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1
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Xiang Z, Ma B, Pei X, Wang W, Gong W. Mechanism of action of genistein on breast cancer and differential effects of different age stages. PHARMACEUTICAL BIOLOGY 2025; 63:141-155. [PMID: 39996512 PMCID: PMC11864014 DOI: 10.1080/13880209.2025.2469607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 02/12/2025] [Accepted: 02/14/2025] [Indexed: 02/26/2025]
Abstract
CONTEXT Genistein, a soy-derived isoflavone, exhibits structural similarities with 17β-estradiol and demonstrates antioxidant, anti-inflammatory, and estrogenic properties. Despite its low bioavailability limiting its clinical application, it shows potential for breast cancer prevention and treatment. OBJECTIVE This review aims to summarize the pharmacological effects and molecular mechanisms of genistein in breast cancer, focusing on its therapeutic potential, strategies to overcome bioavailability limitations, and its role in personalized medicine. Differential impacts among population subgroups are also discussed. METHODS A systematic review was conducted using PubMed, ScienceDirect, and Google Scholar databases. Studies were selected based on their focus on genistein's mechanisms of action, strategies to enhance its bioavailability, and interactions with other therapies. RESULTS Genistein exerted anticancer effects by modulating estrogen receptor β (ERβ), inhibiting angiogenesis, arresting the cell cycle, and inducing apoptosis. Its antioxidant properties help mitigate tumor-associated oxidative stress. Bioavailability enhancement strategies, such as nanoparticle and lipid-based formulations, show promise. Age-dependent effects were evident, with distinct responses observed in prepubertal, menopausal, and postmenopausal populations, underscoring its potential for personalized therapies. Furthermore, genistein influences epigenetic modifications, including DNA methylation and miRNA expression, bolstering its anticancer efficacy. CONCLUSION Genistein is a promising candidate for breast cancer therapy, particularly for personalized treatment. Strategies to enhance bioavailability and further clinical research are essential to optimize its therapeutic potential and evaluate its efficacy in combination therapies.
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Affiliation(s)
- Zhebin Xiang
- Zhejiang Chinese Medical University, Hangzhou, China
| | - Bo Ma
- Zhejiang Hospital, Hangzhou, China
| | - Xiujun Pei
- Shandong Provincial Hospital, Shandong, China
| | - Wenjie Wang
- Zhejiang Chinese Medical University, Hangzhou, China
| | - Weilun Gong
- Zhejiang Chinese Medical University, Hangzhou, China
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2
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Konstantinou EK, Gioxari A, Dimitriou M, Panoutsopoulos GI, Panagiotopoulos AA. Molecular Pathways of Genistein Activity in Breast Cancer Cells. Int J Mol Sci 2024; 25:5556. [PMID: 38791595 PMCID: PMC11122029 DOI: 10.3390/ijms25105556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 05/12/2024] [Accepted: 05/16/2024] [Indexed: 05/26/2024] Open
Abstract
The most common malignancy in women is breast cancer. During the development of cancer, oncogenic transcription factors facilitate the overproduction of inflammatory cytokines and cell adhesion molecules. Antiapoptotic proteins are markedly upregulated in cancer cells, which promotes tumor development, metastasis, and cell survival. Promising findings have been found in studies on the cell cycle-mediated apoptosis pathway for medication development and treatment. Dietary phytoconstituents have been studied in great detail for their potential to prevent cancer by triggering the body's defense mechanisms. The underlying mechanisms of action may be clarified by considering the role of polyphenols in important cancer signaling pathways. Phenolic acids, flavonoids, tannins, coumarins, lignans, lignins, naphthoquinones, anthraquinones, xanthones, and stilbenes are examples of natural chemicals that are being studied for potential anticancer drugs. These substances are also vital for signaling pathways. This review focuses on innovations in the study of polyphenol genistein's effects on breast cancer cells and presents integrated chemical biology methods to harness mechanisms of action for important therapeutic advances.
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Affiliation(s)
| | | | | | | | - Athanasios A. Panagiotopoulos
- Department of Nutritional Science and Dietetics, School of Health Sciences, University of the Peloponnese, Antikalamos, 24100 Kalamata, Greece; (E.K.K.); (A.G.); (M.D.); (G.I.P.)
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3
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Targeting Breast Cancer Stem Cells Using Naturally Occurring Phytoestrogens. Int J Mol Sci 2022; 23:ijms23126813. [PMID: 35743256 PMCID: PMC9224163 DOI: 10.3390/ijms23126813] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 05/31/2022] [Accepted: 06/09/2022] [Indexed: 12/12/2022] Open
Abstract
Breast cancer therapies have made significant strides in improving survival for patients over the past decades. However, recurrence and drug resistance continue to challenge long-term recurrence-free and overall survival rates. Mounting evidence supports the cancer stem cell model in which the existence of a small population of breast cancer stem cells (BCSCs) within the tumor enables these cells to evade conventional therapies and repopulate the tumor, giving rise to more aggressive, recurrent tumors. Thus, successful breast cancer therapy would need to target these BCSCs, as well the tumor bulk cells. Since the Women’s Health Initiative study reported an increased risk of breast cancer with the use of conventional hormone replacement therapy in postmenopausal women, many have turned their attention to phytoestrogens as a natural alternative. Phytoestrogens are plant compounds that share structural similarities with human estrogens and can bind to the estrogen receptors to alter the endocrine responses. Recent studies have found that phytoestrogens can also target BCSCs and have the potential to complement conventional therapy eradicating BCSCs. This review summarized the latest findings of different phytoestrogens and their effect on BCSCs, along with their mechanisms of action, including selective estrogen receptor binding and inhibition of molecular pathways used by BCSCs. The latest results of phytoestrogens in clinical trials are also discussed to further evaluate the use of phytoestrogen in the treatment and prevention of breast cancer.
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Prajapati KS, Gupta S, Kumar S. Targeting Breast Cancer-Derived Stem Cells by Dietary Phytochemicals: A Strategy for Cancer Prevention and Treatment. Cancers (Basel) 2022; 14:2864. [PMID: 35740529 PMCID: PMC9221436 DOI: 10.3390/cancers14122864] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 06/06/2022] [Accepted: 06/08/2022] [Indexed: 02/05/2023] Open
Abstract
Breast cancer is heterogeneous disease with variable prognosis and therapeutic response. Approximately, 70% of diagnosed breast cancer represents the luminal A subtype. This subpopulation has a fair prognosis with a lower rate of relapse than the other clinical subtypes. Acquisition of stemness in luminal A subtype modifies the phenotype plasticity to accomplish increased aggressiveness and therapeutic resistance. Therefore, targeting luminal A-derived breast cancer stem cells (BCSCs) could be a promising strategy for its prevention and treatment. Extensive studies reveal that dietary phytochemicals have the potential to target BCSCs by modulating the molecular and signal transduction pathways. Dietary phytochemicals alone or in combination with standard therapeutic modalities exert higher efficacy in targeting BCSCs through changes in stemness, self-renewal properties and hypoxia-related factors. These combinations offer achieving higher radio- and chemo- sensitization through alteration in the key signaling pathways such as AMPK, STAT3, NF-ĸB, Hedgehog, PI3K/Akt/mTOR, Notch, GSK3β, and Wnt related to cancer stemness and drug resistance. In this review, we highlight the concept of targeting luminal A-derived BCSCs with dietary phytochemicals by summarizing the pathways and underlying mechanism(s) involved during therapeutic resistance.
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Affiliation(s)
- Kumari Sunita Prajapati
- Molecular Signaling & Drug Discovery Laboratory, Department of Biochemistry, Central University of Punjab, Guddha, Bathinda 151401, India;
| | - Sanjay Gupta
- Department of Urology, Nutrition, Pharmacology and Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Shashank Kumar
- Molecular Signaling & Drug Discovery Laboratory, Department of Biochemistry, Central University of Punjab, Guddha, Bathinda 151401, India;
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5
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Bhat SS, Prasad SK, Shivamallu C, Prasad KS, Syed A, Reddy P, Cull CA, Amachawadi RG. Genistein: A Potent Anti-Breast Cancer Agent. Curr Issues Mol Biol 2021; 43:1502-1517. [PMID: 34698063 PMCID: PMC8929066 DOI: 10.3390/cimb43030106] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 09/28/2021] [Accepted: 10/01/2021] [Indexed: 12/15/2022] Open
Abstract
Genistein is an isoflavonoid present in high quantities in soybeans. Possessing a wide range of bioactives, it is being studied extensively for its tumoricidal effects. Investigations into mechanisms of the anti-cancer activity have revealed many pathways including induction of cell proliferation, suppression of tyrosine kinases, regulation of Hedgehog-Gli1 signaling, modulation of epigenetic activities, seizing of cell cycle and Akt and MEK signaling pathways, among others via which the cancer cell proliferation can be controlled. Notwithstanding, the observed activities have been time- and dose-dependent. In addition, genistein has also shown varying results in women depending on the physiological parameters, such as the early or post-menopausal states.
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Affiliation(s)
- Smitha S. Bhat
- Department of Biotechnology and Bioinformatics, Faculty of Life Sciences, JSS Academy of Higher Education and Research, Mysuru 570015, Karnataka, India; (S.S.B.); (S.K.P.); (C.S.)
| | - Shashanka K. Prasad
- Department of Biotechnology and Bioinformatics, Faculty of Life Sciences, JSS Academy of Higher Education and Research, Mysuru 570015, Karnataka, India; (S.S.B.); (S.K.P.); (C.S.)
| | - Chandan Shivamallu
- Department of Biotechnology and Bioinformatics, Faculty of Life Sciences, JSS Academy of Higher Education and Research, Mysuru 570015, Karnataka, India; (S.S.B.); (S.K.P.); (C.S.)
| | - Kollur Shiva Prasad
- Department of Sciences, Amrita School of Arts and Sciences, Amrita Vishwa Vidyapeetham, Mysuru Campus, Mysuru 570026, Karnataka, India;
| | - Asad Syed
- Department of Botany and Microbiology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia;
| | - Pruthvish Reddy
- Department of Biotechnology, Acharya Institute of Technology, Bengaluru 560107, Karnataka, India;
| | | | - Raghavendra G. Amachawadi
- Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA
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6
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Wang X, Ha D, Yoshitake R, Chan YS, Sadava D, Chen S. Exploring the Biological Activity and Mechanism of Xenoestrogens and Phytoestrogens in Cancers: Emerging Methods and Concepts. Int J Mol Sci 2021; 22:8798. [PMID: 34445499 PMCID: PMC8395949 DOI: 10.3390/ijms22168798] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 07/30/2021] [Accepted: 08/08/2021] [Indexed: 12/11/2022] Open
Abstract
Xenoestrogens and phytoestrogens are referred to as "foreign estrogens" that are produced outside of the human body and have been shown to exert estrogen-like activity. Xenoestrogens are synthetic industrial chemicals, whereas phytoestrogens are chemicals present in the plant. Considering that these environmental estrogen mimics potentially promote hormone-related cancers, an understanding of how they interact with estrogenic pathways in human cells is crucial to resolve their possible impacts in cancer. Here, we conducted an extensive literature evaluation on the origins of these chemicals, emerging research techniques, updated molecular mechanisms, and ongoing clinical studies of estrogen mimics in human cancers. In this review, we describe new applications of patient-derived xenograft (PDX) models and single-cell RNA sequencing (scRNA-seq) techniques in shaping the current knowledge. At the molecular and cellular levels, we provide comprehensive and up-to-date insights into the mechanism of xenoestrogens and phytoestrogens in modulating the hallmarks of cancer. At the systemic level, we bring the emerging concept of window of susceptibility (WOS) into focus. WOS is the critical timing during the female lifespan that includes the prenatal, pubertal, pregnancy, and menopausal transition periods, during which the mammary glands are more sensitive to environmental exposures. Lastly, we reviewed 18 clinical trials on the application of phytoestrogens in the prevention or treatment of different cancers, conducted from 2002 to the present, and provide evidence-based perspectives on the clinical applications of phytoestrogens in cancers. Further research with carefully thought-through concepts and advanced methods on environmental estrogens will help to improve understanding for the identification of environmental influences, as well as provide novel mechanisms to guide the development of prevention and therapeutic approaches for human cancers.
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Affiliation(s)
| | | | | | | | | | - Shiuan Chen
- Department of Cancer Biology, Beckman Research Institute, City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010, USA; (X.W.); (D.H.); (R.Y.); (Y.S.C.); (D.S.)
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7
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Gairola K, Gururani S, Bahuguna A, Garia V, Pujari R, Dubey SK. Natural products targeting cancer stem cells: Implications for cancer chemoprevention and therapeutics. J Food Biochem 2021; 45:e13772. [PMID: 34028051 DOI: 10.1111/jfbc.13772] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 04/06/2021] [Accepted: 05/03/2021] [Indexed: 12/14/2022]
Abstract
Cancer, being the leading cause of death in the globe, has been one of the major thrust areas of research worldwide. In a new paradigm about neoplastic transformations, the initiation and recurrence of disease is attributed to few mutated cells in bulk of tumor called cancer stem cells (CSCs). CSCs have capacity of self-renewal and differentiation, which are known for resistance to radio and chemotherapy leading to recurrence of the disease even after treatment. Most of traditional drugs implicated in cancer therapy targeting primary tumors have substantial toxicity to the physiological system and have not been efficient in targeting these CSCs leading to poor prognosis. Targeting these CSCs in bulk of tumor might be novel strategy for cancer chemoprevention and therapeutics. Diet-derived interventions and diverse natural products are known to target these CSCs and related signaling pathways, namely, Wnt, Notch, and Hedgehog pathways, which are implicated for CSC self-renewal. PRACTICAL APPLICATIONS: Cancer remains a global challenge even in this century. Poor prognosis, survival rate, and recurrence of the disease have been the major concerns in traditional cancer therapy regimes. Targeting cancer stem cells might be novel strategy for elimination and cure of the chronic disease as they are known to modulate all stages of carcinogenesis and responsible for recurrence and resistance to chemotherapy and radiotherapy. The evidence support that natural products might inhibit, delay, or reverse the process of tumorigenesis and modulate the different signaling pathways implicated for cancer stem cells self-renewal and differentiation. Natural products have minimal toxicity compared to traditional cancer therapy drugs since they have long been utilized in our food habits without any major side effects reported. Thus, targeting cancer stem cells with natural product might be a novel strategy for drug development in cancer chemoprevention and therapeutics.
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Affiliation(s)
- Kanchan Gairola
- Department of Biochemistry, G. B. Pant University of Agriculture and Technology, Pantnagar, India
| | - Shriya Gururani
- Department of Biochemistry, G. B. Pant University of Agriculture and Technology, Pantnagar, India
| | - Ananya Bahuguna
- Department of Biochemistry, G. B. Pant University of Agriculture and Technology, Pantnagar, India
| | - Vaishali Garia
- Department of Biochemistry, G. B. Pant University of Agriculture and Technology, Pantnagar, India
| | - Rohit Pujari
- Department of Biochemistry, G. B. Pant University of Agriculture and Technology, Pantnagar, India
| | - Shiv K Dubey
- Department of Biochemistry, G. B. Pant University of Agriculture and Technology, Pantnagar, India
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8
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Castelli V, Giordano A, Benedetti E, Giansanti F, Quintiliani M, Cimini A, d’Angelo M. The Great Escape: The Power of Cancer Stem Cells to Evade Programmed Cell Death. Cancers (Basel) 2021; 13:328. [PMID: 33477367 PMCID: PMC7830655 DOI: 10.3390/cancers13020328] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/13/2021] [Accepted: 01/14/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer is one of the primary causes of death worldwide. Tumour malignancy is related to tumor heterogeneity, which has been suggested to be due to a small subpopulation of tumor cells named cancer stem cells (CSCs). CSCs exert a key role in metastasis development, tumor recurrence, and also epithelial-mesenchymal transition, apoptotic resistance, self-renewal, tumorigenesis, differentiation, and drug resistance. Several current therapies fail to eradicate tumors due to the ability of CSCs to escape different programmed cell deaths. Thus, developing CSC-selective and programmed death-inducing therapeutic approaches appears to be of primary importance. In this review, we discuss the main programmed cell death occurring in cancer and the promising CSC-targeting agents developed in recent years. Even if the reported studies are encouraging, further investigations are necessary to establish a combination of agents able to eradicate CSCs or inhibit their growth and proliferation.
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Affiliation(s)
- Vanessa Castelli
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (V.C.); (E.B.); (F.G.); (M.Q.)
| | - Antonio Giordano
- Department of Medical Biotechnology, University of Siena, 53100 Siena, Italy;
- Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Temple University, Philadelphia, PA 19122, USA
| | - Elisabetta Benedetti
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (V.C.); (E.B.); (F.G.); (M.Q.)
| | - Francesco Giansanti
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (V.C.); (E.B.); (F.G.); (M.Q.)
| | - Massimiliano Quintiliani
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (V.C.); (E.B.); (F.G.); (M.Q.)
| | - Annamaria Cimini
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (V.C.); (E.B.); (F.G.); (M.Q.)
- Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Temple University, Philadelphia, PA 19122, USA
| | - Michele d’Angelo
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (V.C.); (E.B.); (F.G.); (M.Q.)
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Network Pharmacology Analysis to Identify Phytochemicals in Traditional Chinese Medicines That May Regulate ACE2 for the Treatment of COVID-19. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:7493281. [PMID: 33204291 PMCID: PMC7661114 DOI: 10.1155/2020/7493281] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 09/16/2020] [Accepted: 09/28/2020] [Indexed: 01/08/2023]
Abstract
“Three formulas and three medicines,” which include Jinhua Qinggan granule, Lianhua Qingwen capsule/granule, Xuebijing injection, Qingfei Paidu decoction, HuaShiBaiDu formula, and XuanFeiBaiDu granule, have been proven to be effective in curbing coronavirus disease 2019 (COVID-19), according to the State Administration of Traditional Chinese Medicine. The aims of this study were to identify the active components of “Three formulas and three medicines” that can be used to treat COVID-19, determine their mechanism of action via angiotensin-converting enzyme 2 (ACE2) by integrating network pharmacological approaches, and confirm the most effective components for COVID-19 treatment or prevention. We investigated all the compounds present in the aforementioned herbal ingredients. Compounds that could downregulate the transcription factors (TFs) of ACE2 and upregulate miRNAs of ACE2 were screened via a network pharmacology approach. Hepatocyte nuclear factor 4 alpha (HNF4A), peroxisome proliferator-activated receptor gamma (PPARG), hsa-miR-2113, and hsa-miR-421 were found to regulate ACE2. Several compounds, such as quercetin, decreased ACE2 expression by regulating the aforementioned TFs or miRNAs. After comparison with the compounds present in Glycyrrhiza Radix et Rhizoma, quercetin, glabridin, and gallic acid present in the herbal formulas and medicines were found to alter ACE2 expression. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used to search for possible molecular mechanisms of these compounds. In conclusion, traditional Chinese medicine (TCM) plays a pivotal role in the prevention and treatment of COVID-19. Quercetin, glabridin, and gallic acid, the active components of recommended TCM formulas and medicines, can inhibit COVID-19 by downregulating ACE2.
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Bozorgi A, Khazaei S, Khademi A, Khazaei M. Natural and herbal compounds targeting breast cancer, a review based on cancer stem cells. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2020; 23:970-983. [PMID: 32952942 PMCID: PMC7478260 DOI: 10.22038/ijbms.2020.43745.10270] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 03/09/2020] [Indexed: 12/13/2022]
Abstract
Cancer stem cells (CSCs) are known as the major reason for therapy resistance. Recently, natural herbal compounds are suggested to have a significant role in inhibiting the breast cancer stem cells (BCSCs). The aim of this study was to explore the effective natural herbal compounds against BCSCs.This review article was designed based on the BCSCs, mechanisms of therapy resistance and natural herbal compounds effective to inhibit their activity. Therefore, Science direct, PubMed and Scopus databases were explored and related original articles were investigated from 2010 to 2019. BCSCs use different mechanisms including special membrane transporters, anti-apoptotic, pro-survival, and self-renewal- related signaling pathways. Natural herbal compounds could disturb these mechanisms, therefore may inhibit or eradicate the BCSCs. Studies show that a broad range of plants, either as a food or medicine, contain anti-cancer agents that phenolic components and their different derivatives share a large quantity. Natural herbal compounds play a pivotal role in the eradication of BCSCs, through the inhibition of biological activities and induction of apoptosis. Although it is necessary to conduct more clinical investigation.
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Affiliation(s)
- Azam Bozorgi
- Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Saber Khazaei
- Dental Research Center, Dental Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Abbasali Khademi
- Dental Research Center, Dental Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mozafar Khazaei
- Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
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Liu R, Yu X, Chen X, Zhong H, Liang C, Xu X, Xu W, Cheng Y, Wang W, Yu L, Wu Y, Yan N, Hu X. Individual factors define the overall effects of dietary genistein exposure on breast cancer patients. Nutr Res 2019; 67:1-16. [DOI: 10.1016/j.nutres.2019.03.015] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 03/03/2019] [Accepted: 03/25/2019] [Indexed: 12/18/2022]
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12
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Abstract
Breast cancer is a common malignancy with poor prognosis. Cancer cells are heterogeneous and cancer stem cells (CSCs) are primarily responsible for tumor relapse, treatment-resistance and metastasis, so for breast cancer stem cells (BCSCs). Diets are known to be associated with carcinogenesis. Food-derived polyphenols are able to attenuate the formation and virulence of BCSCs, implying that these compounds and their analogs might be promising agents for preventing breast cancer. In the present review, we summarized the origin and surface markers of BCSCs and possible mechanisms responsible for the inhibitory effects of polyphenols on BCSCs. The suppressive effects of common dietary polyphenols against BCSCs, such as curcumin, epigallocatechin gallate (EGCG) and related polyphenolic compounds were further discussed.
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Affiliation(s)
- Hao-Feng Gu
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing, China
- College of Food Science & Nutritional Engineering, China Agricultural University, Beijing, China
| | - Xue-Ying Mao
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing, China
- College of Food Science & Nutritional Engineering, China Agricultural University, Beijing, China
| | - Min Du
- Department of Animal Sciences, Washington State University, Pullman, Washington, USA
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13
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Chan MM, Chen R, Fong D. Targeting cancer stem cells with dietary phytochemical - Repositioned drug combinations. Cancer Lett 2018; 433:53-64. [PMID: 29960048 PMCID: PMC7117025 DOI: 10.1016/j.canlet.2018.06.034] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Revised: 06/11/2018] [Accepted: 06/25/2018] [Indexed: 12/21/2022]
Abstract
The tumor microenvironment is complex with the cancer stem cell (CSC) as a member within its community. This population possesses the capacity to self-renew and to cause cellular heterogeneity of the tumor. CSCs are resistant to conventional anti-proliferative drugs. In order to be curative, it is imperative that CSCs must be eliminated by cancer therapy. A variety of dietary phytochemicals and repositioned drugs can act synergistically with conventional anti-cancer agents. In this review, we advocate the development of a novel approach, namely combination therapy by incorporating both phytochemicals and repositioned drugs to target CSCs. We cover select dietary phytochemicals (curcumin, resveratrol, EGCG, genistein) and repurposed drugs (metformin, niclosamide, thioridazine, chloroquine). Five of the eight (curcumin, resveratrol, EGCG, genistein, metformin) are listed in "The Halifax Project", that explores "the concept of a low-toxicity 'broad-spectrum' therapeutic approach that could simultaneously target many key pathways and mechanisms" [1]. For these compounds, we discuss their mechanisms of action, in which models their anti-CSC activities were identified, as well as advantages, challenges and potentials of combination therapy.
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Affiliation(s)
- Marion M Chan
- Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, 3400 North Broad Street, Philadelphia, PA, 19140, USA.
| | - Rensa Chen
- Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, 3400 North Broad Street, Philadelphia, PA, 19140, USA; Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, NJ, 08854, USA
| | - Dunne Fong
- Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, NJ, 08854, USA.
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14
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Malik SS, Saeed A, Baig M, Asif N, Masood N, Yasmin A. Anticarcinogenecity of microbiota and probiotics in breast cancer. INTERNATIONAL JOURNAL OF FOOD PROPERTIES 2018. [DOI: 10.1080/10942912.2018.1448994] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- Saima Shakil Malik
- Department of Environmental Sciences, Microbiology and Biotechnology Research Lab, Fatima Jinnah Women University, Rawalpindi, Pakistan
- Surgery Department, Armed Forces Institute of Pathology, Rawalpindi, Pakistan
| | - Ayesha Saeed
- Department of Environmental Sciences, Microbiology and Biotechnology Research Lab, Fatima Jinnah Women University, Rawalpindi, Pakistan
| | - Mehreen Baig
- Chemical Pathology and Endocrinology, Fauji Foundation Hospital, Rawalpindi, Pakistan
| | - Naveed Asif
- Surgery Department, Armed Forces Institute of Pathology, Rawalpindi, Pakistan
| | - Nosheen Masood
- Department of Environmental Sciences, Microbiology and Biotechnology Research Lab, Fatima Jinnah Women University, Rawalpindi, Pakistan
| | - Azra Yasmin
- Department of Environmental Sciences, Microbiology and Biotechnology Research Lab, Fatima Jinnah Women University, Rawalpindi, Pakistan
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Li L, Liu CC, Chen X, Xu S, Hernandez Cortes-Manno S, Cheng SH. Mechanistic Study of Bakuchiol-Induced Anti-breast Cancer Stem Cell and in Vivo Anti-metastasis Effects. Front Pharmacol 2017; 8:746. [PMID: 29093680 PMCID: PMC5651275 DOI: 10.3389/fphar.2017.00746] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 10/03/2017] [Indexed: 12/21/2022] Open
Abstract
Cancer stem cells are involved in cancer establishment, progression, and resistance to current treatments. We demonstrated the in vitro and in vivo anti-breast cancer effect of bakuchiol in a previous study. However, the ability of bakuchiol to target breast cancer stem cells (BCSCs) and inhibit breast cancer metastasis remains unknown. In the current study, we used the cell surface markers CD44 and CD24 to distinguish BCSCs from MCF-7 cells. Bakuchiol inhibited mammosphere formation and aldehyde dehydrogenase activity in BCSCs. Moreover, bakuchiol induced apoptosis and suppressed the mitochondrial membrane potential of BCSCs. Bakuchiol upregulated the expression levels of pro-apoptotic genes, BNIP3 and DAPK2. Bakuchiol induced oxidative stress and altered lipogenesis in BCSCs. In zebrafish xenografts, bakuchiol inhibited breast cancer cell metastasis in vivo. In addition, bakuchiol altered the expression levels of metastasis-related genes through upregulating CK18 and downregulating Notch3, FASN, TGFBR1, and ACVR1B. Our study provides evidence for the anti-breast cancer potential of bakuchiol.
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Affiliation(s)
- Li Li
- Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong
| | - Chi C Liu
- Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong
| | - Xueping Chen
- Vitargent (International) Biotechnology Limited, Sha Tin, Hong Kong
| | - Shisan Xu
- Department of Infectious Diseases and Public Health, City University of Hong Kong, Kowloon, Hong Kong
| | | | - Shuk H Cheng
- Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong
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16
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Bahrami A, Hassanian SM, Khazaei M, Hasanzadeh M, Shahidsales S, Maftouh M, Ferns GA, Avan A. The Therapeutic Potential of Targeting Tumor Microenvironment in Breast Cancer: Rational Strategies and Recent Progress. J Cell Biochem 2017; 119:111-122. [DOI: 10.1002/jcb.26183] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Accepted: 06/01/2017] [Indexed: 01/05/2023]
Affiliation(s)
- Afsane Bahrami
- Department of Modern Sciences and Technologies, Faculty of MedicineMashhad University of Medical SciencesMashhadIran
- Metabolic Syndrome Research CenterMashhad University of Medical SciencesMashhadIran
- Student Research Committee, Faculty of MedicineMashhad University of Medical SciencesMashhadIran
| | - Seyed Mahdi Hassanian
- Metabolic Syndrome Research CenterMashhad University of Medical SciencesMashhadIran
- Department of Medical Biochemistry, School of MedicineMashhad University of Medical SciencesMashhadIran
| | - Majid Khazaei
- Department of Physiology, Faculty of MedicineMashhad University of Medical SciencesMashhadIran
| | - Malihe Hasanzadeh
- Department of Gynecology Oncology, Woman Health Research CenterMashhad University of Medical SciencesMashhadIran
| | | | - Mina Maftouh
- Metabolic Syndrome Research CenterMashhad University of Medical SciencesMashhadIran
| | - Gordon A. Ferns
- Brighton & Sussex Medical SchoolDivision of Medical EducationFalmer, BrightonSussex BN1 9PH, UK
| | - Amir Avan
- Metabolic Syndrome Research CenterMashhad University of Medical SciencesMashhadIran
- Cancer Research CenterMashhad University of Medical SciencesMashhadIran
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17
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Affiliation(s)
- Jairam Vanamala
- Department of Food Science, Pennsylvania State University, University Park, Pennsylvania, USA
- The Penn State Hershey Cancer Institute, Pennsylvania, USA
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18
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Majidinia M, Yousefi B. Breast tumor stroma: A driving force in the development of resistance to therapies. Chem Biol Drug Des 2017; 89:309-318. [PMID: 28042683 DOI: 10.1111/cbdd.12893] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2016] [Revised: 09/15/2016] [Accepted: 10/11/2016] [Indexed: 12/12/2022]
Abstract
Breast cancer is the most common cancer and the second leading cause of cancer-related death in women worldwide. In spite of huge advancements in early detection and ever-increasing knowledge of breast cancer biology, approximately 30% of patients with early-stage breast cancer experience disease recurrence. Most patients are chemosensitive and cancer free immediately after the treatment. About 50% to 70% of breast cancer patients, however, will relapse within 1 year. Such a relapse is usually concomitant with adenocarcinoma cells acquiring a chemoresistant phenotype. Both de novo and acquired chemoresistance are poorly understood and present a major burden in the treatment of breast cancer. Although, previously, chemoresistance was largely linked to genetic alterations within the cancer cells, recent investigations are indicating that chemoresistance can also be associated with the tumor microenvironment. Nowadays, it is widely believed that tumor microenvironment is a key player in tumor progression and response to treatment. In this study, we will review the interactions of breast tumor cells with their microenvironment, present the latest research on the resistance mediated by the stromal component in breast cancer, and discuss the potential therapeutic strategies that can be exploited to treat breast cancers by targeting tumor microenvironment.
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Affiliation(s)
- Maryam Majidinia
- Department of Clinical Biochemistry, Faculty of Medicine, Urmia University Medical Sciences, Urmia, Iran.,Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Bahman Yousefi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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19
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Therapeutic Use of Estrogen Receptor β Agonists in Prevention and Treatment of Endocrine Therapy Resistant Breast Cancers: Observations From Preclinical Models. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2017; 151:177-194. [DOI: 10.1016/bs.pmbts.2017.08.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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20
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Dandawate PR, Subramaniam D, Jensen RA, Anant S. Targeting cancer stem cells and signaling pathways by phytochemicals: Novel approach for breast cancer therapy. Semin Cancer Biol 2016; 40-41:192-208. [PMID: 27609747 DOI: 10.1016/j.semcancer.2016.09.001] [Citation(s) in RCA: 212] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Revised: 09/01/2016] [Accepted: 09/03/2016] [Indexed: 02/07/2023]
Abstract
Breast cancer is the most common form of cancer diagnosed in women worldwide and the second leading cause of cancer-related deaths in the USA. Despite the development of newer diagnostic methods, selective as well as targeted chemotherapies and their combinations, surgery, hormonal therapy, radiotherapy, breast cancer recurrence, metastasis and drug resistance are still the major problems for breast cancer. Emerging evidence suggest the existence of cancer stem cells (CSCs), a population of cells with the capacity to self-renew, differentiate and be capable of initiating and sustaining tumor growth. In addition, CSCs are believed to be responsible for cancer recurrence, anticancer drug resistance, and metastasis. Hence, compounds targeting breast CSCs may be better therapeutic agents for treating breast cancer and control recurrence and metastasis. Naturally occurring compounds, mainly phytochemicals have gained immense attention in recent times because of their wide safety profile, ability to target heterogeneous populations of cancer cells as well as CSCs, and their key signaling pathways. Therefore, in the present review article, we summarize our current understanding of breast CSCs and their signaling pathways, and the phytochemicals that affect these cells including curcumin, resveratrol, tea polyphenols (epigallocatechin-3-gallate, epigallocatechin), sulforaphane, genistein, indole-3-carbinol, 3, 3'-di-indolylmethane, vitamin E, retinoic acid, quercetin, parthenolide, triptolide, 6-shogaol, pterostilbene, isoliquiritigenin, celastrol, and koenimbin. These phytochemicals may serve as novel therapeutic agents for breast cancer treatment and future leads for drug development.
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Affiliation(s)
- Prasad R Dandawate
- Department of Surgery, The University of Kansas Medical Center, Kansas City, KS 66160, USA; Department of Molecular and Integrative Physiology, The University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Dharmalingam Subramaniam
- Department of Surgery, The University of Kansas Medical Center, Kansas City, KS 66160, USA; Department of Molecular and Integrative Physiology, The University of Kansas Medical Center, Kansas City, KS 66160, USA; The University of Kansas Cancer Center, The University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Roy A Jensen
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA; The University of Kansas Cancer Center, The University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Shrikant Anant
- Department of Surgery, The University of Kansas Medical Center, Kansas City, KS 66160, USA; Department of Molecular and Integrative Physiology, The University of Kansas Medical Center, Kansas City, KS 66160, USA; The University of Kansas Cancer Center, The University of Kansas Medical Center, Kansas City, KS 66160, USA.
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21
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Yang J, Xiong L, Wang R, Yuan Q, Xia Y, Sun J, Horch RE. In vitro expression of cytokeratin 18, 19 and tube formation of adipose-derived stem cells induced by the breast epithelial cell line HBL-100. J Cell Mol Med 2015; 19:2827-31. [PMID: 26416346 PMCID: PMC4687699 DOI: 10.1111/jcmm.12673] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Accepted: 08/03/2015] [Indexed: 12/12/2022] Open
Abstract
Fat transplantation is increasingly used in breast augmentation; and recently, the issue of safety concerns from a cellular and molecular point of view has been raised. In this study, attentions were paid to the interaction between adipose-derived stem cells (ADSC) and mammary epithelial cells: human breast cancer cell line - 100 (HBL - 100) cells were used to simulate the normal microenvironment in breast tissue, ADSCs were harvest from human and co-cultured with HBL-100 cells. It was found that ADSCs formed tube-like structures in the co-culture with HBL-100 cells in contrast to the normal morphology of ADSCs in the control group. In addition, the immunofluorescence imaging showed that cytokeratin 18 and 19 (CK18 and 19) were significantly expressed in ADSCs after the co-culture with HBL-100 cells. The ultrastructure of those ADSCs also showed epithelial changes. In conclusion, ADSCs are not biological stable when co-cultured with HBL-100 cells. They differentiate into epithelial-like cells with the expression of epithelial surface marks (CK 18, 19) and form tube-like structures. This may offer an important evidence for the further study of clinical application of transplanting ADSCs rich adipose tissue into the breast in the future.
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Affiliation(s)
- Jie Yang
- Department of Plastic and Reconstructive Surgery, Union Hospital, Huazhong Science & Technology University, Wuhan, Hubei, China
| | - Lingyun Xiong
- Department of Plastic and Reconstructive Surgery, Union Hospital, Huazhong Science & Technology University, Wuhan, Hubei, China
| | - Rongrong Wang
- Department of Plastic and Reconstructive Surgery, Union Hospital, Huazhong Science & Technology University, Wuhan, Hubei, China
| | - Quan Yuan
- Department of Plastic and Reconstructive Surgery, Union Hospital, Huazhong Science & Technology University, Wuhan, Hubei, China
| | - Yun Xia
- Department of Plastic and Reconstructive Surgery, Union Hospital, Huazhong Science & Technology University, Wuhan, Hubei, China
| | - Jiaming Sun
- Department of Plastic and Reconstructive Surgery, Union Hospital, Huazhong Science & Technology University, Wuhan, Hubei, China
| | - Raymund E Horch
- Department of Plastic and Hand Surgery and Laboratory for Tissue Engineering and Regenerative Medicine, University Hospital Erlangen, Friedrich Alexander University, Erlangen-Nuernberg, FAU, Germany
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22
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Polyphenols as Modulator of Oxidative Stress in Cancer Disease: New Therapeutic Strategies. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2015; 2016:6475624. [PMID: 26649142 PMCID: PMC4663347 DOI: 10.1155/2016/6475624] [Citation(s) in RCA: 161] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Accepted: 07/21/2015] [Indexed: 12/19/2022]
Abstract
Cancer onset and progression have been linked to oxidative stress by increasing DNA mutations or inducing DNA damage, genome instability, and cell proliferation and therefore antioxidant agents could interfere with carcinogenesis. It is well known that conventional radio-/chemotherapies influence tumour outcome through ROS modulation. Since these antitumour treatments have important side effects, the challenge is to develop new anticancer therapeutic strategies more effective and less toxic for patients. To this purpose, many natural polyphenols have emerged as very promising anticancer bioactive compounds. Beside their well-known antioxidant activities, several polyphenols target epigenetic processes involved in cancer development through the modulation of oxidative stress. An alternative strategy to the cytotoxic treatment is an approach leading to cytostasis through the induction of therapy-induced senescence. Many anticancer polyphenols cause cellular growth arrest through the induction of a ROS-dependent premature senescence and are considered promising antitumour therapeutic tools. Furthermore, one of the most innovative and interesting topics is the evaluation of efficacy of prooxidant therapies on cancer stem cells (CSCs). Several ROS inducers-polyphenols can impact CSCs metabolisms and self-renewal related pathways. Natural polyphenol roles, mainly in chemoprevention and cancer therapies, are described and discussed in the light of the current literature data.
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23
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Docosahexaenoic Acid Modulates a HER2-Associated Lipogenic Phenotype, Induces Apoptosis, and Increases Trastuzumab Action in HER2-Overexpressing Breast Carcinoma Cells. BIOMED RESEARCH INTERNATIONAL 2015; 2015:838652. [PMID: 26640797 PMCID: PMC4659962 DOI: 10.1155/2015/838652] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Revised: 09/11/2015] [Accepted: 10/11/2015] [Indexed: 12/12/2022]
Abstract
In breast cancer, lipid metabolic alterations have been recognized as potential oncogenic stimuli that may promote malignancy. To investigate whether the oncogenic nature of lipogenesis closely depends on the overexpression of HER2 protooncogene, the normal breast cell line, HB4a, was transfected with HER2 cDNA to obtain HER2-overexpressing HB4aC5.2 cells. Both cell lines were treated with trastuzumab and docosahexaenoic acid. HER2 overexpression was accompanied by an increase in the expression of lipogenic genes involved in uptake (CD36), transport (FABP4), and storage (DGAT) of exogenous fatty acids (FA), as well as increased activation of “de novo” FA synthesis (FASN). We further investigate whether this lipogenesis reprogramming might be regulated by mTOR/PPARγ pathway. Inhibition of the mTORC1 pathway markers, p70S6 K1, SREBP1, and LIPIN1, as well as an increase in DEPTOR expression (the main inhibitor of the mTOR) was detected in HB4aC5.2. Based on these results, a PPARγ selective antagonist, GW9662, was used to treat both cells lines, and the lipogenic genes remained overexpressed in the HB4aC5.2 but not HB4a cells. DHA treatment inhibited all lipogenic genes (except for FABP4) in both cell lines yet only induced death in the HB4aC5.2 cells, mainly when associated with trastuzumab. Neither trastuzumab nor GW9662 alone was able to induce cell death. In conclusion, oncogenic transformation of breast cells by HER2 overexpression may require a reprogramming of lipogenic genetic that is independent of mTORC1 pathway and PPARγ activity. This reprogramming was inhibited by DHA.
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24
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Wolfson B, Eades G, Zhou Q. Adipocyte activation of cancer stem cell signaling in breast cancer. World J Biol Chem 2015; 6:39-47. [PMID: 26009703 PMCID: PMC4436905 DOI: 10.4331/wjbc.v6.i2.39] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 03/18/2015] [Accepted: 04/20/2015] [Indexed: 02/05/2023] Open
Abstract
Signaling within the tumor microenvironment has a critical role in cancer initiation and progression. Adipocytes, one of the major components of the breast microenvironment, have been shown to provide pro-tumorigenic signals that promote cancer cell proliferation and invasiveness in vitro and tumorigenicity in vivo. Adipocyte secreted factors such as leptin and interleukin-6 (IL-6) have a paracrine effect on breast cancer cells. In adipocyte-adjacent breast cancer cells, the leptin and IL-6 signaling pathways activate janus kinase 2/signal transducer and activator of transcription 5, promoting the epithelial-mesenchymal transition, and upregulating stemness regulators such as Notch, Wnt and the Sex determining region Y-box 2/octamer binding transcription factor 4/Nanog signaling axis. In this review we will summarize the major signaling pathways that regulate cancer stem cells in breast cancer and describe the effects that adipocyte secreted IL-6 and leptin have on breast cancer stem cell signaling. Finally we will introduce a new potential treatment paradigm of inhibiting the adipocyte-breast cancer cell signaling via targeting the IL-6 or leptin pathways.
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25
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Kitagishi Y, Minami A, Nakanishi A, Ogura Y, Matsuda S. Neuron membrane trafficking and protein kinases involved in autism and ADHD. Int J Mol Sci 2015; 16:3095-115. [PMID: 25647412 PMCID: PMC4346882 DOI: 10.3390/ijms16023095] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Accepted: 01/19/2015] [Indexed: 11/16/2022] Open
Abstract
A brain-enriched multi-domain scaffolding protein, neurobeachin has been identified as a candidate gene for autism patients. Mutations in the synaptic adhesion protein cell adhesion molecule 1 (CADM1) are also associated with autism spectrum disorder, a neurodevelopmental disorder of uncertain molecular origin. Potential roles of neurobeachin and CADM1 have been suggested to a function of vesicle transport in endosomal trafficking. It seems that protein kinase B (AKT) and cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) have key roles in the neuron membrane trafficking involved in the pathogenesis of autism. Attention deficit hyperactivity disorder (ADHD) is documented to dopaminergic insufficiencies, which is attributed to synaptic dysfunction of dopamine transporter (DAT). AKT is also essential for the DAT cell-surface redistribution. In the present paper, we summarize and discuss the importance of several protein kinases that regulate the membrane trafficking involved in autism and ADHD, suggesting new targets for therapeutic intervention.
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Affiliation(s)
- Yasuko Kitagishi
- Department of Food Science and Nutrition, Nara Women's University, Kita-Uoya Nishimachi, Nara 630-8506, Japan.
| | - Akari Minami
- Department of Food Science and Nutrition, Nara Women's University, Kita-Uoya Nishimachi, Nara 630-8506, Japan.
| | - Atsuko Nakanishi
- Department of Food Science and Nutrition, Nara Women's University, Kita-Uoya Nishimachi, Nara 630-8506, Japan.
| | - Yasunori Ogura
- Department of Food Science and Nutrition, Nara Women's University, Kita-Uoya Nishimachi, Nara 630-8506, Japan.
| | - Satoru Matsuda
- Department of Food Science and Nutrition, Nara Women's University, Kita-Uoya Nishimachi, Nara 630-8506, Japan.
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26
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Pistollato F, Giampieri F, Battino M. The use of plant-derived bioactive compounds to target cancer stem cells and modulate tumor microenvironment. Food Chem Toxicol 2015; 75:58-70. [DOI: 10.1016/j.fct.2014.11.004] [Citation(s) in RCA: 112] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Revised: 11/03/2014] [Accepted: 11/06/2014] [Indexed: 12/18/2022]
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27
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Aragón F, Perdigón G, LeBlanc ADMD. Modification in the diet can induce beneficial effects against breast cancer. World J Clin Oncol 2014; 5:455-464. [PMID: 25114859 PMCID: PMC4127615 DOI: 10.5306/wjco.v5.i3.455] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2014] [Revised: 05/15/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
The population tends to consume foods that in addition to their nutritional values can offer some benefits to their health. There are many epidemiological evidences and research studies in animal models suggesting that diet plays an important role in breast cancer prevention or progression. This review summarized some of the relevant researches about nutrition and cancer during the last years, especially in breast cancer. The analysis of probiotics and fermented products containing lactic acid bacteria in cancer prevention and/or treatment was especially discussed. It was observed that a balance of fatty acids similar to those of traditional Mediterranean diet, the consumption of fruits and vegetables, dietary fiber intake, vitamin supplementation are, along with the intake of probiotic products, the most extensively studied by the negative association to breast cancer risk. The consumption of probiotics and fermented products containing lactic acid bacteria was associated to reduce breast cancer risk in some epidemiological studies. The use of animal models showed the modulation of the host’s immune response as one of the important effects associated to the benefices observed with most probiotics. However; future assays in human are very important before the medical community can accept the addition of probiotic or fermented milks containing lactic acid bacteria as supplements for cancer patients.
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28
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Montales MTE, Melnyk SB, Simmen FA, Simmen RCM. Maternal metabolic perturbations elicited by high-fat diet promote Wnt-1-induced mammary tumor risk in adult female offspring via long-term effects on mammary and systemic phenotypes. Carcinogenesis 2014; 35:2102-12. [PMID: 24832086 DOI: 10.1093/carcin/bgu106] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Many adult chronic diseases are thought to be influenced during early life by maternal nutrition; however, the underlying mechanisms remain largely unknown. Obesity-related diseases may be due partly to high fat consumption. Herein, we evaluated mammary tumor risk in female mouse mammary tumor virus-Wnt-1 transgenic (Tg) offspring exposed to high-fat diet (HFD) or control diet (CD) (45% and 17% kcal from fat, respectively) during gestation and lactation, with CD provided to progeny at weaning. In Tg offspring, maternal HFD exposure increased mammary tumor incidence and decreased tumor latency without affecting tumor volume. Tumor risk was associated with higher tumor necrosis factor-α and insulin and altered oxidative stress biomarkers in sera and with early changes in mammary expression of genes linked to tumor promotion [interleukin 6 (Il6)] or inhibition [phosphatase and tensin homolog deleted on chromosome 10 (Pten), B-cell lymphoma 2 (Bcl2)]. Corresponding wild-type progeny exposed to maternal HFD displayed accelerated mammary development, higher mammary adiposity, increased insulin resistance and early changes in Pten, Bcl2 and Il6, than CD-exposed offspring. Dams-fed HFD showed higher serum glucose and oxidative stress biomarkers but comparable adiposity compared with CD-fed counterparts. In human breast cancer MCF-7 cells, sera from maternal HFD-exposed Tg offspring elicited changes in PTEN, BCL2 and IL6 gene expression, mimicking in vivo exposure; increased cell viability and mammosphere formation and induced measures [insulin receptor substrate-1 (IRS-1), IRS-2] of insulin sensitivity. Serum effects on IRS-1 were recapitulated by exogenous insulin and the PTEN-specific inhibitor SF1670. Hyperinsulinemia and PTEN loss-of-function may thus, couple maternal HFD exposure to enhanced insulin sensitivity via increased mammary IRS-1 expression in progeny, to promote breast cancer risk.
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Affiliation(s)
- Maria Theresa E Montales
- Department of Physiology & Biophysics, Department of Pediatrics and Arkansas Children's Hospital Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Stepan B Melnyk
- Department of Pediatrics and Arkansas Children's Hospital Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Frank A Simmen
- Department of Physiology & Biophysics, Department of Pediatrics and Arkansas Children's Hospital Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Rosalia C M Simmen
- Department of Physiology & Biophysics, Department of Pediatrics and Arkansas Children's Hospital Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
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29
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Apoptotic death of cancer stem cells for cancer therapy. Int J Mol Sci 2014; 15:8335-51. [PMID: 24823879 PMCID: PMC4057734 DOI: 10.3390/ijms15058335] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Revised: 04/18/2014] [Accepted: 04/18/2014] [Indexed: 01/08/2023] Open
Abstract
Cancer stem cells (CSCs) play crucial roles in tumor progression, chemo- and radiotherapy resistance, and recurrence. Recent studies on CSCs have advanced understanding of molecular oncology and development of novel therapeutic strategies. This review article updates the hypothesis and paradigm of CSCs with a focus on major signaling pathways and effectors that regulate CSC apoptosis. Selective CSC apoptotic inducers are introduced and their therapeutic potentials are discussed. These include synthetic and natural compounds, antibodies and recombinant proteins, and oligonucleotides.
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