidants for Breast Cancer)
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18 pages, 2904 KiB  
Article
13R,20-Dihydroxydocosahexaenoic Acid, a Novel Dihydroxy- DHA Derivative, Inhibits Breast Cancer Stemness through Regulation of the Stat3/IL-6 Signaling Pathway by Inducing ROS Production
by Lifang Wang, Hack Sun Choi, Binna Lee, Jong Hyun Choi, Yong-Suk Jang and Jeong-Woo Seo
Antioxidants 2021, 10(3), 457; https://doi.org/10.3390/antiox10030457 - 15 Mar 2021
Cited by 5 | Viewed by 2624
Abstract
Breast cancer is a major health problem worldwide. Cancer stem cells (CSCs) are known to mediate breast cancer metastasis and recurrence and are therefore a promising therapeutic target. In this study, we investigated the anti-inflammatory effect of 13R,20-dihydroxydocosahexaenoic acid (13R,20-diHDHA), a [...] Read more.
Breast cancer is a major health problem worldwide. Cancer stem cells (CSCs) are known to mediate breast cancer metastasis and recurrence and are therefore a promising therapeutic target. In this study, we investigated the anti-inflammatory effect of 13R,20-dihydroxydocosahexaenoic acid (13R,20-diHDHA), a novel dihydroxy-DHA derivative, which was synthesized through an enzymatic reaction using cyanobacterial lipoxygenase. We found that 13R,20-diHDHA reduced the macrophage secretion of the inflammatory cytokines, IL-6 and TNF-α, and thus appeared to have anti-inflammatory effects. As the inflammatory tumor microenvironment is largely devoted to supporting the cancer stemness of breast cancer cells, we investigated the effect of 13R,20-diHDHA on breast cancer stemness. Indeed, 13R,20-diHDHA effectively inhibited breast cancer stemness, as evidenced by its ability to dose-dependently inhibit the mammospheres formation, colony formation, migration, and invasion of breast CSCs. 13R,20-diHDHA reduced the populations of CD44high/CD24low and aldehyde dehydrogenase (ALDH)-positive cells and the expression levels of the cancer stemness-related self-renewal genes, Nanog, Sox2, Oct4, c-Myc, and CD44. 13R,20-diHDHA increased reactive oxygen species (ROS) production, and the generated ROS reduced the phosphorylation of nuclear signal transducer and activator of transcription 3 (Stat3) and the secretion of IL-6 by mammospheres. These data collectively suggest that 13R,20-diHDHA inhibits breast cancer stemness through ROS production and downstream regulation of Stat3/IL-6 signaling, and thus might be developed as an anti-cancer agent acting against CSCs. Full article
(This article belongs to the Special Issue Antioxidants for Breast Cancer)
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12 pages, 1790 KiB  
Article
xCT-Driven Expression of GPX4 Determines Sensitivity of Breast Cancer Cells to Ferroptosis Inducers
by Namgyu Lee, Anne E. Carlisle, Austin Peppers, Sung Jin Park, Mihir B. Doshi, Meghan E. Spears and Dohoon Kim
Antioxidants 2021, 10(2), 317; https://doi.org/10.3390/antiox10020317 - 20 Feb 2021
Cited by 72 | Viewed by 7349
Abstract
Inducers of ferroptosis such as the glutathione depleting agent Erastin and the GPX4 inhibitor Rsl-3 are being actively explored as potential therapeutics in various cancers, but the factors that determine their sensitivity are poorly understood. Here, we show that expression levels of both [...] Read more.
Inducers of ferroptosis such as the glutathione depleting agent Erastin and the GPX4 inhibitor Rsl-3 are being actively explored as potential therapeutics in various cancers, but the factors that determine their sensitivity are poorly understood. Here, we show that expression levels of both subunits of the cystine/glutamate antiporter xCT determine the expression of GPX4 in breast cancer, and that upregulation of the xCT/selenocysteine biosynthesis/GPX4 production axis paradoxically renders the cancer cells more sensitive to certain types of ferroptotic stimuli. We find that GPX4 is strongly upregulated in a subset of breast cancer tissues compared to matched normal samples, and that this is tightly correlated with the increased expression of the xCT subunits SLC7A11 and SLC3A2. Erastin depletes levels of the antioxidant selenoproteins GPX4 and GPX1 in breast cancer cells by inhibiting xCT-dependent extracellular reduction which is required for selenium uptake and selenocysteine biosynthesis. Unexpectedly, while breast cancer cells are resistant compared to nontransformed cells against oxidative stress inducing drugs, at the same time they are hypersensitive to lipid peroxidation and ferroptosis induced by Erastin or Rsl-3, indicating that they are ‘addicted’ to the xCT/GPX4 axis. Our findings provide a strategic basis for targeting the anti-ferroptotic machinery of breast cancer cells depending on their xCT status, which can be further explored. Full article
(This article belongs to the Special Issue Antioxidants for Breast Cancer)
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12 pages, 1879 KiB  
Article
Green Tea Catechins Induce Inhibition of PTP1B Phosphatase in Breast Cancer Cells with Potent Anti-Cancer Properties: In Vitro Assay, Molecular Docking, and Dynamics Studies
by Alicja Kuban-Jankowska, Tomasz Kostrzewa, Claudia Musial, Giampaolo Barone, Giosuè Lo-Bosco, Fabrizio Lo-Celso and Magdalena Gorska-Ponikowska
Antioxidants 2020, 9(12), 1208; https://doi.org/10.3390/antiox9121208 - 30 Nov 2020
Cited by 37 | Viewed by 4015
Abstract
The catechins derived from green tea possess antioxidant activity and may have a potentially anticancer effect. PTP1B is tyrosine phosphatase that is oxidative stress regulated and is involved with prooncogenic pathways leading to the formation of a.o. breast cancer. Here, we present the [...] Read more.
The catechins derived from green tea possess antioxidant activity and may have a potentially anticancer effect. PTP1B is tyrosine phosphatase that is oxidative stress regulated and is involved with prooncogenic pathways leading to the formation of a.o. breast cancer. Here, we present the effect of selected green tea catechins on enzymatic activity of PTP1B phosphatase and viability of MCF-7 breast cancer cells. We showed also the computational analysis of the most effective catechin binding with a PTP1B molecule. We observed that epigallocatechin, epigallocatechin gallate, epicatechin, and epicatechin gallate may decrease enzymatic activity of PTP1B phosphatase and viability of MCF-7 cells. Conclusions: From the tested compounds, epigallocatechin and epigallocatechin gallate were the most effective inhibitors of the MCF-7 cell viability. Moreover, epigallocatechin was also the strongest inhibitor of PTP1B activity. Computational analysis allows us also to conclude that epigallocatechin is able to interact and bind to PTP1B. Our results suggest also the most predicted binding site to epigallocatechin binding to PTP1B. Full article
(This article belongs to the Special Issue Antioxidants for Breast Cancer)
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Review

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43 pages, 963 KiB  
Review
Antioxidants for the Treatment of Breast Cancer: Are We There Yet?
by Carmen Griñan-Lison, Jose L. Blaya-Cánovas, Araceli López-Tejada, Marta Ávalos-Moreno, Alba Navarro-Ocón, Francisca E. Cara, Adrián González-González, Jose A. Lorente, Juan A. Marchal and Sergio Granados-Principal
Antioxidants 2021, 10(2), 205; https://doi.org/10.3390/antiox10020205 - 31 Jan 2021
Cited by 46 | Viewed by 9537
Abstract
Breast cancer is the most frequent cancer and the leading cause of cancer death in women. Oxidative stress and the generation of reactive oxygen species (ROS) have been related to cancer progression. Compared to their normal counterparts, tumor cells show higher ROS levels [...] Read more.
Breast cancer is the most frequent cancer and the leading cause of cancer death in women. Oxidative stress and the generation of reactive oxygen species (ROS) have been related to cancer progression. Compared to their normal counterparts, tumor cells show higher ROS levels and tight regulation of REDOX homeostasis to maintain a low degree of oxidative stress. Traditionally antioxidants have been extensively investigated to counteract breast carcinogenesis and tumor progression as chemopreventive agents; however, there is growing evidence indicating their potential as adjuvants for the treatment of breast cancer. Aimed to elucidate whether antioxidants could be a reality in the management of breast cancer patients, this review focuses on the latest investigations regarding the ambivalent role of antioxidants in the development of breast cancer, with special attention to the results derived from clinical trials, as well as their potential use as plausible agents in combination therapy and their power to ameliorate the side effects attributed to standard therapeutics. Data retrieved herein suggest that antioxidants play an important role in breast cancer prevention and the improvement of therapeutic efficacy; nevertheless, appropriate patient stratification based on “redoxidomics” or tumor subtype is mandatory in order to define the dosage for future standardized and personalized treatments of patients. Full article
(This article belongs to the Special Issue Antioxidants for Breast Cancer)
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