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1
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Demir K, Turgut R, Şentürk S, Işıklar H, Günalan E. The Therapeutic Effects of Bioactive Compounds on Colorectal Cancer via PI3K/Akt/mTOR Signaling Pathway: A Critical Review. Food Sci Nutr 2024; 12:9951-9973. [PMID: 39723045 PMCID: PMC11666977 DOI: 10.1002/fsn3.4534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 09/25/2024] [Accepted: 09/28/2024] [Indexed: 12/28/2024] Open
Abstract
Understanding the molecular signaling pathways of colorectal cancer (CRC) can be accepted as the first step in treatment strategy. Permanent mTOR signaling activation stimulates the CRC process via various biological processes. It supplies the survival of CRC stem cells, tumorigenesis, morbidity, and decreased response to drugs in CRC pathogenesis. Therefore, inhibition of the mTOR signaling by numerous bioactive components may be effective against CRC. The study aims to discuss the therapeutic capacity of various polyphenols, terpenoids, and alkaloids on CRC via the PI3K/Akt/mTOR pathway. The potential molecular effects of bioactive compounds on the mTOR pathway's upstream and downstream targets are examined. Each bioactive component causes various physiological processes, such as triggering free radical production, disruption of mitochondrial membrane potential, cell cycle arrest, inhibition of CRC stem cell migration, and suppression of glycolysis through mTOR signaling inhibition. As a result, carcinogenesis is inhibited by inducing apoptosis and autophagy. However, it should be noted that studies are primarily in vitro dose-dependent treatment researchers. This study raises awareness about the role of phenolic compounds in treating CRC, contributing to their future use as anticancer agents. These bioactive compounds have the potential to be developed into food supplementation to prevent and treat various cancer types including CRC. This review has the potential to lead to further development of clinical studies. In the future, mTOR inhibition by applying several bioactive agents using advanced drug delivery systems may contribute to CRC treatment with 3D cell culture and in vivo clinical studies.
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Affiliation(s)
- Kübra Demir
- Institute of Graduate EducationIstanbul Health and Technology UniversityIstanbulTürkiye
- Faculty of Health Science, Department of Nutrition and DieteticsSabahattin Zaim UniversityIstanbulTürkiye
| | - Rana Turgut
- Institute of Graduate EducationIstanbul Health and Technology UniversityIstanbulTürkiye
| | - Selcen Şentürk
- Institute of Graduate EducationIstanbul Health and Technology UniversityIstanbulTürkiye
| | - Handan Işıklar
- Faculty of Medicine, Department of Internal MedicineYalova UniversityYalovaTürkiye
| | - Elif Günalan
- Faculty of Health Science, Department of Nutrition and DieteticsIstanbul Health and Technology UniversityIstanbulTürkiye
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2
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Runa F, Ortiz-Soto G, de Barros NR, Kelber JA. Targeting SMAD-Dependent Signaling: Considerations in Epithelial and Mesenchymal Solid Tumors. Pharmaceuticals (Basel) 2024; 17:326. [PMID: 38543112 PMCID: PMC10975212 DOI: 10.3390/ph17030326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 02/19/2024] [Accepted: 02/23/2024] [Indexed: 04/01/2024] Open
Abstract
SMADs are the canonical intracellular effector proteins of the TGF-β (transforming growth factor-β). SMADs translocate from plasma membrane receptors to the nucleus regulated by many SMAD-interacting proteins through phosphorylation and other post-translational modifications that govern their nucleocytoplasmic shuttling and subsequent transcriptional activity. The signaling pathway of TGF-β/SMAD exhibits both tumor-suppressing and tumor-promoting phenotypes in epithelial-derived solid tumors. Collectively, the pleiotropic nature of TGF-β/SMAD signaling presents significant challenges for the development of effective cancer therapies. Here, we review preclinical studies that evaluate the efficacy of inhibitors targeting major SMAD-regulating and/or -interacting proteins, particularly enzymes that may play important roles in epithelial or mesenchymal compartments within solid tumors.
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Affiliation(s)
- Farhana Runa
- Department of Biology, California State University Northridge, Northridge, CA 91330, USA
| | | | | | - Jonathan A Kelber
- Department of Biology, California State University Northridge, Northridge, CA 91330, USA
- Department of Biology, Baylor University, Waco, TX 76706, USA
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3
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Xiao B, Jiang Y, Yuan S, Cai L, Xu T, Jia L. Silibinin, a potential fasting mimetic, inhibits hepatocellular carcinoma by triggering extrinsic apoptosis. MedComm (Beijing) 2024; 5:e457. [PMID: 38222315 PMCID: PMC10784426 DOI: 10.1002/mco2.457] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 11/21/2023] [Accepted: 11/22/2023] [Indexed: 01/16/2024] Open
Abstract
Fasting, without inducing malnutrition, has been shown to have various beneficial effects, including the inhibition of tumor initiation and progression. However, prolonged fasting poses challenges for many cancer patients, particularly those in intermediate and terminal stages. Thus, there is an urgent need for the development of fasting mimetics which harness the protective effects of fasting but more suitable for patients. In this study, we first highlighted the pivotal role of silibinin in AMP-activated protein kinase (AMPK) pathway and may serve, as a potential fasting mimetic via screening hepatoprotective drugs. Further metabolic analysis showed that silibinin inhibited the adenosine triphosphate (ATP) levels, glucose uptake and diminished glycolysis process, which further confirmed that silibinin served as a fasting mimetic. In addition, fasting synergized with silibinin, or used independently, to suppress the growth of hepatocellular carcinoma (HCC) in vivo. Mechanistically, silibinin upregulated death receptor 5 (DR5) through AMPK activation, and thus promoting extrinsic apoptosis and inhibiting HCC growth both in vitro and in vivo. Inhibition of AMPK using small interfering RNA (siRNA) or compound C, an AMPK inhibitor, significantly attenuated the upregulation of DR5 and the apoptotic response induced by silibinin. These findings suggest that silibinin holds promise as a fasting mimetic and may serve as an adjuvant drug for HCC treatment.
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Affiliation(s)
- Biying Xiao
- Cancer InstituteLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Yanyu Jiang
- Cancer InstituteLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Shuying Yuan
- Cancer InstituteLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Lili Cai
- Cancer InstituteLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Tong Xu
- Departmnent of OncologyAffiliated Hospital of Jiangnan UniversityWuxiChina
| | - Lijun Jia
- Cancer InstituteLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
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4
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Du YX, Mamun AA, Lyu AP, Zhang HJ. Natural Compounds Targeting the Autophagy Pathway in the Treatment of Colorectal Cancer. Int J Mol Sci 2023; 24:7310. [PMID: 37108476 PMCID: PMC10138367 DOI: 10.3390/ijms24087310] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 04/03/2023] [Accepted: 04/12/2023] [Indexed: 04/29/2023] Open
Abstract
Autophagy is a highly conserved intracellular degradation pathway by which misfolded proteins or damaged organelles are delivered in a double-membrane vacuolar vesicle and finally degraded by lysosomes. The risk of colorectal cancer (CRC) is high, and there is growing evidence that autophagy plays a critical role in regulating the initiation and metastasis of CRC; however, whether autophagy promotes or suppresses tumor progression is still controversial. Many natural compounds have been reported to exert anticancer effects or enhance current clinical therapies by modulating autophagy. Here, we discuss recent advancements in the molecular mechanisms of autophagy in regulating CRC. We also highlight the research on natural compounds that are particularly promising autophagy modulators for CRC treatment with clinical evidence. Overall, this review illustrates the importance of autophagy in CRC and provides perspectives for these natural autophagy regulators as new therapeutic candidates for CRC drug development.
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Affiliation(s)
| | | | - Ai-Ping Lyu
- School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon Tong, Kowloon, Hong Kong SAR, China; (Y.-X.D.); (A.A.M.)
| | - Hong-Jie Zhang
- School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon Tong, Kowloon, Hong Kong SAR, China; (Y.-X.D.); (A.A.M.)
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5
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Liao W, Zhang L, Chen X, Xiang J, Zheng Q, Chen N, Zhao M, Zhang G, Xiao X, Zhou G, Zeng J, Tang J. Targeting cancer stem cells and signalling pathways through phytochemicals: A promising approach against colorectal cancer. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 108:154524. [PMID: 36375238 DOI: 10.1016/j.phymed.2022.154524] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 10/10/2022] [Accepted: 10/24/2022] [Indexed: 06/16/2023]
Abstract
BACKGROUND Cancer stem cells (CSCs) are strongly associated with high tumourigenicity, chemotherapy or radiotherapy resistance, and metastasis and recurrence, particularly in colorectal cancer (CRC). Therefore, targeting CSCs may be a promising approach. Recently, discovery and research on phytochemicals that effectively target colorectal CSCs have been gaining popularity because of their broad safety profile and multi-target and multi-pathway modes of action. PURPOSE This review aimed to elucidate and summarise the effects and mechanisms of phytochemicals with potential anti-CSC agents that could contribute to the better management of CRC. METHODS We reviewed PubMed, EMBASE, Web of Science, Ovid, ScienceDirect and China National Knowledge Infrastructure databases from the original publication date to March 2022 to review the mechanisms by which phytochemicals inhibit CRC progression by targeting CSCs and their key signalling pathways. Phytochemicals were classified and summarised based on the mechanisms of action. RESULTS We observed that phytochemicals could affect the biological properties of colorectal CSCs. Phytochemicals significantly inhibit self-renewal, migration, invasion, colony formation, and chemoresistance and induce apoptosis and differentiation of CSCs by regulating the Wnt/β-catenin pathway (e.g., diallyl trisulfide and genistein), the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin pathway (e.g., caffeic acid and piperlongumine), the neurogenic locus notch homolog protein pathway (e.g., honokiol, quercetin, and α-mangostin), the Janus kinase-signal transducer and activator of transcription pathway (e.g., curcumin, morin, and ursolic acid), and other key signalling pathways. It is worth noting that several phytochemicals, such as resveratrol, silibinin, evodiamine, and thymoquinone, highlight multi-target and multi-pathway effects in restraining the malignant biological behaviour of CSCs. CONCLUSIONS This review demonstrates the potential of targeted therapies for colorectal CSCs using phytochemicals. Phytochemicals could serve as novel therapeutic agents for CRC and aid in drug development.
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Affiliation(s)
- Wenhao Liao
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China
| | - Lanlan Zhang
- State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Key Laboratory of Plant Resources and Chemistry in Arid Regions, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xian Chen
- Department of Pathology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China
| | - Juyi Xiang
- Center for drug evaluation, National Medical Products Administration, Beijing 100022, China
| | - Qiao Zheng
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China
| | - Nianzhi Chen
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China
| | - Maoyuan Zhao
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China
| | - Gang Zhang
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China
| | - Xiaolin Xiao
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China
| | - Gang Zhou
- Center for drug evaluation, National Medical Products Administration, Beijing 100022, China.
| | - Jinhao Zeng
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China; Department of Geriatrics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China.
| | - Jianyuan Tang
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China.
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Sun L, Xiong H, Chen L, Dai X, Yan X, Wu Y, Yang M, Shan M, Li T, Yao J, Jiang W, He H, He F, Lian J. Deacetylation of ATG4B promotes autophagy initiation under starvation. SCIENCE ADVANCES 2022; 8:eabo0412. [PMID: 35921421 PMCID: PMC9348796 DOI: 10.1126/sciadv.abo0412] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 06/20/2022] [Indexed: 06/15/2023]
Abstract
Eukaryotes initiate autophagy when facing environmental changes such as a lack of external nutrients. However, the mechanisms of autophagy initiation are still not fully elucidated. Here, we showed that deacetylation of ATG4B plays a key role in starvation-induced autophagy initiation. Specifically, we demonstrated that ATG4B is activated during starvation through deacetylation at K39 by the deacetylase SIRT2. Moreover, starvation triggers SIRT2 dephosphorylation and activation in a cyclin E/CDK2 suppression-dependent manner. Meanwhile, starvation down-regulates p300, leading to a decrease in ATG4B acetylation at K39. K39 deacetylation also enhances the interaction of ATG4B with pro-LC3, which promotes LC3-II formation. Furthermore, an in vivo experiment using Sirt2 knockout mice also confirmed that SIRT2-mediated ATG4B deacetylation at K39 promotes starvation-induced autophagy initiation. In summary, this study reveals an acetylation-dependent regulatory mechanism that controls the role of ATG4B in autophagy initiation in response to nutritional deficiency.
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Affiliation(s)
- Liangbo Sun
- Department of Clinical Biochemistry, Army Medical University (Third Military Medical University), Chongqing 400038, China
- Department of Biochemistry and Molecular Biology, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Haojun Xiong
- Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Lingxi Chen
- Department of Biochemistry and Molecular Biology, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Xufang Dai
- Department of Educational College, Chongqing Normal University, Chongqing 400047, China
| | - Xiaojing Yan
- Department of Clinical Biochemistry, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Yaran Wu
- Department of Clinical Biochemistry, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Mingzhen Yang
- Department of Clinical Biochemistry, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Meihua Shan
- Department of Clinical Biochemistry, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Tao Li
- Department of Clinical Biochemistry, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Jie Yao
- Institute of Digital Medicine, Biomedical Engineering College, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Wenbin Jiang
- Department of Biochemistry and Molecular Biology, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Haiyan He
- Department of Biochemistry and Molecular Biology, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Fengtian He
- Department of Biochemistry and Molecular Biology, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Jiqin Lian
- Department of Clinical Biochemistry, Army Medical University (Third Military Medical University), Chongqing 400038, China
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7
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Hussain Y, Khan H, Alam W, Aschner M, Abdullah, Alsharif KF, Saso L. Flavonoids Targeting the mTOR Signaling Cascades in Cancer: A Potential Crosstalk in Anti-Breast Cancer Therapy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:4831833. [PMID: 35795855 PMCID: PMC9252758 DOI: 10.1155/2022/4831833] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 06/04/2022] [Indexed: 12/19/2022]
Abstract
Cancer is one of the leading causes of death worldwide. Breast cancer is the second leading cause of death in women, with triple-negative breast cancer being the most lethal and aggressive form. Conventional therapies, such as radiation, surgery, hormonal, immune, gene, and chemotherapy, are widely used, but their therapeutic efficacy is limited due to adverse side effects, toxicities, resistance, recurrence, and therapeutic failure. Many molecules have been identified and investigated as potential therapeutic agents for breast cancer, with a focus on various signaling pathways. Flavonoids are a versatile class of phytochemicals that have been used in cancer treatment to overcome issues with traditional therapies. Cell proliferation, growth, apoptosis, autophagy, and survival are all controlled by mammalian target of rapamycin (mTOR) signaling. Flavonoids target mTOR signaling in breast cancer, and when this signaling pathway is regulated or deregulated, various signaling pathways provide potential therapeutic means. The role of various flavonoids as phytochemicals in targeting mTOR signaling pathways in breast cancer is highlighted in this review.
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Affiliation(s)
- Yaseen Hussain
- College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
- Department of Pharmacy, Bashir Institute of Health Sciences, Islamabad, Pakistan
| | - Haroon Khan
- Department of Pharmacy, Faculty of Chemical and Life Sciences, Abdul Wali Khan University, Mardan 23200, Pakistan
| | - Waqas Alam
- Department of Pharmacy, Faculty of Chemical and Life Sciences, Abdul Wali Khan University, Mardan 23200, Pakistan
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Abdullah
- Department of Pharmacy, University of Malakand, Chakdara, Dir Lower, Pakistan
| | - Khalaf F. Alsharif
- Department of Clinical Laboratory, College of Applied Medical Science, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Luciano Saso
- Department of Physiology and Pharmacology “Vittorio Erspamer” Sapienza University, 00185 Rome, Italy
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8
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Wang G, Wang JJ, Xu XN, Shi F, Fu XL. Targeting cellular energy metabolism- mediated ferroptosis by small molecule compounds for colorectal cancer therapy. J Drug Target 2022; 30:819-832. [PMID: 35481396 DOI: 10.1080/1061186x.2022.2071909] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Alterations in cellular energy metabolism, including glycolysis, glutamine and lipid metabolism that affects ferroptosis in the tumour microenvironment (TME), play a critical role in the development and progression of colorectal cancer (CRC) and offer evolutionary advantages to tumour cells and even enhance their aggressive phenotype. This review summarises the findings on the dysregulated energy metabolism pathways, including lipid and fatty acid metabolism especially for regulating the ferroptosis in TME. Moreover, the cellular energy metabolism and tumour ferroptosis to be regulated by small molecule compounds, which targeting the different aspects of metabolic pathways of energy production as well as metabolic enzymes that connect with the tumour cell growth and ferroptosis in CRC are also discussed. In this review, we will provide a comprehensive summary on small molecule compounds regulatory function of different energy metabolic routes on ferroptosis in tumour cells and discuss those metabolic vulnerabilities for the development of potential ferroptosis-based tumour therapies for colorectal cancer.
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Affiliation(s)
- Gang Wang
- Department of Pharmaceutics, Shanghai Eighth People's Hospital, Jiangsu University, Shanghai, China
| | - Jun-Jie Wang
- Department of Pharmaceutics, Shanghai Eighth People's Hospital, Jiangsu University, Shanghai, China
| | - Xiao-Na Xu
- Department of Medicine, Jiangsu University, Zhenjiang City, China
| | - Feng Shi
- Department of Medicine, Jiangsu University, Zhenjiang City, China
| | - Xing-Li Fu
- Department of Medicine, Jiangsu University, Zhenjiang City, China
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9
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Hua C, Wang X, Liang S, Chen X, Li C, You G, Wang C, Luo T, Wang Z, Ge P. BNIP3 contributes to silibinin-induced DNA double strand breaks in glioma cells via inhibition of mTOR. Biochem Biophys Res Commun 2021; 589:1-8. [PMID: 34883284 DOI: 10.1016/j.bbrc.2021.11.110] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 11/30/2021] [Indexed: 12/19/2022]
Abstract
BNIP3 is found to eliminate cancer cells via causing mitochondrial damage and endoplasmic reticulum stress, but it remains elusive of its role in regulating DNA double strand breaks (DSBs). In this study, we find that silibinin triggers DNA DSBs, ROS accumulation and expressional upregulation of BNIP3 in glioma cells. Mitigation of ROS with antioxidant GSH significantly inhibits silibinin-induced DNA DSBs and glioma cell death. Then, we find knockdown of BNIP3 with SiRNA obviously prevents silibinin-induced DNA DSBs and ROS accumulation. Mechanistically, BNIP3 knockdown not only reverses silibinin-triggered depletion of cysteine and GSH via maintaining xCT level, but also abrogates catalase decrease. Notably, silibinin-induced dephosphorylation of mTOR is also prevented when BNIP3 is knocked down. Given that activated mTOR could promote xCT expression and inhibit autophagic degradation of catalase, our data suggest that BNIP3 contributes to silibinin-induced DNA DSBs via improving intracellular ROS by inhibition of mTOR.
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Affiliation(s)
- Cong Hua
- Department of Neurosurgery, First Hospital of Jilin University, Changchun, 130021, China; Research Center of Neuroscience, First Hospital of Jilin University, Changchun, 130021, China
| | - Xuanzhong Wang
- Department of Neurosurgery, First Hospital of Jilin University, Changchun, 130021, China; Research Center of Neuroscience, First Hospital of Jilin University, Changchun, 130021, China
| | - Shipeng Liang
- Department of Neurosurgery, First Hospital of Jilin University, Changchun, 130021, China; Research Center of Neuroscience, First Hospital of Jilin University, Changchun, 130021, China
| | - Xi Chen
- Department of Neurosurgery, First Hospital of Jilin University, Changchun, 130021, China; Research Center of Neuroscience, First Hospital of Jilin University, Changchun, 130021, China
| | - Chen Li
- Department of Neurosurgery, First Hospital of Jilin University, Changchun, 130021, China; Research Center of Neuroscience, First Hospital of Jilin University, Changchun, 130021, China
| | - Guangqiang You
- Department of General Surgery, Second Hospital of Jilin University, Changchun, 130021, China
| | - Chongcheng Wang
- Department of Neurosurgery, First Hospital of Jilin University, Changchun, 130021, China; Research Center of Neuroscience, First Hospital of Jilin University, Changchun, 130021, China
| | - Tianfei Luo
- Research Center of Neuroscience, First Hospital of Jilin University, Changchun, 130021, China; Department of Neurology, First Hospital of Jilin University, Changchun, 130021, China
| | - Zhenchuan Wang
- Department of Neurosurgery, First Hospital of Jilin University, Changchun, 130021, China; Research Center of Neuroscience, First Hospital of Jilin University, Changchun, 130021, China
| | - Pengfei Ge
- Department of Neurosurgery, First Hospital of Jilin University, Changchun, 130021, China; Research Center of Neuroscience, First Hospital of Jilin University, Changchun, 130021, China.
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10
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Fallah M, Davoodvandi A, Nikmanzar S, Aghili S, Mirazimi SMA, Aschner M, Rashidian A, Hamblin MR, Chamanara M, Naghsh N, Mirzaei H. Silymarin (milk thistle extract) as a therapeutic agent in gastrointestinal cancer. Biomed Pharmacother 2021; 142:112024. [PMID: 34399200 PMCID: PMC8458260 DOI: 10.1016/j.biopha.2021.112024] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 08/01/2021] [Accepted: 08/07/2021] [Indexed: 02/07/2023] Open
Abstract
Silymarin contains a group of closely-related flavonolignan compounds including silibinin, and is extracted from Silybum marianum species, also called milk thistle. Silymarin has been shown to protect the liver in both experimental models and clinical studies. The chemopreventive activity of silymarin has shown some efficacy against cancer both in vitro and in vivo. Silymarin can modulate apoptosis in vitro and survival in vivo, by interfering with the expression of cell cycle regulators and apoptosis-associated proteins. In addition to its anti-metastatic activity, silymarin has also been reported to exhibit anti-inflammatory activity. The chemoprotective effects of silymarin and silibinin (its major constituent) suggest they could be applied to reduce the side effects and increase the anti-cancer effects of chemotherapy and radiotherapy in various cancer types, especially in gastrointestinal cancers. This review examines the recent studies and summarizes the mechanistic pathways and down-stream targets of silymarin in the therapy of gastrointestinal cancer.
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Affiliation(s)
- Maryam Fallah
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran; Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Amirhossein Davoodvandi
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran; Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Shahin Nikmanzar
- Department of Neurosurgery, School of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Sarehnaz Aghili
- Department of Gynecology and Obstetrics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Mohammad Ali Mirazimi
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran; School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10463, USA
| | - Amir Rashidian
- Department of Pharmacology, School of Medicine, Aja University of Medical Sciences, Tehran, Iran
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa
| | - Mohsen Chamanara
- Department of Pharmacology, School of Medicine, Aja University of Medical Sciences, Tehran, Iran; Toxicology Research Center, Aja University of Medical Sciences, Tehran, Iran.
| | - Navid Naghsh
- Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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11
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Arslan FD, Kocak A, Aydın C, Pala EE, Oncel D, Diniz G, Kaya T, Ugurlu L, Degirmenci M, Ozkan B, Soysal Y, Said HM. Evaluation of potential tumor markers that may predict neoadjuvant treatment efficiency in rectal cancer. TURKISH JOURNAL OF BIOCHEMISTRY 2021; 46:445-454. [DOI: 10.1515/tjb-2020-0507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/01/2024]
Abstract
Abstract
Objectives
The recurrence of rectal cancer or its resistance to neoadjuvant treatment develops due to the adaptation to hypoxia, apoptosis or autophagy. Survivin, one of the inhibitors of apoptosis; Beclin 1, which is a positive regulator in the autophagy pathway; and hypoxia-inducible factor-1α (HIF-1α) and carbonic anhydrase-9 (CA9), which are associated with tumor tissue hypoxia, may be related to resistance to treatment. Our aim was to evaluate the potential tumor markers that may help to monitor the response to neoadjuvant treatment in locally advanced rectal cancer (RC).
Methods
Twenty-five patients with locally advanced RC were included in the study. Gene expression and protein levels of Beclin 1, Survivin, HIF-1α, and CA9 were analyzed in fresh tissue specimens and blood samples. The relationships of these markers to tumor staging and regression grade were evaluated.
Results
Higher blood CA9 gene expression levels and lower blood HIF-1α protein levels were found in the response group according to tumor regression grade. After neoadjuvant treatment, tissue Beclin 1 and blood Survivin gene expressions and tissue CA9, blood Beclin 1 and blood HIF-1α protein levels decreased significantly.
Conclusion
Beclin 1, Survivin, HIF-1α ve CA9 may help to predict the effects of the applied treatment approach.
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Affiliation(s)
- Fatma Demet Arslan
- Department of Medical Biochemistry , University of Health Sciences, Tepecik Training and Research Hospital , Izmir , Turkey
- Department of Molecular Medicine, Institute of Health Sciences , Dokuz Eylül University , Izmir , Turkey
| | - Ayse Kocak
- Department of Molecular Medicine, Institute of Health Sciences , Dokuz Eylül University , Izmir , Turkey
| | - Cengiz Aydın
- General Surgery Clinic , University of Health Sciences, Tepecik Training and Research Hospital , Izmir , Turkey
| | - Emel Ebru Pala
- Medical Pathology Clinic , University of Health Sciences, Tepecik Training and Research Hospital , Izmir , Turkey
| | - Dilek Oncel
- Radiology Clinic , University of Health Sciences, Tepecik Training and Research Hospital , Izmir , Turkey
| | - Gulden Diniz
- Medical Pathology Clinic , University of Health Sciences, Tepecik Training and Research Hospital , Izmir , Turkey
| | - Tayfun Kaya
- General Surgery Clinic , University of Health Sciences, Tepecik Training and Research Hospital , Izmir , Turkey
| | - Levent Ugurlu
- General Surgery Clinic , University of Health Sciences, Tepecik Training and Research Hospital , Izmir , Turkey
| | - Mustafa Degirmenci
- Oncology Clinic , University of Health Sciences, Tepecik Training and Research Hospital , Izmir , Turkey
| | - Bulent Ozkan
- Department of Biostatistics , Faculty of Medicine, Katip Çelebi University , Izmir , Turkey
| | - Yasemin Soysal
- Department of Molecular Medicine, Institute of Health Sciences , Dokuz Eylül University , Izmir , Turkey
| | - Harun Muayad Said
- Department of Molecular Medicine, Institute of Health Sciences , Dokuz Eylül University , Izmir , Turkey
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12
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Wang G, Yu Y, Wang YZ, Yin PH, Xu K, Zhang H. The effects and mechanisms of isoliquiritigenin loaded nanoliposomes regulated AMPK/mTOR mediated glycolysis in colorectal cancer. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2021; 48:1231-1249. [PMID: 32985258 DOI: 10.1080/21691401.2020.1825092] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
In this study, isoliquiritigenin (ISL) incorporated nanoliposomes were prepared and their effects on colorectal cancer (CRC) cell lines were investigated. Herein, we sought to explore the anti-cancer mechanisms of ISL loaded nanoliposomes (ISL-NLs) on AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) pathways mediated glycolysis. Also, the key targets such as caveolin 1 (CAV1), glucose transporters and Akt/mTOR that promote glycolysis, and are activated via the induction of α-enolase (ENO1), fructose bisphosphate aldolase A (ALDOA) and monocarboxylate transporter 4 (MCT4) expressions were also investigated. It was shown that ISL-NLs significantly suppressed the proliferation and glucose uptake of CRC cell by potentially regulating the glycolysis and lactate targets as well as pathways that formed the basis of the anti-CRC effects of ISL-NLs. The mechanism underlying this effect was further validated via the regulation of some key targets such as ENO1, ALDOA, lactate dehydrogenase A (LDHA) and MCT4 in glycolysis coupled with cellular myelocytomatosis oncogene (c-myc), hypoxia-inducible factor 1-alpha (HIF-1α) in protein kinase B/mTOR (Akt/mTOR) pathways. Moreover, the AMPK proteins were identified to be up-regulated while the lactic acid production was suppressed by ISL-NLs in the CRC cells, indicating that ISL-NLs had an inhibitory effect on AMPK mediated glycolysis and lactate production. Altogether, these results have provided insights into the mechanism underlying the key role that liposomal ISL played in the multiple inhibition of AMPK and Akt/mTOR mediated glycolysis and lactate generation, which may be regulated as the alternative metabolic pathways of CRC as well as serve as adjuvant therapy for the disease.
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Affiliation(s)
- Gang Wang
- Department of Pharmaceutics, Shanghai Eighth People's Hospital, Jiangsu University, Shanghai, China
| | - Yang Yu
- School of Pharmacy, Jiangsu University Zhenjiang City, China
| | - Yu-Zhu Wang
- School of Pharmacy, Jiangsu University Zhenjiang City, China
| | - Pei-Hao Yin
- Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ke Xu
- Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Heng Zhang
- Department of General Surgery, Nanjing Lishui District People's Hospital, Zhongda Hospital Lishui Branch, Southeast University, Nanjing, China
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Tuli HS, Mittal S, Aggarwal D, Parashar G, Parashar NC, Upadhyay SK, Barwal TS, Jain A, Kaur G, Savla R, Sak K, Kumar M, Varol M, Iqubal A, Sharma AK. Path of Silibinin from diet to medicine: A dietary polyphenolic flavonoid having potential anti-cancer therapeutic significance. Semin Cancer Biol 2021; 73:196-218. [PMID: 33130037 DOI: 10.1016/j.semcancer.2020.09.014] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 09/11/2020] [Accepted: 09/29/2020] [Indexed: 02/07/2023]
Abstract
In the last few decades, targeting cancer by the use of dietary phytochemicals has gained enormous attention. The plausible reason and believe or mind set behind this fact is attributed to either lesser or no side effects of natural compounds as compared to the modern chemotherapeutics, or due to their conventional use as dietary components by mankind for thousands of years. Silibinin is a naturally derived polyphenol (a flavonolignans), possess following biochemical features; molecular formula C25H22O10, Molar mass: 482.44 g/mol, Boiling point 793 °C, with strikingly high antioxidant and anti-tumorigenic properties. The anti-cancer properties of Silibinin are determined by a variety of cellular pathways which include induction of apoptosis, cell cycle arrest, inhibition of angiogenesis and metastasis. In addition, Silibinin controls modulation of the expression of aberrant miRNAs, inflammatory response, and synergism with existing anti-cancer drugs. Therefore, modulation of a vast array of cellular responses and homeostatic aspects makes Silibinin an attractive chemotherapeutic agent. However, like other polyphenols, the major hurdle to declare Silibinin a translational chemotherapeutic agent, is its lesser bioavailability. After summarizing the chemistry and metabolic aspects of Silibinin, this extensive review focuses on functional aspects governed by Silibinin in chemoprevention with an ultimate goal of summarizing the evidence supporting the chemopreventive potential of Silibinin and clinical trials that are currently ongoing, at a single platform.
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Affiliation(s)
- Hardeep Singh Tuli
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, 133 207, Haryana, India
| | - Sonam Mittal
- School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
| | - Diwakar Aggarwal
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, 133 207, Haryana, India
| | - Gaurav Parashar
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, 133 207, Haryana, India
| | | | - Sushil Kumar Upadhyay
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, 133 207, Haryana, India
| | - Tushar Singh Barwal
- Department of Zoology, Central University of Punjab, Bathinda, 151 001, Punjab, India
| | - Aklank Jain
- Department of Zoology, Central University of Punjab, Bathinda, 151 001, Punjab, India
| | - Ginpreet Kaur
- Department of Pharmacology, Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM's, NMIMS, Mumbai, 400 056, Maharastra, India
| | - Raj Savla
- Department of Pharmacology, Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM's, NMIMS, Mumbai, 400 056, Maharastra, India
| | | | - Manoj Kumar
- Department of Chemistry, Maharishi Markandeshwar University, Sadopur, India
| | - Mehmet Varol
- Department of Molecular Biology and Genetics, Faculty of Science, Mugla Sitki Kocman University, Mugla, TR48000, Turkey
| | - Ashif Iqubal
- Department of Pharmacology, School of Pharmaceutical Education and Research (Formerly Faculty of Pharmacy), Jamia Hamdard (Deemed to be University), Delhi, India
| | - Anil Kumar Sharma
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, 133 207, Haryana, India.
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14
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Sameri S, Mohammadi C, Mehrabani M, Najafi R. Targeting the hallmarks of cancer: the effects of silibinin on proliferation, cell death, angiogenesis, and migration in colorectal cancer. BMC Complement Med Ther 2021; 21:160. [PMID: 34059044 PMCID: PMC8168007 DOI: 10.1186/s12906-021-03330-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 05/18/2021] [Indexed: 12/25/2022] Open
Abstract
Background Silibinin, as a chemopreventive agent, has shown anti-cancer efficacy against different types of cancers. In the present study, we investigated the anti-cancer activities of silibinin on CT26 mouse colon cell line. Methods CT26 cells were treated with different concentrations of silibinin. To examine the cytotoxic effect of silibinin on proliferation, apoptosis, autophagy, angiogenesis, and migration, MTT, colony-forming assay, Annexin V/PI flow cytometry, RT-qPCR, and Scratch assay were used. Results Silibinin was found to significantly reduce CT26 cells survival. Furthermore, silibinin strongly induced apoptosis and autophagy by up-regulating the expression of Bax, Caspase-3, Atg5, Atg7 and BECN1 and down-regulating Bcl-2. Silibinin considerably down-regulated the expression of COX-2, HIF-1α, VEGF, Ang-2, and Ang-4 as well as the expression of MMP-2, MMP-9, CCR-2 and CXCR-4. Conclusions The present study revealed that silibinin shows anticancer activities by targeting proliferation, cell survival, angiogenesis, and migration of CT26 cells.
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Affiliation(s)
- Saba Sameri
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Chiman Mohammadi
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mehrnaz Mehrabani
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Rezvan Najafi
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
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15
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du Plessis M, Davis T, Loos B, Pretorius E, de Villiers WJS, Engelbrecht AM. Molecular regulation of autophagy in a pro-inflammatory tumour microenvironment: New insight into the role of serum amyloid A. Cytokine Growth Factor Rev 2021; 59:71-83. [PMID: 33727011 DOI: 10.1016/j.cytogfr.2021.01.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 01/28/2021] [Accepted: 01/29/2021] [Indexed: 02/07/2023]
Abstract
Chronic inflammation, systemic or local, plays a vital role in tumour progression and metastasis. Dysregulation of key physiological processes such as autophagy elicit unfavourable immune responses to induce chronic inflammation. Cytokines, growth factors and acute phase proteins present in the tumour microenvironment regulate inflammatory responses and alter crosstalk between various signalling pathways involved in the progression of cancer. Serum amyloid A (SAA) is a key acute phase protein secreted by the liver during the acute phase response (APR) following infection or injury. However, cancer and cancer-associated cells produce SAA, which when present in high levels in the tumour microenvironment contributes to cancer initiation, progression and metastasis. SAA can activate several signalling pathways such as the PI3K and MAPK pathways, which are also known modulators of the intracellular degradation process, autophagy. Autophagy can be regarded as having a double edged sword effect in cancer. Its dysregulation can induce malignant transformation through metabolic stress which manifests as oxidative stress, endoplasmic reticulum (ER) stress and DNA damage. On the other hand, autophagy can promote cancer survival during metabolic stress, hypoxia and senescence. Autophagy has been utilised to promote the efficiency of chemotherapeutic agents and can either be inhibited or induced to improve treatment outcomes. This review aims to address the known mechanisms that regulate autophagy as well as illustrating the role of SAA in modulating these pathways and its clinical implications for cancer therapy.
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Affiliation(s)
- M du Plessis
- Department of Physiological Sciences, University of Stellenbosch, Stellenbosch, South Africa.
| | - T Davis
- Department of Physiological Sciences, University of Stellenbosch, Stellenbosch, South Africa
| | - B Loos
- Department of Physiological Sciences, University of Stellenbosch, Stellenbosch, South Africa
| | - E Pretorius
- Department of Physiological Sciences, University of Stellenbosch, Stellenbosch, South Africa
| | - W J S de Villiers
- African Cancer Institute (ACI), Department of Global Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa; Department of Internal Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg Campus, South Africa
| | - A M Engelbrecht
- Department of Physiological Sciences, University of Stellenbosch, Stellenbosch, South Africa; Department of Internal Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg Campus, South Africa
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16
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Elyasi S. Silybum marianum, antioxidant activity, and cancer patients. Cancer 2021. [DOI: 10.1016/b978-0-12-819547-5.00043-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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17
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Kaipa JM, Starkuviene V, Erfle H, Eils R, Gladilin E. Transcriptome profiling reveals Silibinin dose-dependent response network in non-small lung cancer cells. PeerJ 2020; 8:e10373. [PMID: 33362957 PMCID: PMC7749657 DOI: 10.7717/peerj.10373] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 10/26/2020] [Indexed: 12/20/2022] Open
Abstract
Silibinin (SIL), a natural flavonolignan from the milk thistle (Silybum marianum), is known to exhibit remarkable hepatoprotective, antineoplastic and EMT inhibiting effects in different cancer cells by targeting multiple molecular targets and pathways. However, the predominant majority of previous studies investigated effects of this phytocompound in a one particular cell line. Here, we carry out a systematic analysis of dose-dependent viability response to SIL in five non-small cell lung cancer (NSCLC) lines that gradually differ with respect to their intrinsic EMT stage. By correlating gene expression profiles of NSCLC cell lines with the pattern of their SIL IC50 response, a group of cell cycle, survival and stress responsive genes, including some prominent targets of STAT3 (BIRC5, FOXM1, BRCA1), was identified. The relevancy of these computationally selected genes to SIL viability response of NSCLC cells was confirmed by the transient knockdown test. In contrast to other EMT-inhibiting compounds, no correlation between the SIL IC50 and the intrinsic EMT stage of NSCLC cells was observed. Our experimental results show that SIL viability response of differently constituted NSCLC cells is linked to a subnetwork of tightly interconnected genes whose transcriptomic pattern can be used as a benchmark for assessment of individual SIL sensitivity instead of the conventional EMT signature. Insights gained in this study pave the way for optimization of customized adjuvant therapy of malignancies using Silibinin.
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Affiliation(s)
- Jagan Mohan Kaipa
- Helmholtz Center for Infection Research, Braunschweig, Germany.,BioQuant, University Heidelberg, Heidelberg, Germany.,Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany
| | - Vytaute Starkuviene
- BioQuant, University Heidelberg, Heidelberg, Germany.,Institute of Biosciences, Vilnius University Life Science Center, Vilnius, Lithuania
| | - Holger Erfle
- BioQuant, University Heidelberg, Heidelberg, Germany
| | - Roland Eils
- Center for Digital Health, Berlin Institute of Health and Charité Universitätsmedizin Berlin, Berlin, Germany.,Health Data Science Unit, Heidelberg University Hospital, Heidelberg, Germany
| | - Evgeny Gladilin
- BioQuant, University Heidelberg, Heidelberg, Germany.,Leibniz Institute of Plant Genetics and Crop Plant Research, Seeland, Germany.,Applied Bioinformatics, German Cancer Research Center, Heidelberg, Germany
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18
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Beyoğlu D, Idle JR. Metabolomic insights into the mode of action of natural products in the treatment of liver disease. Biochem Pharmacol 2020; 180:114171. [DOI: 10.1016/j.bcp.2020.114171] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 07/19/2020] [Accepted: 07/20/2020] [Indexed: 02/08/2023]
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19
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Zhao Q, Peng C, Zheng C, He XH, Huang W, Han B. Recent Advances in Characterizing Natural Products that Regulate Autophagy. Anticancer Agents Med Chem 2020; 19:2177-2196. [PMID: 31749434 DOI: 10.2174/1871520619666191015104458] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 11/16/2018] [Accepted: 08/26/2019] [Indexed: 02/07/2023]
Abstract
Autophagy, an intricate response to nutrient deprivation, pathogen infection, Endoplasmic Reticulum (ER)-stress and drugs, is crucial for the homeostatic maintenance in living cells. This highly regulated, multistep process has been involved in several diseases including cardiovascular and neurodegenerative diseases, especially in cancer. It can function as either a promoter or a suppressor in cancer, which underlines the potential utility as a therapeutic target. In recent years, increasing evidence has suggested that many natural products could modulate autophagy through diverse signaling pathways, either inducing or inhibiting. In this review, we briefly introduce autophagy and systematically describe several classes of natural products that implicated autophagy modulation. These compounds are of great interest for their potential activity against many types of cancer, such as ovarian, breast, cervical, pancreatic, and so on, hoping to provide valuable information for the development of cancer treatments based on autophagy.
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Affiliation(s)
- Qian Zhao
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Chengdu 611137, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Chengdu 611137, China
| | - Chuan Zheng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Chengdu 611137, China
| | - Xiang-Hong He
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Chengdu 611137, China
| | - Wei Huang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Chengdu 611137, China
| | - Bo Han
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Chengdu 611137, China.,The RNA Institute, University at Albany, State University of New York, Albany, NY 12222, United States
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20
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Fan Y, Hou T, Dan W, Liu T, Luan J, Liu B, Li L, Zeng J. Silibinin inhibits epithelial‑mesenchymal transition of renal cell carcinoma through autophagy‑dependent Wnt/β‑catenin signaling. Int J Mol Med 2020; 45:1341-1350. [PMID: 32323735 PMCID: PMC7138295 DOI: 10.3892/ijmm.2020.4521] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Accepted: 01/22/2020] [Indexed: 01/07/2023] Open
Abstract
Silibinin is a flavonoid extracted from milk thistle seeds which has been widely used as a hepatoprotective and antioxidant agent. Recently, accumulating evidence has demonstrated the anti-cancer effects of silibinin in various cancer models. It was previously reported that silibinin induced apoptosis and decreased metastasis by activating autophagy in renal cell carcinoma (RCC). However, the underlying molecular mechanisms by which silibinin regulates autophagy remain largely unknown. The aim of the present study was to investigate the effects of silibinin on RCC metastasis in vitro and in vivo, with a focus on autophagy-dependent Wnt/β-catenin signaling. Human RCC 786-O and ACHN cell lines were used as the model system in vitro and RCC xenografts of nude mice were used for in vivo studies. Silibinin inhibited metastasis and epithelial-mesenchymal transition (EMT) of RCC in vitro and in vivo, by regulating the Wnt/β-catenin signaling pathway. Furthermore, silibinin inhibited the Wnt/β-catenin signaling pathway in an autophagy-dependent manner. Autophagic degradation of β-catenin induced by silibinin was associated with the anti-metastatic effects of silibinin against RCC. These findings identify a novel mechanism by which silibinin inhibits EMT and metastasis of RCC, highlighting a potential novel strategy for treating metastatic RCC.
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Affiliation(s)
- Yizeng Fan
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Tao Hou
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Weichao Dan
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Tianjie Liu
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Jiaxin Luan
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Bo Liu
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Lei Li
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Jin Zeng
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
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21
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Zhang X, Jiang J, Chen Z, Cao M. Silibinin inhibited autophagy and mitochondrial apoptosis in pancreatic carcinoma by activating JNK/SAPK signaling. Pathol Res Pract 2019; 215:152530. [PMID: 31351801 DOI: 10.1016/j.prp.2019.152530] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 06/12/2019] [Accepted: 07/05/2019] [Indexed: 02/02/2023]
Abstract
BACKGROUND Previous investigation have indicated Silibinin induces apoptosis and JNK/SAPK in human pancreatic cancer cells. This study aims to evaluate the further mechanism of Silibinin in pancreatic cancer treatment. MATERIALS AND METHODS Human pancreatic cancer cell lines SW1990 was treated with Silibinin and/or JNK/SAPK inhibitor SP600125 followed by measurement of cell viability, apoptosis, autophagy, ROS and ATP, and western blotting. RESULTS Silibinin promoted cell viability and promoted cell apoptosis. The expression of ROS and ATP associated with mitochondrial function was also promoted by the treatment of silibinin. Silibinin also promoted autophagy in pancreatic cancer cells. All these biological effects of Silibinin can be reversed by JNK/SAPK inhibitor. CONCLUSIONS The biological effects regulated by Silibinin can be mediated by JNK/SAPK signaling. This provides a solid theoretical basis for the role of Silibinin in the treatment of pancreatic cancer.
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Affiliation(s)
- Xiaokai Zhang
- Department of General Surgery, The First People's Hospital of Nanyang City, Nanyang, Henan 473000, China.
| | - Jianwei Jiang
- Department of Biochemistry, Medical College, Jinan University, Guangzhou, Guangdong 510630, China
| | - Zhiwei Chen
- Department of General Surgery, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong 510630, China
| | - Mingrong Cao
- Department of General Surgery, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong 510630, China.
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22
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Montal ED, Bhalla K, Dewi RE, Ruiz CF, Haley JA, Ropell AE, Gordon C, Haley JD, Girnun GD. Inhibition of phosphoenolpyruvate carboxykinase blocks lactate utilization and impairs tumor growth in colorectal cancer. Cancer Metab 2019; 7:8. [PMID: 31388420 PMCID: PMC6670241 DOI: 10.1186/s40170-019-0199-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 06/13/2019] [Indexed: 11/10/2022] Open
Abstract
Background Metabolic reprogramming is a key feature of malignant cells. While glucose is one of the primary substrates for malignant cells, cancer cells also display a remarkable metabolic flexibility. Depending on nutrient availability and requirements, cancer cells will utilize alternative fuel sources to maintain the TCA cycle for bioenergetic and biosynthetic requirements. Lactate was typically viewed as a passive byproduct of cancer cells. However, studies now show that lactate is an important substrate for the TCA cycle in breast, lung, and pancreatic cancer. Methods Metabolic analysis of colorectal cancer (CRC) cells was performed using a combination of bioenergetic analysis and 13C stable isotope tracing. Results We show here that CRC cells use lactate to fuel the TCA cycle and promote growth especially under nutrient-deprived conditions. This was mediated in part by maintaining cellular bioenergetics. Therefore targeting the ability of cancer cells to utilize lactate via the TCA cycle would have a significant therapeutic benefit. Phosphoenolpyruvate carboxykinase (PEPCK) is an important cataplerotic enzyme that promotes TCA cycle activity in CRC cells. Treatment of CRC cells with low micromolar doses of a PEPCK inhibitor (PEPCKi) developed for diabetes decreased cell proliferation and utilization of lactate by the TCA cycle in vitro and in vivo. Mechanistically, we observed that the PEPCKi increased nutrient stress as determined by decreased cellular bioenergetics including decreased respiration, ATP levels, and increased AMPK activation. 13C stable isotope tracing showed that the PEPCKi decreased the incorporation of lactate into the TCA cycle. Conclusions These studies highlight lactate as an important substrate for CRC and the use of PEPCKi as a therapeutic approach to target lactate utilization in CRC cells.
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Affiliation(s)
- Emily D Montal
- 1Department of Pharmacological Sciences, Stony Brook University, 100 Nicolls Rd, Stony Brook, NY 11794 USA.,2Department of Pathology, Stony Brook University School of Medicine, 100 Nicolls Rd, Stony Brook, NY 11794 USA
| | - Kavita Bhalla
- 3Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, 22 S Greene St, Baltimore, MD 21201 USA
| | - Ruby E Dewi
- 4Stanford University, 450 Serra Mall, Stanford, CA 94305 USA
| | - Christian F Ruiz
- 2Department of Pathology, Stony Brook University School of Medicine, 100 Nicolls Rd, Stony Brook, NY 11794 USA
| | - John A Haley
- 2Department of Pathology, Stony Brook University School of Medicine, 100 Nicolls Rd, Stony Brook, NY 11794 USA
| | - Ashley E Ropell
- 2Department of Pathology, Stony Brook University School of Medicine, 100 Nicolls Rd, Stony Brook, NY 11794 USA
| | - Chris Gordon
- 2Department of Pathology, Stony Brook University School of Medicine, 100 Nicolls Rd, Stony Brook, NY 11794 USA
| | - John D Haley
- 2Department of Pathology, Stony Brook University School of Medicine, 100 Nicolls Rd, Stony Brook, NY 11794 USA
| | - Geoffrey D Girnun
- 1Department of Pharmacological Sciences, Stony Brook University, 100 Nicolls Rd, Stony Brook, NY 11794 USA.,2Department of Pathology, Stony Brook University School of Medicine, 100 Nicolls Rd, Stony Brook, NY 11794 USA.,5Department of Pathology, Stony Brook University, 101 Nicolls Rd, BST Level 9, Room 191, Stony Brook, NY 11794 USA
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23
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Yu Y, Li LF, Tao J, Zhou XM, Xu C. Silibinin induced apoptosis of human epidermal cancer A431 cells by promoting mitochondrial NOS. Free Radic Res 2019; 53:714-726. [DOI: 10.1080/10715762.2019.1603376] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Yang Yu
- Life Science and Biology Pharmacy College, Shenyang Pharmaceutical University, Shenyang, PR China
| | - Lan-fang Li
- Life Science and Biology Pharmacy College, Shenyang Pharmaceutical University, Shenyang, PR China
| | - Jing Tao
- Life Science and Biology Pharmacy College, Shenyang Pharmaceutical University, Shenyang, PR China
| | - Xiao-mian Zhou
- Life Science and Biology Pharmacy College, Shenyang Pharmaceutical University, Shenyang, PR China
| | - Cheng Xu
- Life Science and Biology Pharmacy College, Shenyang Pharmaceutical University, Shenyang, PR China
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Hossainzadeh S, Ranji N, Naderi Sohi A, Najafi F. Silibinin encapsulation in polymersome: A promising anticancer nanoparticle for inducing apoptosis and decreasing the expression level of miR-125b/miR-182 in human breast cancer cells. J Cell Physiol 2019; 234:22285-22298. [PMID: 31073992 DOI: 10.1002/jcp.28795] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 04/12/2019] [Accepted: 04/17/2019] [Indexed: 12/13/2022]
Abstract
Silibinin, a polyphenolic flavonolignan, is well-known as a safe therapeutic drug without any side effects in the treatment of many malignancies especially cancerous cells. In this study, to overcome problems such as low solubility of silibinin and to enhance its delivery to cancerous cells, we encapsulated silibinin in polymersome nanoparticles. Physicochemical measurements such as dynamic light scattering, transmission electron microscopy, scanning electron microscopy, and atomic force microscopy confirmed the proper encapsulation of silibinin in nanoparticles. Furthermore, antiproliferative and apoptotic activities of silibinin encapsulated in polymersome nanoparticles (SPNs) on MDA-MB-231 breast cancer cell line were validated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, Annexin V/Propidium Iodide measurement, and cell cycle analysis. In addition, quantitative reverse transcription polymerase chain reaction analysis confirmed that SPNs can repress oncogenic microRNAs (miRNAs) such as miR-125b and miR-182, as well as antiapoptotic genes such as Bcl2. SPNs can also induce overexpression of proapoptotic target genes such as P53, CASP9, and BAX directly and/or indirectly (through regulation of miRNAs). Our results suggested that polymersomes can be used as stable carriers in nano-dimensions and SPNs can be considered as a promising pharmacological agent for cancer therapy.
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Affiliation(s)
- Samaneh Hossainzadeh
- Department of Biology, Faculty of Sciences, Rasht Branch, Islamic Azad University, Rasht, Iran
| | - Najmeh Ranji
- Department of Biology, Faculty of Sciences, Rasht Branch, Islamic Azad University, Rasht, Iran
| | - Alireza Naderi Sohi
- Nanotechnology and Tissue Engineering, Stem Cell Technology Research Center, Tehran, Iran
| | - Farhood Najafi
- Department of Resin and Additives, Institute for Color Science and Technology, Tehran, Iran
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25
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Wu Y, Tang L, Wang B, Sun Q, Zhao P, Li W. The role of autophagy in maintaining intestinal mucosal barrier. J Cell Physiol 2019; 234:19406-19419. [PMID: 31020664 DOI: 10.1002/jcp.28722] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 03/23/2019] [Accepted: 04/02/2019] [Indexed: 12/12/2022]
Abstract
The intestinal mucosal barrier is the first line to defense against luminal content penetration and performs numerous biological functions. The intestinal epithelium contains a huge surface that is lined by a monolayer of intestinal epithelial cells (IECs). IECs are dominant mediators in maintaining intestinal homeostasis that drive diverse functions including nutrient absorption, physical segregation, secretion of antibacterial peptides, and modulation of immune responses. Autophagy is a cellular self-protection mechanism in response to various stresses, and accumulating studies have revealed its importance in participating physiological processes of IECs. The regulatory effects of autophagy depend on the specific IEC types. This review aims to elucidate the myriad roles of autophagy in regulating the functions of different IECs (stem cells, enterocytes, goblet cells, and Paneth cells), and present the progress of autophagy-targeting therapy in intestinal diseases. Understanding the involved mechanisms can provide new preventive and therapeutic strategies for gastrointestinal dysfunction and diseases.
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Affiliation(s)
- Yanping Wu
- Key Laboratory of Molecular Animal Nutrition of the Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Li Tang
- Key Laboratory of Molecular Animal Nutrition of the Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Baikui Wang
- Key Laboratory of Molecular Animal Nutrition of the Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Qiming Sun
- Department of Biochemistry, School of Medicine, Zhejiang University, Hangzhou, China
| | - Pengwei Zhao
- Department of Biochemistry, School of Medicine, Zhejiang University, Hangzhou, China
| | - Weifen Li
- Key Laboratory of Molecular Animal Nutrition of the Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou, China
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26
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Giampieri F, Afrin S, Forbes-Hernandez TY, Gasparrini M, Cianciosi D, Reboredo-Rodriguez P, Varela-Lopez A, Quiles JL, Battino M. Autophagy in Human Health and Disease: Novel Therapeutic Opportunities. Antioxid Redox Signal 2019; 30:577-634. [PMID: 29943652 DOI: 10.1089/ars.2017.7234] [Citation(s) in RCA: 89] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
SIGNIFICANCE In eukaryotes, autophagy represents a highly evolutionary conserved process, through which macromolecules and cytoplasmic material are degraded into lysosomes and recycled for biosynthetic or energetic purposes. Dysfunction of the autophagic process has been associated with the onset and development of many human chronic pathologies, such as cardiovascular, metabolic, and neurodegenerative diseases as well as cancer. Recent Advances: Currently, comprehensive research is being carried out to discover new therapeutic agents that are able to modulate the autophagic process in vivo. Recent evidence has shown that a large number of natural bioactive compounds are involved in the regulation of autophagy by modulating several transcriptional factors and signaling pathways. CRITICAL ISSUES Critical issues that deserve particular attention are the inadequate understanding of the complex role of autophagy in disease pathogenesis, the limited availability of therapeutic drugs, and the lack of clinical trials. In this context, the effects that natural bioactive compounds exert on autophagic modulation should be clearly highlighted, since they depend on the type and stage of the pathological conditions of diseases. FUTURE DIRECTIONS Research efforts should now focus on understanding the survival-supporting and death-promoting roles of autophagy, how natural compounds interact exactly with the autophagic targets so as to induce or inhibit autophagy and on the evaluation of their pharmacological effects in a more in-depth and mechanistic way. In addition, clinical studies on autophagy-inducing natural products are strongly encouraged, also to highlight some fundamental aspects, such as the dose, the duration, and the possible synergistic action of these compounds with conventional therapy.
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Affiliation(s)
- Francesca Giampieri
- 1 Dipartimento di Scienze Cliniche Specialistiche ed Odontostomatologiche-Sez. Biochimica , Facoltà di Medicina, Università Politecnica delle Marche , Ancona, Italy
| | - Sadia Afrin
- 1 Dipartimento di Scienze Cliniche Specialistiche ed Odontostomatologiche-Sez. Biochimica , Facoltà di Medicina, Università Politecnica delle Marche , Ancona, Italy
| | - Tamara Y Forbes-Hernandez
- 1 Dipartimento di Scienze Cliniche Specialistiche ed Odontostomatologiche-Sez. Biochimica , Facoltà di Medicina, Università Politecnica delle Marche , Ancona, Italy .,2 Area de Nutricion y Salud, Universidad Internacional Iberoamericana , Campeche, Mexico
| | - Massimiliano Gasparrini
- 1 Dipartimento di Scienze Cliniche Specialistiche ed Odontostomatologiche-Sez. Biochimica , Facoltà di Medicina, Università Politecnica delle Marche , Ancona, Italy
| | - Danila Cianciosi
- 1 Dipartimento di Scienze Cliniche Specialistiche ed Odontostomatologiche-Sez. Biochimica , Facoltà di Medicina, Università Politecnica delle Marche , Ancona, Italy
| | - Patricia Reboredo-Rodriguez
- 1 Dipartimento di Scienze Cliniche Specialistiche ed Odontostomatologiche-Sez. Biochimica , Facoltà di Medicina, Università Politecnica delle Marche , Ancona, Italy .,3 Departamento de Quimica Analıtica y Alimentaria, Grupo de Nutricion y Bromatologıa, Universidade Vigo , Ourense, Spain
| | - Alfonso Varela-Lopez
- 1 Dipartimento di Scienze Cliniche Specialistiche ed Odontostomatologiche-Sez. Biochimica , Facoltà di Medicina, Università Politecnica delle Marche , Ancona, Italy
| | - Jose L Quiles
- 4 Department of Physiology, Institute of Nutrition and Food Technology "Jose Mataix," Biomedical Research Centre, University of Granada , Granada, Spain
| | - Maurizio Battino
- 1 Dipartimento di Scienze Cliniche Specialistiche ed Odontostomatologiche-Sez. Biochimica , Facoltà di Medicina, Università Politecnica delle Marche , Ancona, Italy .,5 Centre for Nutrition and Health, Universidad Europea del Atlantico (UEA) , Santander, Spain
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27
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The role of autophagy in colitis-associated colorectal cancer. Signal Transduct Target Ther 2018; 3:31. [PMID: 30510778 PMCID: PMC6265276 DOI: 10.1038/s41392-018-0031-8] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 10/04/2018] [Accepted: 10/17/2018] [Indexed: 12/12/2022] Open
Abstract
Autophagy is an evolutionarily conserved catabolic process that eliminates harmful components through lysosomal degradation. In addition to its role in maintaining cellular homeostasis, autophagy is critical to pathological processes, such as inflammation and cancer. Colitis-associated colorectal cancer (CAC) is a specific type of colorectal cancer that develops from long-standing colitis in inflammatory bowel disease (IBD) patients. Accumulating evidence indicates that autophagy of microenvironmental cells plays different but vital roles during tumorigenesis and CAC development. Herein, after summarizing the recent advances in understanding the role of autophagy in regulating the tumor microenvironment during different CAC stages, we draw the following conclusions: autophagy in intestinal epithelial cells inhibits colitis and CAC initiation but promotes CAC progression; autophagy in macrophages inhibits colitis, but its function on CAC is currently unclear; autophagy in neutrophils and cancer-associated fibroblasts (CAFs) promotes both colitis and CAC; autophagy in dendritic cells (DCs) and T cells represses both colitis and CAC; autophagy in natural killer cells (NKs) inhibits colitis, but promotes CAC; and autophagy in endothelial cells plays a controversial role in colitis and CAC. Understanding the role of autophagy in specific compartments of the tumor microenvironment during different stages of CAC may provide insight into malignant transformation, tumor progression, and combination therapy strategies for CAC.
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28
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Chakrabarty S, Kabekkodu SP, Singh RP, Thangaraj K, Singh KK, Satyamoorthy K. Mitochondria in health and disease. Mitochondrion 2018; 43:25-29. [PMID: 29944924 DOI: 10.1016/j.mito.2018.06.006] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Accepted: 06/21/2018] [Indexed: 12/20/2022]
Abstract
Mitochondrial biology has become an area of intense research owing to the unique physiology of the organelle and its role in several types of cancers and other disorders. It has been found that mitochondria-encoded proteins, mitochondrial DNA and even RNA influence the functioning of the cell in more ways than were previously imagined. This may contribute to disease phenotypes which require detailed investigation and communication to the community health care providers. Additionally, this provides several novel avenues in drug designing against various cancers, neurodegenerative diseases and other metabolic disorders. The sixth annual conference of the Society for Mitochondrial Research and Medicine - India (SMRM) titled, 'Mitochondria in Health and Disease' was organized by Rana P. Singh at the School of Life Sciences, Jawaharlal Nehru University in New Delhi, India from 10th to 11th February 2017. The underlying objective of the conference was to provide a platform to discuss the recent advances in basic and translational research in mitochondrial biology and diseases. The conference aimed to translate academic research into clinical practice by providing a forum for basic researchers and clinicians to share their knowledge and build collaborations towards development of advanced therapeutic in mitochondrial diseases. To facilitate the knowledge-sharing, six major themes for the scientific sessions were (1) understanding of mitochondrial biology in disease progression, (2) advances in basic and translational mitochondrial research, (3) mitochondria in evolution and development, (4) targeting mitochondria for cancer prevention and treatment, (5) mitochondria in metabolic and neurological disorders and (6) mitochondria in stem cell and regeneration biology. This report summarizes the major outcomes of the discussions at the conference.
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Affiliation(s)
- Sanjiban Chakrabarty
- Department of Cell and Molecular Biology, School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, India
| | - Shama Prasada Kabekkodu
- Department of Cell and Molecular Biology, School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, India
| | - Rana P Singh
- School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India
| | - K Thangaraj
- CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500007, India
| | - Keshav K Singh
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Environmental Health, University of Alabama at Birmingham, Birmingham, AL, USA; Birmingham Veterans Affairs Medical Center, Birmingham, AL, USA
| | - Kapaettu Satyamoorthy
- Department of Cell and Molecular Biology, School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, India.
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29
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Guerra AR, Duarte MF, Duarte IF. Targeting Tumor Metabolism with Plant-Derived Natural Products: Emerging Trends in Cancer Therapy. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2018; 66:10663-10685. [PMID: 30227704 DOI: 10.1021/acs.jafc.8b04104] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Recognition of neoplastic metabolic reprogramming as one of cancer's hallmarks has paved the way for developing novel metabolism-targeted therapeutic approaches. The use of plant-derived natural bioactive compounds for this endeavor is especially promising, due to their diverse structures and multiple targets. Hence, over the past decade, a growing number of studies have assessed the impact of phytochemicals on tumor cell metabolism, aiming at improving current knowledge on their mechanisms of action and, at the same time, evaluating their potential as anti-cancer metabolic modulators. In this Review, we focus on three classes of plant-derived compounds with promising anti-cancer activity-phenolic compounds, isoprenoids, and alkaloids-to describe their effects on major energetic and biosynthetic pathways of human tumor cells. Such a comprehensive and integrated account of the ability of these compounds to hit different metabolic targets is expected to contribute to the rational design and critical assessment of novel anti-cancer therapies based on natural-product-mediated metabolic reprogramming.
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Affiliation(s)
- Angela R Guerra
- Centro de Biotecnologia Agrícola e Agro-Alimentar do Alentejo (CEBAL), Instituto Politécnico de Beja , Apartado 6158 , 7801-908 Beja , Portugal
- CICECO - Instituto de Materiais de Aveiro, Departamento de Quı́mica , Universidade de Aveiro , Campus de Santiago , 3810-193 Aveiro , Portugal
| | - Maria F Duarte
- Centro de Biotecnologia Agrícola e Agro-Alimentar do Alentejo (CEBAL), Instituto Politécnico de Beja , Apartado 6158 , 7801-908 Beja , Portugal
- ICAAM - Instituto de Ciências Agrárias e Ambientais Mediterrânicas , Universidade de Évora , Pólo da Mitra, 7006-554 Évora , Portugal
| | - Iola F Duarte
- CICECO - Instituto de Materiais de Aveiro, Departamento de Quı́mica , Universidade de Aveiro , Campus de Santiago , 3810-193 Aveiro , Portugal
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30
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Autophagy therapeutics: preclinical basis and initial clinical studies. Cancer Chemother Pharmacol 2018; 82:923-934. [PMID: 30225602 DOI: 10.1007/s00280-018-3688-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2018] [Accepted: 09/10/2018] [Indexed: 12/12/2022]
Abstract
Autophagy captures and degrades intracellular components such as proteins and organelles to sustain metabolism and homeostasis. Rapidly accumulating attention is being paid to the role of autophagy in the development of cancer, which makes autophagy attractive tools and targets for novel therapeutic approaches. Functional studies have confirmed that autophagy dysregulation is causal in many cases of cancer, with autophagy acting as tumor suppressors or tumor promoters, and autophagy inhibitor or promoter has shown promise in preclinical studies. The autophagy-targeted therapeutics using chloroquine/hydroxychloroquine have reached clinical development for treating cancer, but these drugs are actually not efficient probably because of a reduced penetration within the tumor. In this review, we first discuss the discoveries related to dual function of autophagy in cancer. Then, we provide an overview of preclinical studies and clinical trials involved in the development of autophagy therapeutics and finally discuss the future of such therapies.
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31
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Zhou J, Fan Y, Zhong J, Huang Z, Huang T, Lin S, Chen H. TAK1 mediates excessive autophagy via p38 and ERK in cisplatin-induced acute kidney injury. J Cell Mol Med 2018; 22:2908-2921. [PMID: 29504713 PMCID: PMC5908118 DOI: 10.1111/jcmm.13585] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2017] [Accepted: 01/24/2018] [Indexed: 12/31/2022] Open
Abstract
The ability of cisplatin (cis-diamminedichloroplatinum II) toxicity to induce acute kidney injury (AKI) has attracted people's attention and concern for a long time, but its molecular mechanisms are still widely unknown. We found that the expression of transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) could be increased in kidneys of mice administrated with cisplatin. Autophagy is an evolutionarily conserved catabolic pathway and is involved in various acute and chronic injuries. Moreover, p38 MAPK (mitogen-activated protein kinase) and ERK regulate autophagy in response to various stimuli. Therefore, our hypothesis is that cisplatin activates TAK1, which phosphorylates p38 and ERK, leading to excessive autophagy of tubular epithelial cells and thus exacerbating kidney damage. Here, BALB/c mice were intraperitoneally injected with a TAK1 inhibitor and were then administrated with sham or cisplatin at 20 mg/kg by intraperitoneal injection. Compared with mice in the vehicle cisplatin group, mice intraperitoneally injected with a TAK1 inhibitor were found to have lower serum creatinine and less tubular damage following cisplatin-induced AKI. Furthermore, inhibition of TAK1 reduced p38 and Erk phosphorylation, decreased expression of LC3II and reversed the down-regulation of P62 expression induced by cisplatin. The hypothesis was verified with tubular epithelial cells administrated with cisplatin in vitro. Finally, p38 inhibitor or ERK inhibitor abated autophagy activation and cell viability reduction in tubular epithelial cells treated with cisplatin plus TAK1 overexpression vector. Taken together, our results show that cisplatin activates TAK1, which phosphorylates p38 and ERK, leading to excessive autophagy of tubular epithelial cells that exacerbates kidney damage.
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Affiliation(s)
- Jun Zhou
- Department of AnesthesiologyThe First People's Hospital of FoshanFoshanChina
| | - Youling Fan
- Department of AnesthesiologyPanyu Central HospitalGuangzhouChina
| | - Jiying Zhong
- Department of AnesthesiologyThe First People's Hospital of FoshanFoshanChina
| | - Zhenxing Huang
- Department of AnesthesiologyThe First People's Hospital of FoshanFoshanChina
| | - Teng Huang
- Department of AnesthesiologyThe First People's Hospital of FoshanFoshanChina
| | - Sen Lin
- Department of AnesthesiologyThe First People's Hospital of FoshanFoshanChina
| | - Hongtao Chen
- Department of AnesthesiologyEighth People's Hospital of GuangzhouGuangzhouChina
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32
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Zheng Z, Xu L, Zhang S, Li W, Tou F, He Q, Rao J, Shen Q. Peiminine inhibits colorectal cancer cell proliferation by inducing apoptosis and autophagy and modulating key metabolic pathways. Oncotarget 2018; 8:47619-47631. [PMID: 28496003 PMCID: PMC5564592 DOI: 10.18632/oncotarget.17411] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Accepted: 03/29/2017] [Indexed: 01/18/2023] Open
Abstract
Peiminine, a compound extracted from the bulbs of Fritillaria thunbergii and traditionally used as a medication in China and other Asian countries, was reported to inhibit colorectal cancer cell proliferation and tumor growth by inducing autophagic cell death. However, its mechanism of anticancer action is not well understood, especially at the metabolic level, which was thought to primarily account for peiminine's efficacy against cancer. Using an established metabolomic profiling platform combining ultra-performance liquid chromatography/tandem mass spectrometry with gas chromatography/mass spectrometry, we identified metabolic alterations in colorectal cancer cell line HCT-116 after peiminine treatment. Among the identified 236 metabolites, the levels of 57 of them were significantly (p < 0.05) different between peiminine-treated and -untreated cells in which 45 metabolites were increased and the other 12 metabolites were decreased. Several of the affected metabolites, including glucose, glutamine, oleate (18:1n9), and lignocerate (24:0), may be involved in regulation of the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway and in the oxidative stress response upon peiminine exposure. Peiminine predominantly modulated the pathways responsible for metabolism of amino acids, carbohydrates, and lipids. Collectively, these results provide new insights into the mechanisms by which peiminine modulates metabolic pathways to inhibit colorectal cancer cell growth, supporting further exploration of peiminine as a potential new strategy for treating colorectal cancer.
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Affiliation(s)
- Zhi Zheng
- Department of Internal Medicine 5th Division, Jiangxi Provincial Key Laboratory of Translational Medicine and Oncology, Jiangxi Cancer Hospital, Jiangxi Cancer Center, Nanchang, 330029, PR China.,School of Graduate Study, Medical College of Nanchang University, Nanchang, 330029, PR China.,Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Liting Xu
- Department of Internal Medicine 5th Division, Jiangxi Provincial Key Laboratory of Translational Medicine and Oncology, Jiangxi Cancer Hospital, Jiangxi Cancer Center, Nanchang, 330029, PR China.,School of Graduate Study, Medical College of Nanchang University, Nanchang, 330029, PR China
| | - Shuofeng Zhang
- Department of Pharmacology, Beijing University of Chinese Medicine, Beijing, 100102, PR China
| | - Wuping Li
- Department of Internal Medicine 5th Division, Jiangxi Provincial Key Laboratory of Translational Medicine and Oncology, Jiangxi Cancer Hospital, Jiangxi Cancer Center, Nanchang, 330029, PR China
| | - Fangfang Tou
- Department of Internal Medicine 5th Division, Jiangxi Provincial Key Laboratory of Translational Medicine and Oncology, Jiangxi Cancer Hospital, Jiangxi Cancer Center, Nanchang, 330029, PR China.,School of Graduate Study, Medical College of Nanchang University, Nanchang, 330029, PR China
| | - Qinsi He
- Department of Internal Medicine 5th Division, Jiangxi Provincial Key Laboratory of Translational Medicine and Oncology, Jiangxi Cancer Hospital, Jiangxi Cancer Center, Nanchang, 330029, PR China.,School of Graduate Study, Medical College of Nanchang University, Nanchang, 330029, PR China
| | - Jun Rao
- Department of Internal Medicine 5th Division, Jiangxi Provincial Key Laboratory of Translational Medicine and Oncology, Jiangxi Cancer Hospital, Jiangxi Cancer Center, Nanchang, 330029, PR China.,School of Graduate Study, Medical College of Nanchang University, Nanchang, 330029, PR China
| | - Qiang Shen
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
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33
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Hou X, Du H, Quan X, Shi L, Zhang Q, Wu Y, Liu Y, Xiao J, Li Y, Lu L, Ai X, Zhan M, Yuan S, Sun L. Silibinin Inhibits NSCLC Metastasis by Targeting the EGFR/LOX Pathway. Front Pharmacol 2018; 9:21. [PMID: 29472856 PMCID: PMC5809401 DOI: 10.3389/fphar.2018.00021] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Accepted: 01/08/2018] [Indexed: 12/16/2022] Open
Abstract
Tumor metastasis is the most lethal and debilitating process that threatens cancer patients. Among the regulators involved in tumor metastasis, lysyl oxidase (LOX) is an important contributor for tumor invasion, migration and the formation of the pre-metastatic niche. Although the relationship between LOX and poor prognosis of lung patients has been preliminary reported, the mechanism remains poorly understood. Here, we found that LOX overexpression is closely related to the survival of lung adenocarcinoma patients but not squamous cell carcinoma patients. Moreover, we confirmed that LOX expression is regulated by the activation of epidermal growth factor receptor (EGFR) via the PI3K/AKT, MEK/ERK, and SAPK/JNK signaling pathways in non-small cell lung cancer (NSCLC). Meanwhile, the study also suggested that the traditional anti-fibrosis drug silibinin inhibited NSCLC cell migration in an EGFR/LOX dependent manner. In addition, an orthotopic implantation metastasis model also confirmed that the EGFR inhibitor WZ4002 and silibinin decreased tumor metastasis through the EGFR/LOX pathway. Altogether, this study revealed that LOX expression is regulated by the EGFR pathway and this may account for the anti-cancer metastasis effects of silibinin, indicating LOX as a potentially therapeutic target for NSCLC treatment.
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Affiliation(s)
- Xiaoying Hou
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China
| | - Hongzhi Du
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China
| | - Xingping Quan
- Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, China
| | - Lei Shi
- Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, China
| | - Qianqian Zhang
- School of Pharmaceutical, Lanzhou University, Lanzhou, China
| | - Yao Wu
- Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, China
| | - Yang Liu
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China
| | - Jing Xiao
- Center of Intervention Radiology, Zhuhai Precision Medicine Center, Zhuhai People's Hospital, Zhuhai, China
| | - Yong Li
- Center of Intervention Radiology, Zhuhai Precision Medicine Center, Zhuhai People's Hospital, Zhuhai, China
| | - Ligong Lu
- Center of Intervention Radiology, Zhuhai Precision Medicine Center, Zhuhai People's Hospital, Zhuhai, China
| | - Xun Ai
- Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, IL, United States
| | - Meixiao Zhan
- Center of Intervention Radiology, Zhuhai Precision Medicine Center, Zhuhai People's Hospital, Zhuhai, China
| | - Shengtao Yuan
- Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, China
| | - Li Sun
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China
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34
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Dilshara MG, Jayasooriya RGPT, Molagoda IMN, Jeong JW, Lee S, Park SR, Kim GY, Choi YH. Silibinin sensitizes TRAIL-mediated apoptosis by upregulating DR5 through ROS-induced endoplasmic reticulum stress-Ca 2+-CaMKII-Sp1 pathway. Oncotarget 2017. [PMID: 29535810 PMCID: PMC5828202 DOI: 10.18632/oncotarget.23129] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
In this study, we addressed how silibinin enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in various cancer cells. Combined treatment with silibinin and TRAIL (silibinin/TRAIL) induced apoptosis accompanied by the activation of caspase-3, caspase-8, caspase-9, and Bax, and cytosolic accumulation of cytochrome c. Anti-apoptotic proteins such as Bcl-2, IAP-1, and IAP-2 were inhibited as well. Silibinin also triggered TRAIL-induced apoptosis in A549 cells through upregulation of death receptor 5 (DR5). Pretreatment with DR5/Fc chimeric protein and DR5-targeted small interfering RNA (siRNA) significantly blocked silibinin/TRAIL-mediated apoptosis in A549 cells. Furthermore, silibinin increased the production of reactive oxygen species (ROS), which led to the induction of TRAIL-mediated apoptosis through DR5 upregulation. Antioxidants such as N-acetyl-L-cysteine and glutathione reversed the apoptosis-inducing effects of TRAIL. Silibinin further induced endoplasmic reticulum (ER) stress as was indicated by the increase in ER marker proteins such as PERK, eIF2α, and ATF-4, which stimulate the expression of CCAAT/enhancer binding protein homologous protein (CHOP). CHOP-targeted siRNA eliminated the induction of DR5 and resulted in a significant decrease in silibinin/TRAIL-mediated apoptosis. We also found that silibinin/TRAIL-induced apoptosis was accompanied with intracellular influx of Ca2+, which was stimulated by ER stress and the Ca2+ chelator, ethylene glycol tetraacetic acid (EGTA). Ca2+/calmodulin-dependent protein kinase (CaMKII) inhibitor, K252a, blocked silibinin/TRAIL-induced DR5 expression along with TRAIL-mediated apoptosis. Accordingly, we showed that ROS/ER stress-induced CaMKII activated Sp1, which is an important transcription factor for DR5 expression. Our results showed that silibinin enhanced TRAIL-induced apoptosis by upregulating DR5 expression through the ROS-ER stress-CaMKII-Sp1 axis.
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Affiliation(s)
| | | | | | - Jin-Woo Jeong
- Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan 47227, Republic of Korea
| | - Seungheon Lee
- Department of Marine Life Sciences, Jeju National University, Jeju 63243, Republic of Korea
| | - Sang Rul Park
- Department of Marine Life Sciences, Jeju National University, Jeju 63243, Republic of Korea
| | - Gi-Young Kim
- Department of Marine Life Sciences, Jeju National University, Jeju 63243, Republic of Korea
| | - Yung Hyun Choi
- Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan 47227, Republic of Korea
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Dionisie V, Clichici S, Ion RM, Danila OO, Moldovan R, Decea N, Gheban D, Olteanu FC, Filip GA. In vivosilymarin’s antioxidant and anti-apoptotic effects on photodynamic therapy’s responsiveness. J PORPHYR PHTHALOCYA 2017. [DOI: 10.1142/s1088424617500304] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Several studies have shown that some anti-oxidant natural compounds in combination with photodynamic therapy (PDT) can enhance the effectiveness of treatment. The aim of this study is to evaluate the effect of silymarin (SIL) in combination with 5,10,15,20-tetra-sulphonato-phenyl-porphyrin (TSPP) based photodynamic therapy, on experimental tumors. 30 Wistar rats with Walker carcinosarcoma, were divided into 6 groups: group 0 (control) — control, untreated group; group 1 (TSPP) — one dose of TSPP; group 2 (SIL) — silymarin; group 3 (PDT) — TSPP and irradiation 24 h after; group 4 (SIL[Formula: see text]PDT) — silymarin, TSPP and irradiation 24 h after; group 5 (SIL[Formula: see text]IR) and group 6 (IR) — irradiation and in addition, group 5 received SIL. Silymarin administered before photodynamic therapy decreased the lipid peroxidation ([Formula: see text] < 0.05) and modulated the antioxidant defense in tumor treated with PDT and silymarin suggesting that silymarin administration along with photodynamic therapy has an anti-oxidant effect. The caspase — 8 level and -3 activity increased in PDT and PDT [Formula: see text] SIL groups compared to the control; between the two groups there was a significant difference in term of apoptosis in favor to PDT. In conclusion, silymarin administration inhibited the reactive oxygen species generation and reduced the tumoral cells’ apoptosis, suggesting that natural compound administered before photodynamic therapy did not improve the therapy’s effect.
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Affiliation(s)
- Vlad Dionisie
- Department of Physiology, “Iuliu Hatieganu” University of Medicine and Pharmacy, 1 Clinicilor Street, 400006 Cluj-Napoca, Romania
| | - Simona Clichici
- Department of Physiology, “Iuliu Hatieganu” University of Medicine and Pharmacy, 1 Clinicilor Street, 400006 Cluj-Napoca, Romania
| | - Rodica M. Ion
- National Research and Development Institute for Chemistry and Petrochemistry, ICECHIM, 202 Splaiul, Independentei, 060021 Bucharest, Romania
| | - Oana O. Danila
- Department of Physiology, “Iuliu Hatieganu” University of Medicine and Pharmacy, 1 Clinicilor Street, 400006 Cluj-Napoca, Romania
| | - Remus Moldovan
- Department of Physiology, “Iuliu Hatieganu” University of Medicine and Pharmacy, 1 Clinicilor Street, 400006 Cluj-Napoca, Romania
| | - Nicoleta Decea
- Department of Physiology, “Iuliu Hatieganu” University of Medicine and Pharmacy, 1 Clinicilor Street, 400006 Cluj-Napoca, Romania
| | - Dan Gheban
- Department of Morphopathology, “Iuliu Hatieganu” University of Medicine and Pharmacy, 35 Clinicilor Street, 400006 Cluj-Napoca, Romania
| | - Florin Catalin Olteanu
- Industrial Engineering and Management Department, Transylvania University, 29 Eroilor Boulevard, 500036, Brasov, Romania
| | - Gabriela A. Filip
- Department of Physiology, “Iuliu Hatieganu” University of Medicine and Pharmacy, 1 Clinicilor Street, 400006 Cluj-Napoca, Romania
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Russo GL, Tedesco I, Spagnuolo C, Russo M. Antioxidant polyphenols in cancer treatment: Friend, foe or foil? Semin Cancer Biol 2017; 46:1-13. [PMID: 28511887 DOI: 10.1016/j.semcancer.2017.05.005] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Revised: 04/18/2017] [Accepted: 05/08/2017] [Indexed: 02/07/2023]
Abstract
Cancer prevention can be probably obtained with easier, faster and less financial strains by pursuing educational programs aimed to induce changes in lifestyle, starting from dietary habits. In the past decades, observational and case-control studies tried to establish a functional relationship between cancer mortality and morbidity and diet. The field becomes even more intricate when scientists investigated which dietary components are responsible for the putative, protective effects of fruits and vegetables against cancer. A relevant part of the literature focused on the positive role of "antioxidant" compounds in foods, including polyphenols. The present review critically evaluate clinical and pre-clinical studies based on polyphenol administration, which contributed to support the concept, deeply rooted in the general population, that antioxidant polyphenols can fight cancer. The controversial and contradictory issues related to the pros and cons on the use of polyphenols against cancer reflect the confounding assumption that cancer treatment and cancer prevention may overlap. We conclude that a clear cut must be done between these two concepts and that the experimental approaches to investigate one or the other should be significantly different, starting from adequate and specifically selected cellular models.
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Affiliation(s)
- Gian Luigi Russo
- Institute of Food Sciences, National Research Council, 83100, Avellino, Italy.
| | - Idolo Tedesco
- Institute of Food Sciences, National Research Council, 83100, Avellino, Italy
| | - Carmela Spagnuolo
- Institute of Food Sciences, National Research Council, 83100, Avellino, Italy
| | - Maria Russo
- Institute of Food Sciences, National Research Council, 83100, Avellino, Italy
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Autophagy Induced by Areca Nut Extract Contributes to Decreasing Cisplatin Toxicity in Oral Squamous Cell Carcinoma Cells: Roles of Reactive Oxygen Species/AMPK Signaling. Int J Mol Sci 2017; 18:ijms18030524. [PMID: 28257034 PMCID: PMC5372540 DOI: 10.3390/ijms18030524] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2017] [Revised: 02/14/2017] [Accepted: 02/22/2017] [Indexed: 02/07/2023] Open
Abstract
Chewing areca nut is closely associated with oral squamous cell carcinoma (OSCC). The current study aimed to investigate potential associations between areca nut extract (ANE) and cisplatin toxicity in OSCC cells. OSCC cells (Cal-27 and Scc-9) viability and apoptosis were analyzed after treatment with ANE and/or cisplatin. The expressions of proteins associated with autophagy and the AMP-activated protein kinase (AMPK) signaling network were evaluated. We revealed that advanced OSCC patients with areca nut chewing habits presented higher LC3 expression and poorer prognosis. Reactive oxygen species (ROS)-mediated autophagy was induced after pro-longed treatment of ANE (six days, 3 μg). Cisplatin toxicity (IC50, 48 h) was decreased in OSCC cells after ANE treatment (six days, 3 μg). Cisplatin toxicity could be enhanced by reversed autophagy by pretreatment of 3-methyladenine (3-MA), N-acetyl-l-cysteine (NAC), or Compound C. Cleaved-Poly-(ADP-ribose) polymerase (cl-PARP) and cleaved-caspase 3 (cl-caspase 3) were downregulated in ANE-treated OSCC cells in the presence of cisplatin, which was also reversed by NAC and Compound C. Collectively, ANE could decrease cisplatin toxicity of OSCC by inducing autophagy, which involves the ROS and AMPK/mTOR signaling pathway.
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Raina K, Kumar D, Agarwal R. Promise of bitter melon (Momordica charantia) bioactives in cancer prevention and therapy. Semin Cancer Biol 2016; 40-41:116-129. [PMID: 27452666 DOI: 10.1016/j.semcancer.2016.07.002] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Revised: 07/15/2016] [Accepted: 07/20/2016] [Indexed: 02/07/2023]
Abstract
Recently, there is a paradigm shift that the whole food-derived components are not 'idle bystanders' but actively participate in modulating aberrant metabolic and signaling pathways in both healthy and diseased individuals. One such whole food from Cucurbitaceae family is 'bitter melon' (Momordica charantia, also called bitter gourd, balsam apple, etc.), which has gained an enormous attention in recent years as an alternative medicine in developed countries. The increased focus on bitter melon consumption could in part be due to several recent pre-clinical efficacy studies demonstrating bitter melon potential to target obesity/type II diabetes-associated metabolic aberrations as well as its pre-clinical anti-cancer efficacy against various malignancies. The bioassay-guided fractionations have also classified the bitter melon chemical constituents based on their anti-diabetic or cytotoxic effects. Thus, by definition, these bitter melon constituents are at cross roads on the bioactivity parameters; they either have selective efficacy for correcting metabolic aberrations or targeting cancer cells, or have beneficial effects in both conditions. However, given the vast, though dispersed, literature reports on the bioactivity and beneficial attributes of bitter melon constituents, a comprehensive review on the bitter melon components and the overlapping beneficial attributes is lacking; our review attempts to fulfill these unmet needs. Importantly, the recent realization that there are common risk factors associated with obesity/type II diabetes-associated metabolic aberrations and cancer, this timely review focuses on the dual efficacy of bitter melon against the risk factors associated with both diseases that could potentially impact the course of malignancy to advanced stages. Furthermore, this review also addresses a significant gap in our knowledge regarding the bitter melon drug-drug interactions which can be predicted from the available reports on bitter melon effects on metabolism enzymes and drug transporters. This has important implications, given that a large proportion of individuals, taking bitter melon based supplements/phytochemical extracts/food based home-remedies, are also likely to be taking conventional therapeutic drugs at the same time. Accordingly, the comprehensively reviewed information here could be prudently translated to the clinical implications associated with any potential concerns regarding bitter melon consumption by cancer patients.
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Affiliation(s)
- Komal Raina
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States; University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States
| | - Dileep Kumar
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States
| | - Rajesh Agarwal
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States; University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States.
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Chinese Herbs Interfering with Cancer Reprogramming Metabolism. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2016; 2016:9282813. [PMID: 27242914 PMCID: PMC4875995 DOI: 10.1155/2016/9282813] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2015] [Accepted: 02/03/2016] [Indexed: 12/11/2022]
Abstract
Emerging evidence promotes a reassessment of metabolic reprogramming regulation in cancer research. Although there exists a long history of Chinese herbs applied in cancer treatment, few reports have addressed the effects of Chinese herbal components on metabolic reprogramming, which is a central cancer hallmark involved in the slowing or prevention of chemoresistance in cancer cells. In this review, we have focused on four core elements altered by metabolic reprogramming in cancer cells. These include glucose transport, glycolysis, mitochondrial oxidative phosphorylation, and fatty acid synthesis. With this focus, we have summarized recent advances in metabolic reprogramming of cancer cells in response to specific Chinese herbal components. We propose that exploring Chinese herbal interference in cancer metabolic reprogramming might identify new therapeutic targets for cancer and more ways in which to approach metabolism-related diseases.
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40
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Unravelling the relationship between macroautophagy and mitochondrial ROS in cancer therapy. Apoptosis 2016; 21:517-31. [DOI: 10.1007/s10495-016-1236-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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FENG NAN, LUO JIANMIN, GUO XIMIN. Silybin suppresses cell proliferation and induces apoptosis of multiple myeloma cells via the PI3K/Akt/mTOR signaling pathway. Mol Med Rep 2016; 13:3243-8. [DOI: 10.3892/mmr.2016.4887] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2015] [Accepted: 10/21/2015] [Indexed: 11/06/2022] Open
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Chu K, Gao G, Yang X, Ren S, Li Y, Wu H, Huang Y, Zhou C. MiR-512-5p induces apoptosis and inhibits glycolysis by targeting p21 in non-small cell lung cancer cells. Int J Oncol 2015; 48:577-86. [PMID: 26648284 DOI: 10.3892/ijo.2015.3279] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2015] [Accepted: 11/12/2015] [Indexed: 11/06/2022] Open
Abstract
MicroRNAs are a family of small non-coding RNAs that constitute a prevalent gene regulation. In this study, we showed the expression of miR-512-5p is downregulated in non-small cell lung cancer (NSCLC) patient tumor samples compared to its paired normal lung tissues. Moreover, expression of miR-512-5p was increased by retinoic acid treatment. Overexpression of miR-512-5p induced apoptosis of NSCLC cell lines A549 and H1299, and miR-512-5p inhibitor reversed this effect in H1299 cells stably expressing miR-512. miR-512-5p inhibited glycolysis and migration in NSCLC cells, but shows no effect on cell proliferation. We identified p21 as a target gene of miR-512-5p. Overexpression of miR-512-5p led to the decrease of p21 protein and mRNA level. Knockdown of p21 resulted in similar effects on apoptosis and glycolysis as that observed of miR-512-5p overexpression, as well as rescued the effect of miR-512-5p inhibitor on cell apoptosis in H1299 cells stably expressing miR-512. In conclusion, our present study revealed miR-512-5p was able to target p21 to induce apoptosis and inhibit glycolysis in A549 and H1299 cell lines.
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Affiliation(s)
- Kaili Chu
- State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200438, P.R. China
| | - Guanghui Gao
- Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Tongji University Cancer Institute, Shanghai 200433, P.R. China
| | - Xiufang Yang
- State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200438, P.R. China
| | - Shengxiang Ren
- Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Tongji University Cancer Institute, Shanghai 200433, P.R. China
| | - Yao Li
- State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200438, P.R. China
| | - Hai Wu
- State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200438, P.R. China
| | - Yan Huang
- State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200438, P.R. China
| | - Caicun Zhou
- Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Tongji University Cancer Institute, Shanghai 200433, P.R. China
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Wang Z, Dabrosin C, Yin X, Fuster MM, Arreola A, Rathmell WK, Generali D, Nagaraju GP, El-Rayes B, Ribatti D, Chen YC, Honoki K, Fujii H, Georgakilas AG, Nowsheen S, Amedei A, Niccolai E, Amin A, Ashraf SS, Helferich B, Yang X, Guha G, Bhakta D, Ciriolo MR, Aquilano K, Chen S, Halicka D, Mohammed SI, Azmi AS, Bilsland A, Keith WN, Jensen LD. Broad targeting of angiogenesis for cancer prevention and therapy. Semin Cancer Biol 2015; 35 Suppl:S224-S243. [PMID: 25600295 PMCID: PMC4737670 DOI: 10.1016/j.semcancer.2015.01.001] [Citation(s) in RCA: 336] [Impact Index Per Article: 33.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2014] [Revised: 12/25/2014] [Accepted: 01/08/2015] [Indexed: 12/20/2022]
Abstract
Deregulation of angiogenesis--the growth of new blood vessels from an existing vasculature--is a main driving force in many severe human diseases including cancer. As such, tumor angiogenesis is important for delivering oxygen and nutrients to growing tumors, and therefore considered an essential pathologic feature of cancer, while also playing a key role in enabling other aspects of tumor pathology such as metabolic deregulation and tumor dissemination/metastasis. Recently, inhibition of tumor angiogenesis has become a clinical anti-cancer strategy in line with chemotherapy, radiotherapy and surgery, which underscore the critical importance of the angiogenic switch during early tumor development. Unfortunately the clinically approved anti-angiogenic drugs in use today are only effective in a subset of the patients, and many who initially respond develop resistance over time. Also, some of the anti-angiogenic drugs are toxic and it would be of great importance to identify alternative compounds, which could overcome these drawbacks and limitations of the currently available therapy. Finding "the most important target" may, however, prove a very challenging approach as the tumor environment is highly diverse, consisting of many different cell types, all of which may contribute to tumor angiogenesis. Furthermore, the tumor cells themselves are genetically unstable, leading to a progressive increase in the number of different angiogenic factors produced as the cancer progresses to advanced stages. As an alternative approach to targeted therapy, options to broadly interfere with angiogenic signals by a mixture of non-toxic natural compound with pleiotropic actions were viewed by this team as an opportunity to develop a complementary anti-angiogenesis treatment option. As a part of the "Halifax Project" within the "Getting to know cancer" framework, we have here, based on a thorough review of the literature, identified 10 important aspects of tumor angiogenesis and the pathological tumor vasculature which would be well suited as targets for anti-angiogenic therapy: (1) endothelial cell migration/tip cell formation, (2) structural abnormalities of tumor vessels, (3) hypoxia, (4) lymphangiogenesis, (5) elevated interstitial fluid pressure, (6) poor perfusion, (7) disrupted circadian rhythms, (8) tumor promoting inflammation, (9) tumor promoting fibroblasts and (10) tumor cell metabolism/acidosis. Following this analysis, we scrutinized the available literature on broadly acting anti-angiogenic natural products, with a focus on finding qualitative information on phytochemicals which could inhibit these targets and came up with 10 prototypical phytochemical compounds: (1) oleanolic acid, (2) tripterine, (3) silibinin, (4) curcumin, (5) epigallocatechin-gallate, (6) kaempferol, (7) melatonin, (8) enterolactone, (9) withaferin A and (10) resveratrol. We suggest that these plant-derived compounds could be combined to constitute a broader acting and more effective inhibitory cocktail at doses that would not be likely to cause excessive toxicity. All the targets and phytochemical approaches were further cross-validated against their effects on other essential tumorigenic pathways (based on the "hallmarks" of cancer) in order to discover possible synergies or potentially harmful interactions, and were found to generally also have positive involvement in/effects on these other aspects of tumor biology. The aim is that this discussion could lead to the selection of combinations of such anti-angiogenic compounds which could be used in potent anti-tumor cocktails, for enhanced therapeutic efficacy, reduced toxicity and circumvention of single-agent anti-angiogenic resistance, as well as for possible use in primary or secondary cancer prevention strategies.
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Affiliation(s)
- Zongwei Wang
- Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
| | - Charlotta Dabrosin
- Department of Oncology, Linköping University, Linköping, Sweden; Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
| | - Xin Yin
- Medicine and Research Services, Veterans Affairs San Diego Healthcare System & University of California, San Diego, San Diego, CA, USA
| | - Mark M Fuster
- Medicine and Research Services, Veterans Affairs San Diego Healthcare System & University of California, San Diego, San Diego, CA, USA
| | - Alexandra Arreola
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
| | - W Kimryn Rathmell
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
| | - Daniele Generali
- Molecular Therapy and Pharmacogenomics Unit, AO Isituti Ospitalieri di Cremona, Cremona, Italy
| | - Ganji P Nagaraju
- Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA
| | - Bassel El-Rayes
- Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA
| | - Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy; National Cancer Institute Giovanni Paolo II, Bari, Italy
| | - Yi Charlie Chen
- Department of Biology, Alderson Broaddus University, Philippi, WV, USA
| | - Kanya Honoki
- Department of Orthopedic Surgery, Arthroplasty and Regenerative Medicine, Nara Medical University, Nara, Japan
| | - Hiromasa Fujii
- Department of Orthopedic Surgery, Arthroplasty and Regenerative Medicine, Nara Medical University, Nara, Japan
| | - Alexandros G Georgakilas
- Physics Department, School of Applied Mathematics and Physical Sciences, National Technical University of Athens, Athens, Greece
| | - Somaira Nowsheen
- Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Elena Niccolai
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Amr Amin
- Department of Biology, College of Science, United Arab Emirate University, United Arab Emirates; Faculty of Science, Cairo University, Cairo, Egypt
| | - S Salman Ashraf
- Department of Chemistry, College of Science, United Arab Emirate University, United Arab Emirates
| | - Bill Helferich
- University of Illinois at Urbana Champaign, Urbana, IL, USA
| | - Xujuan Yang
- University of Illinois at Urbana Champaign, Urbana, IL, USA
| | - Gunjan Guha
- School of Chemical and Bio Technology, SASTRA University, Thanjavur, India
| | - Dipita Bhakta
- School of Chemical and Bio Technology, SASTRA University, Thanjavur, India
| | | | - Katia Aquilano
- Department of Biology, University of Rome "Tor Vergata", Rome, Italy
| | - Sophie Chen
- Ovarian and Prostate Cancer Research Trust Laboratory, Guilford, Surrey, UK
| | | | - Sulma I Mohammed
- Department of Comparative Pathobiology, Purdue University Center for Cancer Research, West Lafayette, IN, USA
| | - Asfar S Azmi
- School of Medicine, Wayne State University, Detroit, MI, USA
| | - Alan Bilsland
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - W Nicol Keith
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Lasse D Jensen
- Department of Medical, and Health Sciences, Linköping University, Linköping, Sweden; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
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Raina K, Kumar S, Dhar D, Agarwal R. Silibinin and colorectal cancer chemoprevention: a comprehensive review on mechanisms and efficacy. J Biomed Res 2015; 30:452-465. [PMID: 27476880 PMCID: PMC5138577 DOI: 10.7555/jbr.30.20150111] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Accepted: 10/12/2015] [Indexed: 02/06/2023] Open
Abstract
Globally, the risk of colorectal cancer (CRC) as well as the incidence of mortality associated with CRC is increasing. Thus, it is imperative that we look at alternative approaches involving intake of non-toxic natural dietary/non-dietary agents, for the prevention of CRC. The ultimate goal of this approach is to reduce the incidence of pre-neoplastic adenomatous polyps and prevent their progression to more advanced forms of CRC, and use these natural agents as a safe intervention strategy during the clinical course of this deadly malignancy. Over the years, pre-clinical studies have shown that silibinin (a flavonolignan isolated from the seeds of milk thistle, Silybum marianum) has strong preventive and therapeutic efficacy against various epithelial cancers, including CRC. The focus of the present review is to provide a comprehensive tabular summary, categorically for an easy accessibility and referencing, pertaining to the efficacy and associated mechanisms of silibinin against CRC growth and progression.
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Affiliation(s)
- Komal Raina
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences.,University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Sushil Kumar
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences
| | - Deepanshi Dhar
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences
| | - Rajesh Agarwal
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences.,University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA;
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Kumar S, Raina K, Agarwal C, Agarwal R. Silibinin strongly inhibits the growth kinetics of colon cancer stem cell-enriched spheroids by modulating interleukin 4/6-mediated survival signals. Oncotarget 2015; 5:4972-89. [PMID: 24970802 PMCID: PMC4148115 DOI: 10.18632/oncotarget.2068] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Involvement of cancer stem cells (CSC) in initiation, progression, relapse, and therapy-resistance of colorectal cancer (CRC) warrants search for small molecules as ‘adjunct-therapy’ to target both colon CSC and bulk tumor population. Herein, we assessed the potential of silibinin to eradicate colon CSC together with associated molecular mechanisms. In studies examining how silibinin modulates dynamics of CSC spheroids in terms of its effect on kinetics of CSC spheroids generated in presence of mitogenic and interleukin (IL)-mediated signaling which provides an autocrine/paracrine amplification loop in CRC, silibinin strongly decreased colon CSC pool together with cell survival of bulk tumor cells. Silibinin effect on colon CSC was mediated via blocking of pro-tumorigenic signaling, notably IL-4/-6 signaling that affects CSC population. These silibinin effects were associated with decreased mRNA and protein levels of various CSC-associated transcription factors, signaling molecules and markers. Furthermore, 2D and 3D differentiation assays indicated formation of more differentiated clones by silibinin. These results highlight silibinin potential to interfere with kinetics of CSC pool by shifting CSC cell division to asymmetric type via targeting various signals associated with the survival and multiplication of colon CSC pool. Together, our findings further support clinical usefulness of silibinin in CRC intervention and therapy.
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Affiliation(s)
- Sushil Kumar
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado. These Authors Contributed equally and share first authorship
| | - Komal Raina
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado. These Authors Contributed equally and share first authorship
| | - Chapla Agarwal
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado. University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Rajesh Agarwal
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado. University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado
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Novel cancer chemotherapy hits by molecular topology: dual Akt and Beta-catenin inhibitors. PLoS One 2015; 10:e0124244. [PMID: 25910265 PMCID: PMC4409212 DOI: 10.1371/journal.pone.0124244] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Accepted: 02/27/2015] [Indexed: 01/12/2023] Open
Abstract
Background and Purpose Colorectal and prostate cancers are two of the most common types and cause of a high rate of deaths worldwide. Therefore, any strategy to stop or at least slacken the development and progression of malignant cells is an important therapeutic choice. The aim of the present work is the identification of novel cancer chemotherapy agents. Nowadays, many different drug discovery approaches are available, but this paper focuses on Molecular Topology, which has already demonstrated its extraordinary efficacy in this field, particularly in the identification of new hit and lead compounds against cancer. This methodology uses the graph theoretical formalism to numerically characterize molecular structures through the so called topological indices. Once obtained a specific framework, it allows the construction of complex mathematical models that can be used to predict physical, chemical or biological properties of compounds. In addition, Molecular Topology is highly efficient in selecting and designing new hit and lead drugs. According to the aforementioned, Molecular Topology has been applied here for the construction of specific Akt/mTOR and β-catenin inhibition mathematical models in order to identify and select novel antitumor agents. Experimental Approach Based on the results obtained by the selected mathematical models, six novel potential inhibitors of the Akt/mTOR and β-catenin pathways were identified. These compounds were then tested in vitro to confirm their biological activity. Conclusion and Implications Five of the selected compounds, CAS n° 256378-54-8 (Inhibitor n°1), 663203-38-1 (Inhibitor n°2), 247079-73-8 (Inhibitor n°3), 689769-86-6 (Inhibitor n°4) and 431925-096 (Inhibitor n°6) gave positive responses and resulted to be active for Akt/mTOR and/or β-catenin inhibition. This study confirms once again the Molecular Topology’s reliability and efficacy to find out novel drugs in the field of cancer.
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Li F, Ma Z, Guan Z, Chen Y, Wu K, Guo P, Wang X, He D, Zeng J. Autophagy induction by silibinin positively contributes to its anti-metastatic capacity via AMPK/mTOR pathway in renal cell carcinoma. Int J Mol Sci 2015; 16:8415-29. [PMID: 25884331 PMCID: PMC4425089 DOI: 10.3390/ijms16048415] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Revised: 03/24/2015] [Accepted: 04/03/2015] [Indexed: 12/12/2022] Open
Abstract
Silibinin, a dietary cancer chemopreventive flavonoid from the seeds of milk thistle, has been reported to exhibit anti-metastatic effects on renal cell carcinoma (RCC), but the mechanism underlying this phenomenon is not fully understood. The present study aimed at examining the potential role of autophagy in regulating silibinin-induced anti-metastatic effects on RCC cells. Using RCC ACHN and 786-O cells as a model system in vitro, we found that silibinin treatment increased the expression of LC3-II, resulted in the formation of autophagolysosome vacuoles, and caused a punctate fluorescence pattern with the monomeric red fluorescence protein-enhanced green fluorescence protein-LC3 (mRFP-EGFP-LC3) protein, which all are markers for cellular autophagy. Autophagy flux was induced by silibinin in RCC cells, as determined by LC3 turnover assay. Mechanically, the adenosine 5'-monophosphate activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway was identified as involved in regulation of silibinin-induced autophagy. Furthermore, autophagy induction was demonstrated to positively contribute to silibinin-induced anti-metastatic effects on RCC cells in vitro. Activation of autophagy enhanced silibinin-induced inhibition of migration and invasion of RCC cells, while inhibition of autophagy attenuated it. These findings thus provide new information about the potential link between autophagy and metastasis inhibition induced by silibinin, and the induction of autophagy may shed some light into future treatment strategies for metastatic RCC.
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Affiliation(s)
- Feng Li
- Department of Urology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
| | - Zhenkun Ma
- Department of Urology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
| | - Zhenfeng Guan
- Department of Urology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
| | - Yule Chen
- Department of Urology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
| | - Kaijie Wu
- Department of Urology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
| | - Peng Guo
- Department of Urology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
| | - Xinyang Wang
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi'an 710061, China.
| | - Dalin He
- Department of Urology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi'an 710061, China.
| | - Jin Zeng
- Department of Urology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
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Prajapati V, Kale RK, Singh RP. Silibinin Combination with Arsenic Strongly Inhibits Survival and Invasiveness of Human Prostate Carcinoma Cells. Nutr Cancer 2015; 67:647-58. [DOI: 10.1080/01635581.2015.1019635] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
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Mi YJ, Geng GJ, Zou ZZ, Gao J, Luo XY, Liu Y, Li N, Li CL, Chen YQ, Yu XY, Jiang J. Dihydroartemisinin inhibits glucose uptake and cooperates with glycolysis inhibitor to induce apoptosis in non-small cell lung carcinoma cells. PLoS One 2015; 10:e0120426. [PMID: 25799586 PMCID: PMC4370589 DOI: 10.1371/journal.pone.0120426] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Accepted: 01/22/2015] [Indexed: 01/16/2023] Open
Abstract
Despite recent advances in the therapy of non-small cell lung cancer (NSCLC), the chemotherapy efficacy against NSCLC is still unsatisfactory. Previous studies show the herbal antimalarial drug dihydroartemisinin (DHA) displays cytotoxic to multiple human tumors. Here, we showed that DHA decreased cell viability and colony formation, induced apoptosis in A549 and PC-9 cells. Additionally, we first revealed DHA inhibited glucose uptake in NSCLC cells. Moreover, glycolytic metabolism was attenuated by DHA, including inhibition of ATP and lactate production. Consequently, we demonstrated that the phosphorylated forms of both S6 ribosomal protein and mechanistic target of rapamycin (mTOR), and GLUT1 levels were abrogated by DHA treatment in NSCLC cells. Furthermore, the upregulation of mTOR activation by high expressed Rheb increased the level of glycolytic metabolism and cell viability inhibited by DHA. These results suggested that DHA-suppressed glycolytic metabolism might be associated with mTOR activation and GLUT1 expression. Besides, we showed GLUT1 overexpression significantly attenuated DHA-triggered NSCLC cells apoptosis. Notably, DHA synergized with 2-Deoxy-D-glucose (2DG, a glycolysis inhibitor) to reduce cell viability and increase cell apoptosis in A549 and PC-9 cells. However, the combination of the two compounds displayed minimal toxicity to WI-38 cells, a normal lung fibroblast cell line. More importantly, 2DG synergistically potentiated DHA-induced activation of caspase-9, -8 and -3, as well as the levels of both cytochrome c and AIF of cytoplasm. However, 2DG failed to increase the reactive oxygen species (ROS) levels elicited by DHA. Overall, the data shown above indicated DHA plus 2DG induced apoptosis was involved in both extrinsic and intrinsic apoptosis pathways in NSCLC cells.
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Affiliation(s)
- Yan-jun Mi
- Department of thoracic surgery, The First Affiliated Hospital of Xiamen University, Xiamen, China
- Department of Medical Oncology, Chenggong Hospital of Xiamen University, Xiamen, China
| | - Guo-jun Geng
- Department of thoracic surgery, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Zheng-zhi Zou
- MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China
| | - Jing Gao
- Department of Head and Neck Surgery, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Xian-yang Luo
- Department of Head and Neck Surgery, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Yu Liu
- Department of thoracic surgery, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Ning Li
- Department of thoracic surgery, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Chun-lei Li
- Department of thoracic surgery, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Yu-qiang Chen
- Department of Medical Oncology, Chenggong Hospital of Xiamen University, Xiamen, China
| | - Xiu-yi Yu
- Department of thoracic surgery, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Jie Jiang
- Department of thoracic surgery, The First Affiliated Hospital of Xiamen University, Xiamen, China
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Derry MM, Somasagara RR, Raina K, Kumar S, Gomez J, Patel M, Agarwal R, Agarwal C. Target identification of grape seed extract in colorectal cancer using drug affinity responsive target stability (DARTS) technique: role of endoplasmic reticulum stress response proteins. Curr Cancer Drug Targets 2015; 14:323-36. [PMID: 24724981 DOI: 10.2174/1568009614666140411101942] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2014] [Revised: 04/10/2014] [Accepted: 04/10/2014] [Indexed: 12/21/2022]
Abstract
Various natural agents, including grape seed extract (GSE), have shown considerable chemopreventive and anti-cancer efficacy against different cancers in pre-clinical studies; however, their specific protein targets are largely unknown and thus, their clinical usefulness is marred by limited scientific evidences about their direct cellular targets. Accordingly, herein, employing, for the first time, the recently developed drug affinity responsive target stability (DARTS) technique, we aimed to profile the potential protein targets of GSE in human colorectal cancer (CRC) cells. Unlike other methods, which can cause chemical alteration of the drug components to allow for detection, this approach relies on the fact that a drug bound protein may become less susceptible to proteolysis and hence the enriched proteins can be detected by Mass Spectroscopy methods. Our results, utilizing the DARTS technique followed by examination of the spectral output by LC/MS and the MASCOT data, revealed that GSE targets endoplasmic reticulum (ER) stress response proteins resulting in overall down regulation of proteins involved in translation and that GSE also causes oxidative protein modifications, specifically on methionine amino acids residues on its protein targets. Corroborating these findings, mechanistic studies revealed that GSE indeed caused ER stress and strongly inhibited PI3k-Akt-mTOR pathway for its biological effects in CRC cells. Furthermore, bioenergetics studies indicated that GSE also interferes with glycolysis and mitochondrial metabolism in CRC cells. Together, the present study identifying GSE molecular targets in CRC cells, combined with its efficacy in vast pre-clinical CRC models, further supports its usefulness for CRC prevention and treatment.
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Affiliation(s)
| | | | | | | | | | | | | | - Chapla Agarwal
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 E. Montview Blvd, C238, Room V20-2118, Aurora, CO 80045, USA.
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