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Peter RM, Sarwar MS, Wang L, Chou P, Wang C, Wang Y, Su X, Kong AN. Dietary phytochemical indole-3-carbinol regulates metabolic reprogramming in mouse prostate tissue. Pharm Res 2025; 42:237-247. [PMID: 39904853 PMCID: PMC11880055 DOI: 10.1007/s11095-025-03820-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 01/08/2025] [Indexed: 02/06/2025]
Abstract
PURPOSE Indole-3-carbinol (I3C) is shown to possess multiple pharmacological activities such as anti-inflammatory, antimicrobial, antioxidant, antiviral, and anti-cancer activities. It is widely accepted as modulator of multiple signaling pathways particularly those related to cell cycle, cell growth and division, angiogenesis, apoptosis and immunity. We explored the metabolic reprogramming based on treatment with I3C in mice prostate tissue. METHODS In this study we utilized Pten knockout (KO)-induced prostate tumorigenesis mouse model to examine mechanism of action of I3C via metabolic rewiring. Phosphatase and tensin homolog deleted on chromosome 10 (Pten), a tumor suppressor gene is frequently found to be mutated or deleted in prostate cancer. Untargeted metabolomics was performed using liquid-chromatography mass-spectrometry (LC-MS) based platform to investigate Pten-dependent and Pten-independent metabolic targets of I3C. RESULTS The most impacted pathways by I3C included pyrimidine metabolism, arginine and proline metabolism, porphyrin metabolism, citrate cycle and lipoic acid metabolism. CONCLUSION These pathways taken together help in understanding the overall health beneficial effects of I3C.
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Affiliation(s)
- Rebecca Mary Peter
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, The State University of New Jersey, RutgersPiscataway, NJ, 08854, USA
- Graduate Program of Pharmaceutical Sciences, Ernest Mario School of Pharmacy, The State University of New Jersey, RutgersPiscataway, NJ, 08854, USA
| | - Md Shahid Sarwar
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, The State University of New Jersey, RutgersPiscataway, NJ, 08854, USA
| | - Lujing Wang
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, The State University of New Jersey, RutgersPiscataway, NJ, 08854, USA
- Graduate Program of Pharmaceutical Sciences, Ernest Mario School of Pharmacy, The State University of New Jersey, RutgersPiscataway, NJ, 08854, USA
| | - Pochung Chou
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, The State University of New Jersey, RutgersPiscataway, NJ, 08854, USA
- Graduate Program of Pharmaceutical Sciences, Ernest Mario School of Pharmacy, The State University of New Jersey, RutgersPiscataway, NJ, 08854, USA
| | - Chao Wang
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, The State University of New Jersey, RutgersPiscataway, NJ, 08854, USA
| | - Yujue Wang
- Metabolomics Shared Resource, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08901, USA
- Department of Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, 08901, USA
| | - Xiaoyang Su
- Metabolomics Shared Resource, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08901, USA
- Department of Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, 08901, USA
| | - Ah-Ng Kong
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, The State University of New Jersey, RutgersPiscataway, NJ, 08854, USA.
- Graduate Program of Pharmaceutical Sciences, Ernest Mario School of Pharmacy, The State University of New Jersey, RutgersPiscataway, NJ, 08854, USA.
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Komatsu R, Fujii R, Ogasawara T, Suzuki-Takahashi Y, Chen S, Sugishita Y, Niki H, Yudoh K. CDK6-Dependent, CDK4-Independent Synovial Hyperplasia in Arthritic Mice and Tumor Necrosis Factor-α-Induced Proliferation of Synovial Fibroblasts. Int J Mol Sci 2025; 26:1151. [PMID: 39940918 PMCID: PMC11817658 DOI: 10.3390/ijms26031151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 01/24/2025] [Accepted: 01/27/2025] [Indexed: 02/16/2025] Open
Abstract
Palbociclib, a dual CDK4/6 kinase inhibitor used for breast cancer, has been explored as a treatment option for rheumatoid arthritis (RA). Preclinical studies have reported palbociclib-induced myelosuppression, but no such effects have been observed in Cdk4 or Cdk6 single-deficient mice. Synoviocyte proliferation-associated in collagen-induced arthritis 1/serum amyloid A-like 1 (SPACIA1/SAAL1) is involved in G1 phase progression. Given that SPACIA1/SAAL1 upregulates CDK6 (but not CDK4) expression, we aimed to determine whether suppressing CDK6 expression alone could prevent synovial hyperplasia without myelosuppression. The effects of CDK6 expression on TNF-α-induced rheumatoid arthritis synovial fibroblast (RASF) proliferation and synovial hyperplasia in collagen-induced arthritis (CIA) mice were investigated by modulating the transcriptional level with a CDK6 expression inhibitor (indole-3-carbinol), CDK6 small interfering RNA (siRNA), and Cdk6-deficient mice. Indole-3-carbinol or CDK6 siRNA inhibited TNF-α-induced RASF proliferation without suppressing CDK4 expression and reduced retinoblastoma protein phosphorylation. In CIA mice, indole-3-carbinol did not cause myelosuppression, considerably delayed CIA onset and progression, and reduced arthritis severity. Cdk6-deficient mice showed similar improvements in CIA pathogenesis but had lower serum anti-type II collagen IgG levels. Notably, synovial hyperplasia was not observed in Cdk6-deficient mice. CIA-synovial hyperplasia depends on CDK6, but not CDK4, expression.
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Affiliation(s)
- Rie Komatsu
- Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki 216-8512, Kanagawa, Japan; (R.K.); (Y.S.-T.); (S.C.); (Y.S.); (K.Y.)
| | - Ryoji Fujii
- Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki 216-8512, Kanagawa, Japan; (R.K.); (Y.S.-T.); (S.C.); (Y.S.); (K.Y.)
| | - Toru Ogasawara
- Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan;
| | - Yuki Suzuki-Takahashi
- Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki 216-8512, Kanagawa, Japan; (R.K.); (Y.S.-T.); (S.C.); (Y.S.); (K.Y.)
| | - Sandy Chen
- Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki 216-8512, Kanagawa, Japan; (R.K.); (Y.S.-T.); (S.C.); (Y.S.); (K.Y.)
| | - Yodo Sugishita
- Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki 216-8512, Kanagawa, Japan; (R.K.); (Y.S.-T.); (S.C.); (Y.S.); (K.Y.)
| | - Hisateru Niki
- Department of Orthopedic Surgery, St. Marianna University School of Medicine, Kawasaki 216-8511, Kanagawa, Japan;
| | - Kazuo Yudoh
- Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki 216-8512, Kanagawa, Japan; (R.K.); (Y.S.-T.); (S.C.); (Y.S.); (K.Y.)
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Kang YM, Kim HM, Lee J, Baek JS, Lee M, An HJ. Indole-3-carbinol alleviates allergic skin inflammation via periostin/thymic stromal lymphopoietin suppression in atopic dermatitis. Chin Med 2024; 19:177. [PMID: 39722037 DOI: 10.1186/s13020-024-01042-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 11/27/2024] [Indexed: 12/28/2024] Open
Abstract
BACKGROUND Atopic dermatitis (AD) is a chronic multifactorial inflammatory skin disorder with a complex etiology. Despite its increasing prevalence, treatment of AD is still limited. Indole-3-carbinol (I3C) is found in cruciferous vegetables and is formed when these vegetables are cut, chewed, or cooked; it exerts diverse pharmacological activities. METHODS HaCaT keratinocytes stimulated with tumor necrosis factor-α and interferon-γ mixture and NC/Nga mice stimulated with 2,4-dinitrochlorobenzen (DNCB) were used for AD models, in vitro and in vivo, respectively. RESULTS The results showed that I3C reduced the expression of pro-inflammatory cytokines, thymic stromal lymphopoietin (TSLP), and periostin in in vitro model. Oral administration of I3C alleviated AD-like skin inflammatory symptoms, including serum IgE levels, epidermal thickening, inflammatory cell infiltration, transepidermal water loss, and scratching behavior. Moreover, I3C decreased the expression of TSLP and periostin and recovered the expression of skin barrier proteins by regulating Aryl Hydrocarbon Receptor and inhibiting the mitogen-activated protein kinase and nuclear factor-κB pathways in the skin of DNCB-induced AD mice. CONCLUSIONS I3C is suggested as a potential therapeutic alternative for the treatment of AD by repressing allergic inflammatory pathways.
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Affiliation(s)
- Yun-Mi Kang
- Department of Herbology, College of Korean Medicine, Sangji University, Wonju, Gangwon-Do, 26339, Republic of Korea
- Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine (KIOM), 70 Cheomdan-Ro, Dong-Gu, Daegu, 41062, Republic of Korea
| | - Hye-Min Kim
- Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, 02447, Republic of Korea
- Department of Herbology, College of Korean Medicine, Sangji University, Wonju, Gangwon-Do, 26339, Republic of Korea
| | - Junho Lee
- Department of Bio-Health Convergence, Kangwon National University, Chuncheon, 24341, Republic of Korea
| | - Jong-Suep Baek
- Department of Bio-Health Convergence, Kangwon National University, Chuncheon, 24341, Republic of Korea
| | - Minho Lee
- Department of Life Science, Dongguk University-Seoul, Ilsandong-Gu, Goyang-Si, 10326, Gyeonggi-do, Republic of Korea.
| | - Hyo-Jin An
- Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, 02447, Republic of Korea.
- Department of Integrated Drug Development and Natural Products, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea.
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Singh V, Shirbhate E, Kore R, Mishra A, Johariya V, Veerasamy R, Tiwari AK, Rajak H. Dietary Plant Metabolites Induced Epigenetic Modification as a Novel Strategy for the Management of Prostate Cancer. Mini Rev Med Chem 2024; 24:1409-1426. [PMID: 38385496 DOI: 10.2174/0113895575283895240207065454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 01/10/2024] [Accepted: 01/19/2024] [Indexed: 02/23/2024]
Abstract
Prostate cancer is a widespread malignancy among men, with a substantial global impact on morbidity and mortality. Despite advances in conventional therapies, the need for innovative and less toxic treatments remains a priority. Emerging evidence suggests that dietary plant metabolites possess epigenetic-modifying properties, making them attractive candidates for prostate cancer treatment. The present work reviews the epigenetic effects of dietary plant metabolites in the context of prostate cancer therapy. We first outline the key epigenetic mechanisms involved in prostate cancer pathogenesis, including histone modifications, DNA methylation, and miRNA or Long Noncoding RNA (lncRNA) dysregulation. Next, we delve into the vast array of dietary plant metabolites that have demonstrated promising anti-cancer effects through epigenetic regulation. Resveratrol, minerals, isothiocyanates, curcumin, tea polyphenols, soy isoflavones and phytoestrogens, garlic compounds, anthocyanins, lycopene, and indoles are among the most extensively studied compounds. These plant-derived bioactive compounds have been shown to influence DNA methylation patterns, histone modifications, and microRNA expression, thereby altering the gene expression allied with prostate cancer progression, cell proliferation, and apoptosis. We also explore preclinical and clinical studies investigating the efficacy of dietary plant metabolites as standalone treatments or in combination with traditional treatments for people with prostate cancer. The present work highlights the potential of dietary plant metabolites as epigenetic modulators to treat prostate cancer. Continued research in this field may pave the way for personalized and precision medicine approaches, moving us closer to the goal of improved prostate cancer management.
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Affiliation(s)
- Vaibhav Singh
- Department of Pharmacy, Guru Ghasidash Vishwavidyalaya University, Bilaspur-495 009, (C.G.), India
| | - Ekta Shirbhate
- Department of Pharmacy, Guru Ghasidash Vishwavidyalaya University, Bilaspur-495 009, (C.G.), India
| | - Rakesh Kore
- Department of Pharmacy, Guru Ghasidash Vishwavidyalaya University, Bilaspur-495 009, (C.G.), India
| | - Aditya Mishra
- Department of Pharmacy, Guru Ghasidash Vishwavidyalaya University, Bilaspur-495 009, (C.G.), India
| | - Varsha Johariya
- Department of Pharmacy, Guru Ghasidash Vishwavidyalaya University, Bilaspur-495 009, (C.G.), India
| | - Ravichandran Veerasamy
- Departement of Pharmaceutical chemistry, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Kedah Darul Aman, Malaysia
| | - Amit K Tiwari
- UAMS College of Pharmacy, College of Pharmacy and Pharmaceutical Sciences, UAMS - University of Arkansas for Medical Sciences, Arkansas, (AR) USA
| | - Harish Rajak
- Department of Pharmacy, Guru Ghasidash Vishwavidyalaya University, Bilaspur-495 009, (C.G.), India
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Kelly R, Aviles D, Krisulevicz C, Hunter K, Krill L, Warshal D, Ostrovsky O. The Effects of Natural Epigenetic Therapies in 3D Ovarian Cancer and Patient-Derived Tumor Explants: New Avenues in Regulating the Cancer Secretome. Biomolecules 2023; 13:1066. [PMID: 37509102 PMCID: PMC10377145 DOI: 10.3390/biom13071066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/26/2023] [Accepted: 06/27/2023] [Indexed: 07/30/2023] Open
Abstract
High mortality rates in ovarian cancer have been linked to recurrence, metastasis, and chemoresistant disease, which are known to involve not only genetic changes but also epigenetic aberrations. In ovarian cancer, adipose-derived stem cells from the omentum (O-ASCs) play a crucial role in supporting the tumor and its tumorigenic microenvironment, further propagating epigenetic abnormalities and dissemination of the disease. Epigallocatechin gallate (EGCG), a DNA methyltransferase inhibitor derived from green tea, and Indole-3-carbinol (I3C), a histone deacetylase inhibitor from cruciferous vegetables, carry promising effects in reprograming aberrant epigenetic modifications in cancer. Therefore, we demonstrate the action of these diet-derived compounds in suppressing the growth of 3D ovarian cancer spheroids or organoids as well as post-treatment cancer recovery through proliferation, migration, invasion, and colony formation assays when compared to the synthetic epigenetic compound Panobinostat with or without standard chemotherapy. Finally, given the regulatory role of the secretome in growth, metastasis, chemoresistance, and relapse of disease, we demonstrate that natural epigenetic compounds can regulate the secretion of protumorigenic growth factors, cytokines, extracellular matrix components, and immunoregulatory markers in human ovarian cancer specimens. While further studies are needed, our results suggest that these treatments could be considered in the future as adjuncts to standard chemotherapy, improving efficiency and patient outcomes.
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Affiliation(s)
- Rebeca Kelly
- Department of Gynecologic Oncology, MD Anderson Cancer Center at Cooper University Hospital, Camden, NJ 08103, USA
| | - Diego Aviles
- Department of Gynecologic Oncology, MD Anderson Cancer Center at Cooper University Hospital, Camden, NJ 08103, USA
| | | | - Krystal Hunter
- Cooper Medical School of Rowan University, Camden, NJ 08103, USA
- Cooper Research Institute, Cooper University Healthcare, Camden, NJ 08103, USA
| | - Lauren Krill
- Department of Gynecologic Oncology, MD Anderson Cancer Center at Cooper University Hospital, Camden, NJ 08103, USA
| | - David Warshal
- Department of Gynecologic Oncology, MD Anderson Cancer Center at Cooper University Hospital, Camden, NJ 08103, USA
| | - Olga Ostrovsky
- Cooper Medical School of Rowan University, Camden, NJ 08103, USA
- Cooper Research Institute, Cooper University Healthcare, Camden, NJ 08103, USA
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Akbar N, Khan NA, Giddey AD, Soares NC, Alharbi AM, Alfahemi H, Siddiqui R. Selected Gut Bacteria from Water Monitor Lizard Exhibit Effects against Pathogenic Acanthamoeba castellanii Belonging to the T4 Genotype. Microorganisms 2023; 11:microorganisms11041072. [PMID: 37110494 PMCID: PMC10142573 DOI: 10.3390/microorganisms11041072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 04/10/2023] [Accepted: 04/17/2023] [Indexed: 04/29/2023] Open
Abstract
Water monitor lizards (WMLs) reside in unhygienic and challenging ecological surroundings and are routinely exposed to various pathogenic microorganisms. It is possible that their gut microbiota produces substances to counter microbial infections. Here we determine whether selected gut bacteria of water monitor lizards (WMLs) possess anti-amoebic properties using Acanthamoeba castellanii of the T4 genotype. Conditioned media (CM) were prepared from bacteria isolated from WML. The CM were tested using amoebicidal, adhesion, encystation, excystation, cell cytotoxicity and amoeba-mediated host cell cytotoxicity assays in vitro. Amoebicidal assays revealed that CM exhibited anti-amoebic effects. CM inhibited both excystation and encystation in A. castellanii. CM inhibited amoebae binding to and cytotoxicity of host cells. In contrast, CM alone showed limited toxic effects against human cells in vitro. Mass spectrometry revealed several antimicrobials, anticancer, neurotransmitters, anti-depressant and other metabolites with biological functions. Overall, these findings imply that bacteria from unusual places, such as WML gut, produce molecules with anti-acanthamoebic capabilities.
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Affiliation(s)
- Noor Akbar
- Department of Clinical Sciences, College of Medicine, University of Sharjah, University City, Sharjah 27272, United Arab Emirates
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Naveed Ahmed Khan
- Department of Clinical Sciences, College of Medicine, University of Sharjah, University City, Sharjah 27272, United Arab Emirates
- Department of Medical Biology, Faculty of Medicine, Istinye University, Istanbul 34010, Turkey
| | - Alexander D Giddey
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Nelson C Soares
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
- Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Ahmad M Alharbi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif 21944, Saudi Arabia
| | - Hasan Alfahemi
- Department of Medical Microbiology, Faculty of Medicine, Al-Baha University, P.O. Box. 1988, Al-Baha 65799, Saudi Arabia
| | - Ruqaiyyah Siddiqui
- Department of Medical Biology, Faculty of Medicine, Istinye University, Istanbul 34010, Turkey
- College of Arts and Sciences, American University of Sharjah, University City, Sharjah 26666, United Arab Emirates
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Wang R, Li Y, Gao J, Luan Y. WRQ-2, a gemcitabine prodrug, reverses gemcitabine resistance caused by hENT1 inhibition. Drug Discov Ther 2022; 16:286-292. [PMID: 36529509 DOI: 10.5582/ddt.2022.01077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Gemcitabine is widely used in the clinic as a first-line antitumor agent. However, intrinsic and acquired resistance hinders its wide clinical application. In this study, a gemcitabine prodrug nominated as WRQ-2 was designed and synthesized by conjugating gemcitabine with the indole-3-methanol analogue OSU-A9 through a carbamate linkage. WRQ-2 exhibited high cytotoxicity against six cancer cell lines (HeLa, A549, MDA-MB-231, HuH-7, MGC-803, and HCT-116) with IC50 values in low micromolar range. WRQ-2 reversed the resistance of HeLa cells to gemcitabine caused by hENT1 inhibition. Compared to gemcitabine, WRQ-2 induced a higher degree of DNA damage and apoptosis in the presence of hENT1 inhibitor. Our study suggests that compound WRQ-2 is a potential gemcitabine prodrug and worth of further antitumor activity investigation.
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Affiliation(s)
- Ruquan Wang
- Department of Pharmacology, School of Pharmacy, Qingdao University Qingdao Medical College, Qingdao University, Qingdao, Shandong, China
| | - Yongliang Li
- Department of Medicinal Chemistry, School of Pharmacy, Qingdao University Qingdao Medical College, Qingdao University, Qingdao, Shandong, China
| | - Jianjun Gao
- Department of Pharmacology, School of Pharmacy, Qingdao University Qingdao Medical College, Qingdao University, Qingdao, Shandong, China
| | - Yepeng Luan
- Department of Medicinal Chemistry, School of Pharmacy, Qingdao University Qingdao Medical College, Qingdao University, Qingdao, Shandong, China
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Indole-3-carbinol in vitro antiviral activity against SARS-Cov-2 virus and in vivo toxicity. Cell Death Dis 2022; 8:491. [PMID: 36522315 PMCID: PMC9751508 DOI: 10.1038/s41420-022-01280-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 11/30/2022] [Accepted: 12/06/2022] [Indexed: 12/23/2022]
Abstract
The effects of indole-3-carbinol (I3C) compound have been described deeply as antitumor drug in multiple cancers. Herein, I3C compound was tested for toxicity and antiviral activity against SARS-CoV-2 infection. Antiviral activity was assessed in vitro in both in VeroE6 cell line and human Lung Organoids (hLORGs) where I3C exhibited a direct anti-SARS-CoV-2 replication activity with an antiviral effect and a modulation of the expression of genes implicated in innate immunity and inflammatory response was observed at 16.67 μM. Importantly, we further show the I3C is also effective against the SARS-CoV-2 Omicron variant. In mouse model, instead, we assessed possible toxicity effects of I3C through two different routes of administration: intragastrically (i.g.) and intraperitoneally (i.p.). The LD50 (lethal dose 50%) values in mice were estimated to be: 1410 and 1759 mg/kg i.g.; while estimated values for i.p. administration were: 444.5 mg/kg and 375 mg/kg in male and female mice, respectively. Below these values, I3C (in particular at 550 mg/kg for i.g. and 250 mg/kg for i.p.) induces neither death, nor abnormal toxic symptoms as well as no histopathological lesions of the tissues analysed. These tolerated doses are much higher than those already proven effective in pre-clinical cancer models and in vitro experiments. In conclusion, I3C exhibits a significant antiviral activity, and no toxicity effects were recorded for this compound at the indicated doses, characterizing it as a safe and potential antiviral compound. The results presented in this study could provide experimental pre-clinical data necessary for the start of human clinical trials with I3C for the treatment of SARS-CoV-2 and beyond.
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An overview of aryl hydrocarbon receptor ligands in the Last two decades (2002–2022): A medicinal chemistry perspective. Eur J Med Chem 2022; 244:114845. [DOI: 10.1016/j.ejmech.2022.114845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 09/28/2022] [Accepted: 10/08/2022] [Indexed: 11/21/2022]
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Chaisiwamongkhol K, Phonchai A, Pon-In S, Bunchuay T, Limbut W. A microplate spectrophotometric method for analysis of indole-3-carbinol in dietary supplements using p-dimethylaminocinnamaldehyde (DMACA) as a chromogenic reagent. ANALYTICAL METHODS : ADVANCING METHODS AND APPLICATIONS 2022; 14:3366-3374. [PMID: 36039897 DOI: 10.1039/d2ay01129h] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
This work presents the development of a microplate spectrophotometric method for determination of indole-3-carbinol in dietary supplements. The colorimetric procedure is based on the reaction of indole-3-carbinol with the p-dimethylaminocinnamaldehyde (DMACA) reagent under acidic conditions. The absorbance of the colored product measured at 675 nm was used to determine the target analyte. To achieve optimal spectrophotometric performance, the DMACA reagent concentration, the hydrochloric acid concentration, and the reaction time were optimized. The developed technique performed well under the optimal conditions, with a linear calibration range of 30 to 300 mg L-1 and a high correlation coefficient (r2 = 0.9954). The limit of detection and limit of quantification were 7.8 mg L-1 and 26.2 mg L-1, respectively. This approach demonstrated good repeatability (intra- and inter-day precision) with a % RSD lower than 9.4%, good accuracy with acceptable relative recoveries in the range of 98 to 106%, and high sample throughput (24 detection per min). This simple, rapid, and multi-sample analysis approach for routine analysis of indole-3-carbinol has the potential to be used for the quality control of dietary supplements.
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Affiliation(s)
- Korbua Chaisiwamongkhol
- School of Science, Mae Fah Luang University, Chiang Rai 57100, Thailand.
- Center of Chemical Innovation for Sustainability (CIS), Mae Fah Luang University, Chiang Rai 57100, Thailand
| | - Apichai Phonchai
- Division of Health and Applied Sciences, Faculty of Science, Prince of Songkla University, Hat Yai, Songkhla 90112, Thailand
- Forensic Science Innovation and Service Center, Prince of Songkla University, Hat Yai, Songkhla 90112, Thailand
| | - Sunisa Pon-In
- Division of Health and Applied Sciences, Faculty of Science, Prince of Songkla University, Hat Yai, Songkhla 90112, Thailand
| | - Thanthapatra Bunchuay
- Department of Chemistry, Center of Excellence for Innovation in Chemistry (PERCH-CIC), Faculty of Science, Mahidol University, 272 Rama VI Rd., Ratchathewi, Bangkok, 10400, Thailand
| | - Warakorn Limbut
- Division of Health and Applied Sciences, Faculty of Science, Prince of Songkla University, Hat Yai, Songkhla 90112, Thailand
- Forensic Science Innovation and Service Center, Prince of Songkla University, Hat Yai, Songkhla 90112, Thailand
- Center of Excellence for Trace Analysis and Biosensor, Prince of Songkla University, Hat Yai, Songkhla 90112, Thailand
- Center of Excellence for Innovation in Chemistry, Faculty of Science, Prince of Songkla University, Hat Yai, Songkhla 90112, Thailand
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Yuan Y, Chen H, Han Y, Qiao F, Yan H. Analysis of anticancer compound, indole-3-carbinol, in broccoli using a new ultrasound-assisted dispersive-filter extraction method based on poly(deep eutectic solvent)-graphene oxide nanocomposite. J Pharm Anal 2022; 12:301-307. [PMID: 35582392 PMCID: PMC9091758 DOI: 10.1016/j.jpha.2021.03.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 03/16/2021] [Accepted: 03/31/2021] [Indexed: 12/02/2022] Open
Abstract
Indole-3-carbinol (I3C), an important anticancer compound found in broccoli, has attracted considerable attention. The rapid extraction and accurate analysis of I3C in the pharmaceutical industry in broccoli is challenging as I3C is unstable at low pH and high temperature. In this study, a rapid, accurate, and low-cost ultrasound-assisted dispersive-filter extraction (UADFE) technique based on poly(deep eutectic solvent)-graphene oxide (PDES-GO) adsorbent was developed for the isolation and analysis of I3C in broccoli for the first time. PDES-GO with multiple adsorption interactions and a fast mass transfer rate was synthesized to accelerate adsorption and desorption. UADFE was developed by combining dispersive solid-phase extraction (DSPE) and filter solid-phase extraction (FSPE) to realize rapid extraction and separation. Based on the above two strategies, the proposed PDES-GO-UADFE method coupled with high-performance liquid chromatography (HPLC) allowed the rapid (15-16 min), accurate (84.3%-96.4%), and low-cost (adsorbent: 3.00 mg) analysis of I3C in broccoli and was superior to solid-phase extraction, DSPE, and FSPE methods. The proposed method showed remarkable linearity (r=0.9998; range: 0.0840-48.0 μg/g), low limit of quantification (0.0840 μg/g), and high precision (relative standard deviation ≤5.6%). Therefore, the PDES-GO-UADFE-HPLC method shows significant potential in the field of pharmaceutical analysis for the separation and analysis of anti-cancer compounds in complex plant samples.
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Affiliation(s)
- Yanan Yuan
- Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, College of Pharmaceutical Science, Hebei University, Baoding, Hebei, 071002, China
- Key Laboratory of Public Health Safety of Hebei Province, Institute of Life Science and Green Development, College of Public Health, Hebei University, Baoding, Hebei, 071002, China
| | - Huanhuan Chen
- Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, College of Pharmaceutical Science, Hebei University, Baoding, Hebei, 071002, China
| | - Yehong Han
- Key Laboratory of Public Health Safety of Hebei Province, Institute of Life Science and Green Development, College of Public Health, Hebei University, Baoding, Hebei, 071002, China
| | - Fengxia Qiao
- College of Biochemistry, Baoding University, Baoding, Hebei, 071000, China
| | - Hongyuan Yan
- Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, College of Pharmaceutical Science, Hebei University, Baoding, Hebei, 071002, China
- Key Laboratory of Public Health Safety of Hebei Province, Institute of Life Science and Green Development, College of Public Health, Hebei University, Baoding, Hebei, 071002, China
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Wyatt M, Greathouse KL. Targeting Dietary and Microbial Tryptophan-Indole Metabolism as Therapeutic Approaches to Colon Cancer. Nutrients 2021; 13:1189. [PMID: 33916690 PMCID: PMC8066279 DOI: 10.3390/nu13041189] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 03/29/2021] [Accepted: 03/31/2021] [Indexed: 12/15/2022] Open
Abstract
Tryptophan metabolism, via the kynurenine (Kyn) pathway, and microbial transformation of tryptophan to indolic compounds are fundamental for host health; both of which are altered in colon carcinogenesis. Alterations in tryptophan metabolism begin early in colon carcinogenesis as an adaptive mechanism for the tumor to escape immune surveillance and metastasize. The microbial community is a key part of the tumor microenvironment and influences cancer initiation, promotion and treatment response. A growing awareness of the impact of the microbiome on tryptophan (Trp) metabolism in the context of carcinogenesis has prompted this review. We first compare the different metabolic pathways of Trp under normal cellular physiology to colon carcinogenesis, in both the host cells and the microbiome. Second, we review how the microbiome, specifically indoles, influence host tryptophan pathways under normal and oncogenic metabolism. We conclude by proposing several dietary, microbial and drug therapeutic modalities that can be utilized in combination to abrogate tumorigenesis.
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Affiliation(s)
- Madhur Wyatt
- Human Health, Performance and Recreation, Robbins College of Health and Human Sciences, Baylor University, Waco, TX 76798-7346, USA;
| | - K. Leigh Greathouse
- Human Science and Design, Robbins College of Health and Human Sciences, Baylor University, Waco, TX 76798-7346, USA
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13
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Islam SU, Ahmed MB, Ahsan H, Islam M, Shehzad A, Sonn JK, Lee YS. An Update on the Role of Dietary Phytochemicals in Human Skin Cancer: New Insights into Molecular Mechanisms. Antioxidants (Basel) 2020; 9:E916. [PMID: 32993035 PMCID: PMC7600476 DOI: 10.3390/antiox9100916] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 09/21/2020] [Accepted: 09/24/2020] [Indexed: 12/24/2022] Open
Abstract
Human skin is continuously subjected to environmental stresses, as well as extrinsic and intrinsic noxious agents. Although skin adopts various molecular mechanisms to maintain homeostasis, excessive and repeated stresses can overwhelm these systems, leading to serious cutaneous damage, including both melanoma and non-melanoma skin cancers. Phytochemicals present in the diet possess the desirable effects of protecting the skin from damaging free radicals as well as other benefits. Dietary phytochemicals appear to be effective in preventing skin cancer and are inexpensive, widely available, and well tolerated. Multiple in vitro and in vivo studies have demonstrated the significant anti-inflammatory, antioxidant, and anti-angiogenic characteristics of dietary phytochemicals against skin malignancy. Moreover, dietary phytochemicals affect multiple important cellular processes including cell cycle, angiogenesis, and metastasis to control skin cancer progression. Herein, we discuss the advantages of key dietary phytochemicals in whole fruits and vegetables, their bioavailability, and underlying molecular mechanisms for preventing skin cancer. Current challenges and future prospects for research are also reviewed. To date, most of the chemoprevention investigations have been conducted preclinically, and additional clinical trials are required to conform and validate the preclinical results in humans.
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Affiliation(s)
- Salman Ul Islam
- School of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu 41566, Korea; (S.U.I.); (M.B.A.); (H.A.); (J.K.S.)
| | - Muhammad Bilal Ahmed
- School of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu 41566, Korea; (S.U.I.); (M.B.A.); (H.A.); (J.K.S.)
| | - Haseeb Ahsan
- School of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu 41566, Korea; (S.U.I.); (M.B.A.); (H.A.); (J.K.S.)
- Department of Pharmacy, Faculty of Life and Environmental Sciences, University of Peshawar, Peshawar 25120, Pakistan
| | - Mazharul Islam
- Department of Chemical Engineering, College of Engineering, Dhofar University, Salalah 2509, Oman;
| | - Adeeb Shehzad
- Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia;
| | - Jong Kyung Sonn
- School of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu 41566, Korea; (S.U.I.); (M.B.A.); (H.A.); (J.K.S.)
| | - Young Sup Lee
- School of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu 41566, Korea; (S.U.I.); (M.B.A.); (H.A.); (J.K.S.)
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14
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Nutritional Therapy to Modulate Tryptophan Metabolism and Aryl Hydrocarbon-Receptor Signaling Activation in Human Diseases. Nutrients 2020; 12:nu12092846. [PMID: 32957545 PMCID: PMC7551725 DOI: 10.3390/nu12092846] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 09/10/2020] [Accepted: 09/12/2020] [Indexed: 02/07/2023] Open
Abstract
The aryl hydrocarbon receptor (AhR) is a nuclear protein which, upon association with certain endogenous and exogenous ligands, translocates into the nucleus, binds DNA and regulates gene expression. Tryptophan (Trp) metabolites are one of the most important endogenous AhR ligands. The intestinal microbiota is a critical player in human intestinal homeostasis. Many of its effects are mediated by an assembly of metabolites, including Trp metabolites. In the intestine, Trp is metabolized by three main routes, leading to kynurenine, serotonin, and indole derivative synthesis under the direct or indirect involvement of the microbiota. Disturbance in Trp metabolism and/or AhR activation is strongly associated with multiple gastrointestinal, neurological and metabolic disorders, suggesting Trp metabolites/AhR signaling modulation as an interesting therapeutic perspective. In this review, we describe the most recent advances concerning Trp metabolism and AhR signaling in human health and disease, with a focus on nutrition as a potential therapy to modulate Trp metabolites acting on AhR. A better understanding of the complex balance between these pathways in human health and disease will yield therapeutic opportunities.
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15
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Alkarkoushi RR, Hui Y, Tavakoli AS, Singh U, Nagarkatti P, Nagarkatti M, Chatzistamou I, Bam M, Testerman TL. Immune and microRNA responses to Helicobacter muridarum infection and indole-3-carbinol during colitis. World J Gastroenterol 2020; 26:4763-4785. [PMID: 32921956 PMCID: PMC7459201 DOI: 10.3748/wjg.v26.i32.4763] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 07/16/2020] [Accepted: 08/12/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Indole-3-carbinol (I3C) and other aryl hydrocarbon receptor agonists are known to modulate the immune system and ameliorate various inflammatory and autoimmune diseases in animal models, including colitis induced by dextran sulfate sodium (DSS). MicroRNAs (miRNAs) are also gaining traction as potential therapeutic agents or diagnostic elements. Enterohepatic Helicobacter (EHH) species are associated with an increased risk of inflammatory bowel disease, but little is known about how these species affect the immune system or response to treatment.
AIM To determine whether infection with an EHH species alters the response to I3C and how the immune and miRNA responses of an EHH species compare with responses to DSS and inflammatory bowel disease.
METHODS We infected C57BL/6 mice with Helicobacter muridarum (H. muridarum), with and without DSS and I3C treatment. Pathological responses were evaluated by histological examination, symptom scores, and cytokine responses. MiRNAs analysis was performed on mesenteric lymph nodes to further evaluate the regional immune response.
RESULTS H. muridarum infection alone caused colonic inflammation and upregulated proinflammatory, macrophage-associated cytokines in the colon similar to changes seen in DSS-treated mice. Further upregulation occurred upon treatment with DSS. H. muridarum infection caused broad changes in mesenteric lymph node miRNA expression, but colitis-associated miRNAs were regulated similarly in H. muridarum-infected and uninfected, DSS-treated mice. In spite of causing colitis exacerbation, H. muridarum infection did not prevent disease amelioration by I3C. I3C normalized both macrophage- and T cell-associated cytokines.
CONCLUSION Thus, I3C may be useful for inflammatory bowel disease patients regardless of EHH infection. The miRNA changes associated with I3C treatment are likely the result of, rather than the cause of immune response changes.
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Affiliation(s)
- Rasha Raheem Alkarkoushi
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, United States
| | - Yvonne Hui
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, United States
| | - Abbas S Tavakoli
- College of Nursing, University of South Carolina, University of South Carolina, Columbia, SC 29208, United States
| | - Udai Singh
- Department of Medicine, Hematology and Oncology, University of Virginia School of Medicine, Charlottesville, VA 22908, United States
| | - Prakash Nagarkatti
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, United States
| | - Mitzi Nagarkatti
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, United States
| | - Ioulia Chatzistamou
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, United States
| | - Marpe Bam
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, United States
| | - Traci L Testerman
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, United States
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16
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Amare DE. Anti-Cancer and Other Biological Effects of a Dietary Compound 3,3ʹ-Diindolylmethane Supplementation: A Systematic Review of Human Clinical Trials . NUTRITION AND DIETARY SUPPLEMENTS 2020. [DOI: 10.2147/nds.s261577] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
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17
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Methyl Jasmonate Treatment of Broccoli Enhanced Glucosinolate Concentration, Which Was Retained after Boiling, Steaming, or Microwaving. Foods 2020; 9:foods9060758. [PMID: 32521670 PMCID: PMC7353551 DOI: 10.3390/foods9060758] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 06/04/2020] [Accepted: 06/06/2020] [Indexed: 12/19/2022] Open
Abstract
Exogenous methyl jasmonate (MeJA) treatment was known to increase the levels of neoglucobrassicin and their bioactive hydrolysis products in broccoli (Brassica oleracea var. italica), but the fate of MeJA-induced glucosinolates (GSLs) after various cooking methods was unknown. This study measured the changes in GSLs and their hydrolysis compounds in broccoli treated with MeJA and the interaction between MeJA and cooking treatments. All cooked MeJA-treated broccoli contained significantly more GSLs than untreated broccoli (p < 0.05). After 5 min of cooking (boil, steam, microwave), MeJA-treated broccoli still contained 1.6- to 2.3-fold higher GSL content than untreated broccoli. Neoglucobrassicin hydrolysis products were also significantly greater in steamed and microwaved MeJA-treated broccoli. The results show that exogenous MeJA treatment increases neoglucobrassicin and its hydrolysis compounds in broccoli even after cooking. Once the positive and negative effects of these compounds are better understood, the results of this experiment can be a valuable tool to help food scientists, nutrition scientists, and dieticians determine how to incorporate raw or cooked broccoli and Brassica vegetables in the diet.
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18
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Karimabad MN, Mahmoodi M, Jafarzadeh A, Darekordi A, Hajizadeh MR, Hassanshahi G. Molecular Targets, Anti-cancer Properties and Potency of Synthetic Indole-3-carbinol Derivatives. Mini Rev Med Chem 2019; 19:540-554. [DOI: 10.2174/1389557518666181116120145] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Revised: 04/25/2017] [Accepted: 04/26/2017] [Indexed: 12/14/2022]
Abstract
The indole-3-carbinol (I3C) displays anti-cancer/proliferative activities against human cancer cells. Cellular proliferation is an event associated with the progress and its continuation. This manifest is described by variation in expression and/or functions of genes that are related with cell cycle relevant proteins. The constitutive activation of several signal transduction pathways stimulates cells proliferation as well. The immediate stages in cancer development are accompanied by a fibrogenic response and the progression of the hypoxic environment is in favor of survival and proliferatory functions of cancer stem cells. A main part for prevention of in cancer cells death may manifest through altering cell metabolism. Cellular proliferation and metastasis are reported to be supported with increased generation of responsible hormones (in hormone dependent malignancies), and further promotion the angiogenesis, with epithelial to mesenchymal transition. This may be facilitated by progression of autophagy phenomenon, as well as via taking cues from neighboring stromal cells. Several signaling pathways in association with various factors specific for cellular viability, including hypoxia inducible factor 1, NF-κB, insulin-like growth factor 1 (IGF-1) receptor, Human foreskin fibroblasts (HFF-1), phosphoinositide 3 kinase/Akt, Wnt, cell cycle related protein, with androgen and estrogen receptor signaling are reported to be inhibited by I3C. These evidences, in association with bioinformatics data represent very important information for describing signaling pathways in parallel with molecular targets that may serve as markers for early diagnosis and/or critical targets for designing and development of novel therapeutic regimes alone or combined with drugs, to prevent tumor formation and further progression. In particular, I3C and DIM have been extensively investigated for their importance against numbers human cancers both in vitro and in vivo. We aimed the present manuscript, current study, to review anticancer properties and the miscellaneous mechanisms underlying the antitumorigenicity in an in-depth study for broadening the I3C treating marvel.
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Affiliation(s)
- Mojgan Noroozi Karimabad
- Molecular Medicine Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Mehdi Mahmoodi
- Molecular Medicine Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Abdolah Jafarzadeh
- Molecular Medicine Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Ali Darekordi
- Department of Chemistry, Faculty of Science, Vali-e-Asr University of Rafsanjan, Rafsanjan, Iran
| | - Mohamad Reza Hajizadeh
- Molecular Medicine Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Gholamhossein Hassanshahi
- Molecular Medicine Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
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19
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Wu Y, Li RW, Huang H, Fletcher A, Yu L, Pham Q, Yu L, He Q, Wang TTY. Inhibition of Tumor Growth by Dietary Indole-3-Carbinol in a Prostate Cancer Xenograft Model May Be Associated with Disrupted Gut Microbial Interactions. Nutrients 2019; 11:nu11020467. [PMID: 30813350 PMCID: PMC6413210 DOI: 10.3390/nu11020467] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 02/16/2019] [Accepted: 02/19/2019] [Indexed: 02/06/2023] Open
Abstract
Accumulated evidence suggests that the cruciferous vegetables-derived compound indole-3-carbinol (I3C) may protect against prostate cancer, but the precise mechanisms underlying its action remain unclear. This study aimed to verify the hypothesis that the beneficial effect of dietary I3C may be due to its modulatory effect on the gut microbiome of mice. Athymic nude mice (5–7 weeks old, male, Balb c/c nu/nu) with established tumor xenografts were fed a basal diet (AIN-93) with or without 1 µmoles I3C/g for 9 weeks. The effects of dietary I3C on gut microbial composition and microbial species interactions were then examined by 16s rRNA gene-based sequencing and co-occurrence network analysis. I3C supplementation significantly inhibited tumor growth (p < 0.0001) and altered the structure of gut microbiome. The abundance of the phylum Deferribacteres, more specifically, Mucispirillum schaedleri, was significantly increased by dietary I3C. Additionally, I3C consumption also changed gut microbial co-occurrence patterns. One of the network modules in the control group, consisting of seven bacteria in family S-27, was positively correlated with tumor size (p < 0.009). Moreover, dietary I3C disrupted microbial interactions and altered this association between specific microbial network and tumor development. Our results unraveled complex relationships among I3C ingestion, gut microbiota, and prostate tumor development and may provide a novel insight into the mechanism for the chemopreventive effect of dietary I3C on prostate cancer.
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Affiliation(s)
- Yanbei Wu
- College of Light Industry, Textile and Food Engineering, Sichuan University, Chengdu 610065, China.
- Department of Nutrition and Food Science, University of Maryland, College Park, MD 20742, USA.
- Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, USDA-ARS, Beltsville, MD 20705, USA.
| | - Robert W Li
- Animal Parasitic Diseases Laboratory, USDA-ARS, Beltsville, MD 20705, USA.
| | - Haiqiu Huang
- Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, USDA-ARS, Beltsville, MD 20705, USA.
| | - Arnetta Fletcher
- Department of Nutrition and Food Science, University of Maryland, College Park, MD 20742, USA.
- Department of Family and Consumer Sciences, Shepherd University, Shepherdstown, WV 25443, USA.
| | - Lu Yu
- Department of Nutrition and Food Science, University of Maryland, College Park, MD 20742, USA.
| | - Quynhchi Pham
- Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, USDA-ARS, Beltsville, MD 20705, USA.
| | - Liangli Yu
- Department of Nutrition and Food Science, University of Maryland, College Park, MD 20742, USA.
| | - Qiang He
- College of Light Industry, Textile and Food Engineering, Sichuan University, Chengdu 610065, China.
| | - Thomas T Y Wang
- Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, USDA-ARS, Beltsville, MD 20705, USA.
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Abstract
A diet rich in cruciferous vegetables such as cauliflower, broccoli, and cabbage has long been considered healthy, and various epidemiological studies suggest that the consumption of cruciferous vegetables contributes to a cancer-protecting diet. While these vegetables contain a vast array of phytochemicals, the mechanism by which these vegetables counteract cancer is still largely unresolved. Numerous
in situ studies have implicated indole-3-carbinol, a breakdown product of the glucosinolate indole-3-ylmethylglucosinolate, as one of the phytochemicals with anti-cancer properties. Indole-3-carbinol influences a range of cellular processes, but the mechanisms by which it acts on cancer cells are slowly being revealed. Recent studies on the role of indole-3-carbinol in Arabidopsis opens the door for cross-kingdom comparisons that can help in understanding the roles of this important phytohormone in both plant biology and combatting cancer.
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Affiliation(s)
- Ella Katz
- School of Plant Sciences and Food Security, Tel Aviv University, Tel Aviv, Israel.,Department of Plant Sciences, University of California , Davis , USA
| | - Sophia Nisani
- School of Plant Sciences and Food Security, Tel Aviv University, Tel Aviv, Israel
| | - Daniel A Chamovitz
- School of Plant Sciences and Food Security, Tel Aviv University, Tel Aviv, Israel
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21
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Bell L, Oloyede OO, Lignou S, Wagstaff C, Methven L. Taste and Flavor Perceptions of Glucosinolates, Isothiocyanates, and Related Compounds. Mol Nutr Food Res 2018; 62:e1700990. [PMID: 29578640 DOI: 10.1002/mnfr.201700990] [Citation(s) in RCA: 107] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Revised: 02/05/2018] [Indexed: 11/07/2022]
Abstract
Brassicaceae plants are renowned for their taste, aroma and trigeminal characteristics; predominantly bitter taste, sulfurous aroma, and pungency. Compounds responsible for these sensations include the glucosinolates (GSLs) and their hydrolysis products, particularly isothiocyanates (ITCs), but also sulfur-containing volatile compounds. This article reviews the relative importance of taste and flavor perceptions resulting from such compounds; collating evidence from papers where findings are based on sensory analytical correlations, and those that have extracted specific compounds prior to sensory evaluation. Where specific GSLs impart bitterness and many ITCs impart pungency, this is clearly not true for all GSLs and ITCs. Designing crop improvement strategies for sensory traits based on total GSL content would be flawed, as it does not consider the relative differences in sensory characteristics of different GSLs and ITCs, nor the contribution from other GSL hydrolysis products. In addition, some Brassicaceae plants are consumed raw, whilst others are cooked; this affects not only the hydrolysis of GSLs, but also the generation and release of sulfides. Therefore, in breeding new plant varieties, it is prudent to consider the individual GSLs, the typical cooking conditions the plant is subjected to, enzyme stability, and resultant composition of both GSL hydrolysis products (including ITCs) and sulfides.
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Affiliation(s)
- Luke Bell
- Department of Food and Nutritional Sciences, University of Reading, Whiteknights, Reading, RG6 6AP, Berkshire, UK
| | - Omobolanle O Oloyede
- Department of Food and Nutritional Sciences, University of Reading, Whiteknights, Reading, RG6 6AP, Berkshire, UK
| | - Stella Lignou
- Department of Food and Nutritional Sciences, University of Reading, Whiteknights, Reading, RG6 6AP, Berkshire, UK
| | - Carol Wagstaff
- Department of Food and Nutritional Sciences, University of Reading, Whiteknights, Reading, RG6 6AP, Berkshire, UK
| | - Lisa Methven
- Department of Food and Nutritional Sciences, University of Reading, Whiteknights, Reading, RG6 6AP, Berkshire, UK
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22
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Muthusamy S, Balasubramani A, Suresh E. A BF3·Et2O catalyzed atom-economical approach to highly substituted indole-3-carbinols from nitrosobenzenes and propargylic alcohols. Org Biomol Chem 2018; 16:756-764. [DOI: 10.1039/c7ob02559a] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The BF3·Et2O catalyzed tandem reaction of nitrosobenzenes and propargylic alcohols for the formation of highly substituted indole-3-carbinols.
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Affiliation(s)
| | | | - Eringathodi Suresh
- Analytical Discipline and Centralized Instrumentation Facility
- Central Salt & Marine Chemicals Research Institute
- Bhavnagar-364002
- India
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23
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Hasanpourghadi M, Pandurangan AK, Mustafa MR. Modulation of oncogenic transcription factors by bioactive natural products in breast cancer. Pharmacol Res 2017; 128:376-388. [PMID: 28923544 DOI: 10.1016/j.phrs.2017.09.009] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Revised: 09/11/2017] [Accepted: 09/14/2017] [Indexed: 12/17/2022]
Abstract
Carcinogenesis, a multi-step phenomenon, characterized by alterations at genetic level and affecting the main intracellular pathways controlling cell growth and development. There are growing number of evidences linking oncogenes to the induction of malignancies, especially breast cancer. Modulations of oncogenes lead to gain-of-function signals in the cells and contribute to the tumorigenic phenotype. These signals yield a large number of proteins that cause cell growth and inhibit apoptosis. Transcription factors such as STAT, p53, NF-κB, c-JUN and FOXM1, are proteins that are conserved among species, accumulate in the nucleus, bind to DNA and regulate the specific genes targets. Oncogenic transcription factors resulting from the mutation or overexpression following aberrant gene expression relay the signals in the nucleus and disrupt the transcription pattern. Activation of oncogenic transcription factors is associated with control of cell cycle, apoptosis, migration and cell differentiation. Among different cancer types, breast cancer is one of top ten cancers worldwide. There are different subtypes of breast cancer cell-lines such as non-aggressive MCF-7 and aggressive and metastatic MDA-MB-231 cells, which are identified with distinct molecular profile and different levels of oncogenic transcription factor. For instance, MDA-MB-231 carries mutated and overexpressed p53 with its abnormal, uncontrolled downstream signalling pathway that account for resistance to several anticancer drugs compared to MCF-7 cells with wild-type p53. Appropriate enough, inhibition of oncogenic transcription factors has become a potential target in discovery and development of anti-tumour drugs against breast cancer. Plants produce diverse amount of organic metabolites. Universally, these metabolites with biological activities are known as "natural products". The chemical structure and function of natural products have been studied since 1850s. Investigating these properties leaded to recognition of their molecular effects as anticancer drugs. Numerous natural products extracted from plants, fruits, mushrooms and mycelia, show potential inhibitory effects against several oncogenic transcription factors in breast cancer. Natural compounds that target oncogenic transcription factors have increased the number of candidate therapeutic agents. This review summarizes the current findings of natural products in targeting specific oncogenic transcription factors in breast cancer.
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Affiliation(s)
- Mohadeseh Hasanpourghadi
- Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia
| | - Ashok Kumar Pandurangan
- Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia
| | - Mohd Rais Mustafa
- Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia; Centre for Natural Products Research and Drug Discovery, Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.
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Karimabad MN, Falahati-Pour SK, Hassanshahi G, Koochakzadeh L. WITHDRAWN: The anti-cancer properties in parallel with toxic effects of indole-3-carbinol derivatives. Immunol Lett 2017:S0165-2478(17)30138-4. [PMID: 28851630 DOI: 10.1016/j.imlet.2017.08.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Revised: 08/14/2017] [Accepted: 08/14/2017] [Indexed: 10/19/2022]
Abstract
This article has been withdrawn at the request of the editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.
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Affiliation(s)
| | | | - Gholamhossein Hassanshahi
- Molecular Medicine Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Immunology, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Lili Koochakzadeh
- Molecular Medicine Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Clinical Biochemistry, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Immunology, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Pistachio Safety Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran.
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25
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The novel Indole-3-formaldehyde (2-AITFEI-3-F) is involved in processes of apoptosis induction? Life Sci 2017; 181:31-44. [PMID: 28549559 DOI: 10.1016/j.lfs.2017.05.026] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 05/16/2017] [Accepted: 05/22/2017] [Indexed: 02/07/2023]
Abstract
AIM AND OBJECTIVES Balancing between Bax and Bcl-2 plays critical roles in both proliferation and self-renewal activation of cancer cells. Indole-3-formaldehyde derivatives limit the growth and facilitate cell death in different cell systems. In this study, we introduced a novel indole derivative (2-AITFEI-3-F) with tendency to facilitate apoptosis in NB4 line in comparison to basal Indole-3-formaldehyde (I3F). METHODS The NB4 cells were cultured in RPMI1640 medium contained 2-AITFEI-3-F and I3F (15.12-1000μg/mL) for 24, 48 and 72h. Inhibition of cell proliferation was assessed by trypan blue staining technique and MTT assay. The fold changes of Bax/Bcl-2 expression against β-actin were determined by real-time-PCR technique. Western blotting analysis was also applied for evaluating the expression of Bax and Bcl2 at protein level. Data were analyzed by student t and repeated measure tests. Differences were considered significant if (P<0.01). RESULTS There was a significant difference in cell viability, when various concentrations of 2-AITFEI-3-F (but similar to I3F) were used for 24, 48 and 72h in comparison to I3F regarding the cellular viability (P<0.05). Real time PCR and Western blotting analysis indicated that the gene and protein expression level of Bcl-2 down-regulated while Bax was up-regulated in compare to untreated control cells and cells treated with I3F (P<0.01). CONCLUSION According to these findings, the novel indole derivative 2-AITFEI-3-F probably triggered apoptosis of NB4 cells by modulating Bax/Bcl-2 ratio. Furthermore, the 2-AITFEI-3-F had markedly displayed anti-cancer activity than I3F.
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26
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Quirit JG, Lavrenov SN, Poindexter K, Xu J, Kyauk C, Durkin KA, Aronchik I, Tomasiak T, Solomatin YA, Preobrazhenskaya MN, Firestone GL. Indole-3-carbinol (I3C) analogues are potent small molecule inhibitors of NEDD4-1 ubiquitin ligase activity that disrupt proliferation of human melanoma cells. Biochem Pharmacol 2016; 127:13-27. [PMID: 27979631 DOI: 10.1016/j.bcp.2016.12.007] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Accepted: 12/09/2016] [Indexed: 11/16/2022]
Abstract
The HECT domain-containing E3 ubiquitin ligase NEDD4-1 (Neural precursor cell Expressed Developmentally Down regulated gene 4-1) is frequently overexpressed in human cancers and displays oncogenic-like properties through the ubiquitin-dependent regulation of multiple protein substrates. However, little is known about small molecule enzymatic inhibitors of HECT domain-containing ubiquitin ligases. We now demonstrate that indole-3-carbinol (I3C), a natural anti-cancer phytochemical derived from cruciferous vegetables such as cabbage and broccoli, represents a new chemical scaffold of small molecule enzymatic inhibitors of NEDD4-1. Using in vitro ubiquitination assays, I3C, its stable synthetic derivative 1-benzyl-I3C and five novel synthetic analogues were shown to directly inhibit NEDD4-1 ubiquitination activity. Compared to I3C, which has an IC50 of 284μM, 1-benzyl-I3C was a significantly more potent NEDD4-1 enzymatic inhibitor with an IC50 of 12.3μM. Compounds 2242 and 2243, the two indolecarbinol analogues with added methyl groups that results in a more nucleophilic benzene ring π system, further enhanced potency with IC50s of 2.71μM and 7.59μM, respectively. Protein thermal shift assays that assess small ligand binding, in combination with in silico binding simulations with the crystallographic structure of NEDD4-1, showed that each of the indolecarbinol compounds bind to the purified catalytic HECT domain of NEDD4-1. The indolecarbinol compounds inhibited human melanoma cell proliferation in a manner that generally correlated with their effectiveness as NEDD4-1 enzymatic inhibitors. Taken together, we propose that I3C analogues represent a novel set of anti-cancer compounds for treatment of human melanomas and other cancers that express indolecarbinol-sensitive target enzymes.
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Affiliation(s)
- Jeanne G Quirit
- Dept. of Molecular and Cell Biology and The Cancer Research Laboratory, University of California at Berkeley, Berkeley, CA, USA.
| | - Sergey N Lavrenov
- Gause Institute of New Antibiotics, B. Pirogovskaya 11, Moscow 119021, Russia.
| | - Kevin Poindexter
- Dept. of Molecular and Cell Biology and The Cancer Research Laboratory, University of California at Berkeley, Berkeley, CA, USA.
| | - Janice Xu
- Dept. of Molecular and Cell Biology and The Cancer Research Laboratory, University of California at Berkeley, Berkeley, CA, USA.
| | - Christine Kyauk
- Dept. of Molecular and Cell Biology and The Cancer Research Laboratory, University of California at Berkeley, Berkeley, CA, USA
| | - Kathleen A Durkin
- Molecular Graphics and Computational Facility, College of Chemistry, University of California, Berkeley, CA, USA.
| | - Ida Aronchik
- Dept. of Molecular and Cell Biology and The Cancer Research Laboratory, University of California at Berkeley, Berkeley, CA, USA.
| | - Thomas Tomasiak
- Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA.
| | | | | | - Gary L Firestone
- Dept. of Molecular and Cell Biology and The Cancer Research Laboratory, University of California at Berkeley, Berkeley, CA, USA.
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27
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Huang H, Jiang X, Xiao Z, Yu L, Pham Q, Sun J, Chen P, Yokoyama W, Yu LL, Luo YS, Wang TTY. Red Cabbage Microgreens Lower Circulating Low-Density Lipoprotein (LDL), Liver Cholesterol, and Inflammatory Cytokines in Mice Fed a High-Fat Diet. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2016; 64:9161-9171. [PMID: 27933986 DOI: 10.1021/acs.jafc.6b03805] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Cardiovascular disease (CVD) is the leading cause of death in the United States, and hypercholesterolemia is a major risk factor. Population studies, as well as animal and intervention studies, support the consumption of a variety of vegetables as a means to reduce CVD risk through modulation of hypercholesterolemia. Microgreens of a variety of vegetables and herbs have been reported to be more nutrient dense compared to their mature counterparts. However, little is known about the effectiveness of microgreens in affecting lipid and cholesterol levels. The present study used a rodent diet-induced obesity (DIO) model to address this question. C57BL/6NCr mice (n = 60, male, 5 weeks old) were randomly assigned to six feeding groups: (1) low-fat diet; (2) high-fat diet; (3) low-fat diet + 1.09% red cabbage microgreens; (4) low-fat diet + 1.66% mature red cabbage; (5) high-fat diet + 1.09% red cabbage microgreens; (6) high-fat diet + 1.66% mature red cabbage. The animals were on their respective diets for 8 weeks. We found microgreen supplementation attenuated high-fat diet induced weight gain. Moreover, supplementation with microgreens significantly lowered circulating LDL levels in animals fed the high-fat diet and reduced hepatic cholesterol ester, triacylglycerol levels, and expression of inflammatory cytokines in the liver. These data suggest that microgreens can modulate weight gain and cholesterol metabolism and may protect against CVD by preventing hypercholesterolemia.
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Affiliation(s)
- Haiqiu Huang
- Diet, Genomics and Immunology Laboratory, Beltsville Human Nutrition Research Center, ARS, U.S. Department of Agriculture , Beltsville, Maryland 20705, United States
- Nutrition and Food Science Department, University of Maryland , College Park, Maryland 20742, United States
| | - Xiaojing Jiang
- Nutrition and Food Science Department, University of Maryland , College Park, Maryland 20742, United States
| | - Zhenlei Xiao
- Food Quality Laboratory, Beltsville Area Research Center, ARS, U.S. Department of Agriculture , Beltsville, Maryland 20705, United States
- Department of Agriculture, Culinology and Hospitality Management, Southwest Minnesota State University , Marshall, Minnesota 56258, United States
| | - Lu Yu
- Nutrition and Food Science Department, University of Maryland , College Park, Maryland 20742, United States
| | - Quynhchi Pham
- Diet, Genomics and Immunology Laboratory, Beltsville Human Nutrition Research Center, ARS, U.S. Department of Agriculture , Beltsville, Maryland 20705, United States
| | - Jianghao Sun
- Food Composition and Methods Development Laboratory, Beltsville Human Nutrition Research Center, ARS, U.S. Department of Agriculture , Beltsville, Maryland 20705, United States
| | - Pei Chen
- Food Composition and Methods Development Laboratory, Beltsville Human Nutrition Research Center, ARS, U.S. Department of Agriculture , Beltsville, Maryland 20705, United States
| | - Wallace Yokoyama
- Healthy Processed Foods Research Unit, Western Regional Research Center, ARS, U.S. Department of Agriculture , Albany, California 94710, United States
| | - Liangli Lucy Yu
- Nutrition and Food Science Department, University of Maryland , College Park, Maryland 20742, United States
| | - Yaguang Sunny Luo
- Food Quality Laboratory, Beltsville Area Research Center, ARS, U.S. Department of Agriculture , Beltsville, Maryland 20705, United States
| | - Thomas T Y Wang
- Diet, Genomics and Immunology Laboratory, Beltsville Human Nutrition Research Center, ARS, U.S. Department of Agriculture , Beltsville, Maryland 20705, United States
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Niedzwiecki A, Roomi MW, Kalinovsky T, Rath M. Anticancer Efficacy of Polyphenols and Their Combinations. Nutrients 2016; 8:E552. [PMID: 27618095 PMCID: PMC5037537 DOI: 10.3390/nu8090552] [Citation(s) in RCA: 338] [Impact Index Per Article: 37.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 08/29/2016] [Accepted: 09/01/2016] [Indexed: 01/08/2023] Open
Abstract
Polyphenols, found abundantly in plants, display many anticarcinogenic properties including their inhibitory effects on cancer cell proliferation, tumor growth, angiogenesis, metastasis, and inflammation as well as inducing apoptosis. In addition, they can modulate immune system response and protect normal cells against free radicals damage. Most investigations on anticancer mechanisms of polyphenols were conducted with individual compounds. However, several studies, including ours, have indicated that anti-cancer efficacy and scope of action can be further enhanced by combining them synergistically with chemically similar or different compounds. While most studies investigated the anti-cancer effects of combinations of two or three compounds, we used more comprehensive mixtures of specific polyphenols and mixtures of polyphenols with vitamins, amino acids and other micronutrients. The mixture containing quercetin, curcumin, green tea, cruciferex, and resveratrol (PB) demonstrated significant inhibition of the growth of Fanconi anemia head and neck squamous cell carcinoma and dose-dependent inhibition of cell proliferation, matrix metalloproteinase (MMP)-2 and -9 secretion, cell migration and invasion through Matrigel. PB was found effective in inhibition of fibrosarcoma HT-1080 and melanoma A2058 cell proliferation, MMP-2 and -9 expression, invasion through Matrigel and inducing apoptosis, important parameters for cancer prevention. A combination of polyphenols (quercetin and green tea extract) with vitamin C, amino acids and other micronutrients (EPQ) demonstrated significant suppression of ovarian cancer ES-2 xenograft tumor growth and suppression of ovarian tumor growth and lung metastasis from IP injection of ovarian cancer A-2780 cells. The EPQ mixture without quercetin (NM) also has shown potent anticancer activity in vivo and in vitro in a few dozen cancer cell lines by inhibiting tumor growth and metastasis, MMP-2 and -9 secretion, invasion, angiogenesis, and cell growth as well as induction of apoptosis. The presence of vitamin C, amino acids and other micronutrients could enhance inhibitory effect of epigallocatechin gallate (EGCG) on secretion of MMPs. In addition, enrichment of NM with quercetin (EPQ mix) enhanced anticancer activity of NM in vivo. In conclusion, polyphenols, especially in combination with other polyphenols or micronutrients, have been shown to be effective against multiple targets in cancer development and progression, and should be considered as safe and effective approaches in cancer prevention and therapy.
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Affiliation(s)
| | - Mohd Waheed Roomi
- Dr. Rath Research Institute, 1260 Memorex Drive, Santa Clara, CA 95050, USA.
| | - Tatiana Kalinovsky
- Dr. Rath Research Institute, 1260 Memorex Drive, Santa Clara, CA 95050, USA.
| | - Matthias Rath
- Dr. Rath Research Institute, 1260 Memorex Drive, Santa Clara, CA 95050, USA.
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Moore RW, Fritz WA, Schneider AJ, Lin TM, Branam AM, Safe S, Peterson RE. 2,3,7,8-Tetrachlorodibenzo-p-dioxin has both pro-carcinogenic and anti-carcinogenic effects on neuroendocrine prostate carcinoma formation in TRAMP mice. Toxicol Appl Pharmacol 2016; 305:242-249. [PMID: 27151233 PMCID: PMC4982706 DOI: 10.1016/j.taap.2016.04.018] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Revised: 04/27/2016] [Accepted: 04/30/2016] [Indexed: 01/08/2023]
Abstract
It is well established that the prototypical aryl hydrocarbon receptor (AHR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can both cause and protect against carcinogenesis in non-transgenic rodents. But because these animals almost never develop prostate cancer with old age or after carcinogen exposure, whether AHR activation can affect cancer of the prostate remained unknown. We used animals designed to develop this disease, Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice, to investigate the potential role of AHR signaling in prostate cancer development. We previously reported that AHR itself has prostate tumor suppressive functions in TRAMP mice; i.e., TRAMP mice in which Ahr was knocked out developed neuroendocrine prostate carcinomas (NEPC) with much greater frequency than did those with both Ahr alleles. In the present study we investigated effects of AHR activation by three different xenobiotics. In utero and lactational TCDD exposure significantly increased NEPC tumor incidence in TRAMP males, while chronic TCDD treatment in adulthood had the opposite effect, a significant reduction in NEPC incidence. Chronic treatment of adult TRAMP mice with the low-toxicity selective AHR modulators indole-3-carbinol or 3,3'-diindolylmethane did not significantly protect against these tumors. Thus, we demonstrate, for the first time, that ligand-dependent activation of the AHR can alter prostate cancer incidence. The nature of the responses depended on the timing of AHR activation and ligand structures.
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Affiliation(s)
- Robert W Moore
- School of Pharmacy, 777 Highland Ave., University of Wisconsin-Madison, Madison, WI 53705, USA; Molecular and Environmental Toxicology Center, 1400 University Ave., University of Wisconsin-Madison, Madison, WI 53706, USA.
| | - Wayne A Fritz
- School of Pharmacy, 777 Highland Ave., University of Wisconsin-Madison, Madison, WI 53705, USA; Molecular and Environmental Toxicology Center, 1400 University Ave., University of Wisconsin-Madison, Madison, WI 53706, USA.
| | - Andrew J Schneider
- School of Pharmacy, 777 Highland Ave., University of Wisconsin-Madison, Madison, WI 53705, USA.
| | - Tien-Min Lin
- School of Pharmacy, 777 Highland Ave., University of Wisconsin-Madison, Madison, WI 53705, USA.
| | - Amanda M Branam
- School of Pharmacy, 777 Highland Ave., University of Wisconsin-Madison, Madison, WI 53705, USA; Molecular and Environmental Toxicology Center, 1400 University Ave., University of Wisconsin-Madison, Madison, WI 53706, USA.
| | - Stephen Safe
- Department of Veterinary Physiology and Pharmacology, 4466 TAMU, Texas A&M University, College Station, TX 77843, USA.
| | - Richard E Peterson
- School of Pharmacy, 777 Highland Ave., University of Wisconsin-Madison, Madison, WI 53705, USA; Molecular and Environmental Toxicology Center, 1400 University Ave., University of Wisconsin-Madison, Madison, WI 53706, USA.
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Licznerska B, Baer-Dubowska W. Indole-3-Carbinol and Its Role in Chronic Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 928:131-154. [PMID: 27671815 DOI: 10.1007/978-3-319-41334-1_6] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Indole-3-carbinol (I3C), a common phytochemical in cruciferous vegetables, and its condensation product, 3,3'-diindolylmethane (DIM) exert several biological activities on cellular and molecular levels, which contribute to their well-recognized chemoprevention potential. Initially, these compounds were classified as blocking agents that increase drug-metabolizing enzyme activity. Now it is widely accepted that I3C and DIM affect multiple signaling pathways and target molecules controlling cell division, apoptosis, or angiogenesis deregulated in cancer cells. Although most of the current data support the role of I3C and DIM in prevention of hormone-dependent cancers, it seems that their application in prevention of the other cancer as well as cardiovascular disease, obesity, and diabetes reduction is also possible. This chapter summarizes the current experimental data on the I3C and DIM activity and the results of clinical studies indicating their role in prevention of chronic diseases.
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Affiliation(s)
- Barbara Licznerska
- Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, Poznan, Poland
| | - Wanda Baer-Dubowska
- Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, Poznan, Poland.
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31
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Akt activation correlates with the tumor aggressiveness in Tunisian patients with bladder cancer. Tumour Biol 2015; 37:7873-9. [DOI: 10.1007/s13277-015-4678-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Accepted: 12/16/2015] [Indexed: 10/22/2022] Open
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Ke H, Lisy JM. Influence of hydration on ion-biomolecule interactions: M(+)(indole)(H2O)(n) (M = Na, K; n = 3-6). Phys Chem Chem Phys 2015; 17:25354-64. [PMID: 26397000 DOI: 10.1039/c5cp01565k] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The indole functional group can be found in many biologically relevant molecules, such as neurotransmitters, pineal hormones and medicines. Indole has been used as a tractable model to study the hydration structures of biomolecules as well as the interplay of non-covalent interactions within ion-biomolecule-water complexes, which largely determine their structure and dynamics. With three potential binding sites: above the six- or five-member ring, and the N-H group, the competition between π and hydrogen bond interactions involves multiple locations. Electrostatic interactions from monovalent cations are in direct competition with hydrogen bonding interactions, as structural configurations involving both direct cation-indole interactions and cation-water-indole bridging interactions were observed. The different charge densities of Na(+) and K(+) give rise to different structural conformers at the same level of hydration. Infrared spectra with parallel hybrid functional-based calculations and Gibbs free energy calculations revealed rich structural insights into the Na(+)/K(+)(indole)(H2O)3-6 cluster ion complexes. Isotopic (H/D) analyses were applied to decouple the spectral features originating from the OH and NH stretches. Results showed no evidence of direct interaction between water and the NH group of indole (via a σ-hydrogen bond) at current levels of hydration with the incorporation of cations. Hydrogen bonding to a π-system, however, was ubiquitous at hydration levels between two and five.
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Affiliation(s)
- Haochen Ke
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
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Hubbard TD, Murray IA, Perdew GH. Indole and Tryptophan Metabolism: Endogenous and Dietary Routes to Ah Receptor Activation. Drug Metab Dispos 2015; 43:1522-35. [PMID: 26041783 PMCID: PMC4576673 DOI: 10.1124/dmd.115.064246] [Citation(s) in RCA: 464] [Impact Index Per Article: 46.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2015] [Accepted: 06/02/2015] [Indexed: 12/31/2022] Open
Abstract
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor recognized for its role in xenobiotic metabolism. The physiologic function of AHR has expanded to include roles in immune regulation, organogenesis, mucosal barrier function, and the cell cycle. These functions are likely dependent upon ligand-mediated activation of the receptor. High-affinity ligands of AHR have been classically defined as xenobiotics, such as polychlorinated biphenyls and dioxins. Identification of endogenous AHR ligands is key to understanding the physiologic functions of this enigmatic receptor. Metabolic pathways targeting the amino acid tryptophan and indole can lead to a myriad of metabolites, some of which are AHR ligands. Many of these ligands exhibit species selective preferential binding to AHR. The discovery of specific tryptophan metabolites as AHR ligands may provide insight concerning where AHR is activated in an organism, such as at the site of inflammation and within the intestinal tract.
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Affiliation(s)
- Troy D Hubbard
- Graduate Program in Biochemistry, Microbiology, and Molecular Biology (T.D.H.), and Center for Molecular Toxicology and Carcinogenesis and the Department of Veterinary and Biomedical Sciences (T.D.H., I.A.M., G.H.P)., Pennsylvania State University, University Park, Pennsylvania
| | - Iain A Murray
- Graduate Program in Biochemistry, Microbiology, and Molecular Biology (T.D.H.), and Center for Molecular Toxicology and Carcinogenesis and the Department of Veterinary and Biomedical Sciences (T.D.H., I.A.M., G.H.P)., Pennsylvania State University, University Park, Pennsylvania
| | - Gary H Perdew
- Graduate Program in Biochemistry, Microbiology, and Molecular Biology (T.D.H.), and Center for Molecular Toxicology and Carcinogenesis and the Department of Veterinary and Biomedical Sciences (T.D.H., I.A.M., G.H.P)., Pennsylvania State University, University Park, Pennsylvania
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Latosińska JN, Latosińska M, Szafrański M, Seliger J, Žagar V, Burchardt DV. Impact of structural differences in carcinopreventive agents indole-3-carbinol and 3,3'-diindolylmethane on biological activity. An X-ray, ¹H-¹⁴N NQDR, ¹³C CP/MAS NMR, and periodic hybrid DFT study. Eur J Pharm Sci 2015; 77:141-53. [PMID: 26066413 DOI: 10.1016/j.ejps.2015.06.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Revised: 06/01/2015] [Accepted: 06/04/2015] [Indexed: 10/23/2022]
Abstract
Three experimental techniques (1)H-(14)N NQDR, (13)C CP/MAS NMR and X-ray and Density Functional Theory (GGA/BLYP with PBC) and Hirshfeld surfaces were applied for the structure-activity oriented studies of two phyto-antioxidants and anticarcinogens: indole-3-carbinol, I3C, and 3,3'-diindolylmethane, DIM, (its bioactive metabolite). One set of (14)N NQR frequencies for DIM (2.310, 2.200 and 0.110 MHz at 295K) and I3C (2.315, 1.985 and 0.330 MHz at 160K) was recorded. The multiplicity of NQR lines recorded at RT revealed high symmetry (chemical and physical equivalence) of both methyl indazole rings of DIM. Carbonyl (13)C CSA tensor components were calculated from the (13)C CP/MAS solid state NMR spectrum of I3C recorded under fast and slow spinning. At room temperature the crystal structure of I3C is orthorhombic: space group Pca21, Z=4, a=5.78922(16), b=15.6434(7) and c=8.4405(2)Å. The I3C molecules are aggregated into ribbons stacked along [001]. The oxygen atomsare disorderedbetween the two sites of different occupancy factors. It implies that the crystal is built of about 70% trans and 30% gauche conformers, and apart from the weak OH⋯O hydrogen bonds (O⋯O=3.106Å) the formation of alternative O'H⋯O bonds (O'⋯O=2.785Å) is possible within the 1D ribbons. The adjacent ribbons are further stabilised by O'H⋯O bonds (O'⋯O=2.951Å). The analysis of spectra and intermolecular interactions pattern by experimental techniques was supported by solid (periodic) DFT calculations. The knowledge of the topology and competition of the interactions in crystalline state shed some light on the preferred conformations of CH2OH in I3C and steric hindrance of methyl indole rings in DIM. A comparison of the local environment in gas phase and solid permitted drawing some conclusions on the nature of the interactions required for effective processes of recognition and binding of a given anticarcinogen to the protein or nucleic acid.
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Affiliation(s)
| | - Magdalena Latosińska
- Faculty of Physics, Adam Mickiewicz University, Umultowska 85, 61-614 Poznań, Poland
| | - Marek Szafrański
- Faculty of Physics, Adam Mickiewicz University, Umultowska 85, 61-614 Poznań, Poland
| | - Janez Seliger
- Faculty of Mathematics and Physics, University of Ljubljana, Jadranska 19, 1000 Ljubljana, Slovenia; "Jozef Stefan" Institute, Jamova 39, 1000 Ljubljana, Slovenia
| | - Veselko Žagar
- "Jozef Stefan" Institute, Jamova 39, 1000 Ljubljana, Slovenia
| | - Dorota V Burchardt
- Department of Paediatric Dentistry, Poznan University of Medical Sciences, Bukowska 70, 60-812 Poznań, Poland
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Katz E, Nisani S, Yadav BS, Woldemariam MG, Shai B, Obolski U, Ehrlich M, Shani E, Jander G, Chamovitz DA. The glucosinolate breakdown product indole-3-carbinol acts as an auxin antagonist in roots of Arabidopsis thaliana. THE PLANT JOURNAL : FOR CELL AND MOLECULAR BIOLOGY 2015; 82:547-55. [PMID: 25758811 DOI: 10.1111/tpj.12824] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2014] [Revised: 02/26/2015] [Accepted: 03/04/2015] [Indexed: 05/21/2023]
Abstract
The glucosinolate breakdown product indole-3-carbinol functions in cruciferous vegetables as a protective agent against foraging insects. While the toxic and deterrent effects of glucosinolate breakdown on herbivores and pathogens have been studied extensively, the secondary responses that are induced in the plant by indole-3-carbinol remain relatively uninvestigated. Here we examined the hypothesis that indole-3-carbinol plays a role in influencing plant growth and development by manipulating auxin signaling. We show that indole-3-carbinol rapidly and reversibly inhibits root elongation in a dose-dependent manner, and that this inhibition is accompanied by a loss of auxin activity in the root meristem. A direct interaction between indole-3-carbinol and the auxin perception machinery was suggested, as application of indole-3-carbinol rescues auxin-induced root phenotypes. In vitro and yeast-based protein interaction studies showed that indole-3-carbinol perturbs the auxin-dependent interaction of Transport Inhibitor Response (TIR1) with auxin/3-indoleacetic acid (Aux/IAAs) proteins, further supporting the possibility that indole-3-carbinol acts as an auxin antagonist. The results indicate that chemicals whose production is induced by herbivory, such as indole-3-carbinol, function not only to repel herbivores, but also as signaling molecules that directly compete with auxin to fine tune plant growth and development.
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Affiliation(s)
- Ella Katz
- Molecular Biology and Ecology of Plants, Tel Aviv University, Ramat Aviv, 69978, Israel
| | - Sophia Nisani
- Molecular Biology and Ecology of Plants, Tel Aviv University, Ramat Aviv, 69978, Israel
| | - Brijesh S Yadav
- Molecular Biology and Ecology of Plants, Tel Aviv University, Ramat Aviv, 69978, Israel
| | | | - Ben Shai
- Cell Research and Immunology, Tel Aviv University, Ramat Aviv, 69978, Israel
| | - Uri Obolski
- Molecular Biology and Ecology of Plants, Tel Aviv University, Ramat Aviv, 69978, Israel
| | - Marcelo Ehrlich
- Cell Research and Immunology, Tel Aviv University, Ramat Aviv, 69978, Israel
| | - Eilon Shani
- Molecular Biology and Ecology of Plants, Tel Aviv University, Ramat Aviv, 69978, Israel
| | - Georg Jander
- Boyce Thompson Institute, Ithaca, NY, 14853, USA
| | - Daniel A Chamovitz
- Molecular Biology and Ecology of Plants, Tel Aviv University, Ramat Aviv, 69978, Israel
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Abstract
Recently, nutraceuticals have received increasing attention as the agents for cancer prevention and supplement with conventional therapy. Prostate cancer (PCa) is the most frequently diagnosed cancer and second leading cause of cancer-related death in men in the US. Growing evidences from epidemiological studies, in vitro experimental studies, animal studies, and clinical trials have shown that nutraceuticals could be very useful for the prevention and treatment of PCa. Several nutraceuticals including isoflavone, indole-3-carbinol, 3,3'-diindolylmethane, lycopene, (-)-epigallocatechin-3-gallate, and curcumin are known to downregulate the signal transductions in AR, Akt, NF-κB, and other signal transduction pathways which are vital for the development of PCa and the progression of PCa from androgen-sensitive to castrate-resistant PCa. Therefore, nutraceutical treatment in combination with conventional therapeutics could achieve better treatment outcome in prostate cancer therapy. Interestingly, some nutraceuticals could regulate the function of cancer stem cell (CSC)-related miRNAs and associated molecules, leading to the inhibition of prostatic CSCs which are responsible for drug resistance, tumor progression, and recurrence of PCa. Hence, nutraceuticals may serve as powerful agents for the prevention of PCa progression and they could also be useful in combination with chemotherapeutics or radiotherapy. Such strategy could become a promising newer approach for the treatment of metastatic PCa with better treatment outcome by improving overall survival.
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Affiliation(s)
- Yiwei Li
- Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, 740 Hudson Webber Cancer Research Center, 4100 John R, Detroit, MI, 48201, USA
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Katz E, Nisani S, Sela M, Behar H, Chamovitz DA. The effect of indole-3-carbinol on PIN1 and PIN2 in Arabidopsis roots. PLANT SIGNALING & BEHAVIOR 2015; 10:e1062200. [PMID: 26252364 PMCID: PMC4883967 DOI: 10.1080/15592324.2015.1062200] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/07/2023]
Abstract
The phytochemical indole-3-carbinol is produced in Cruciferous plants upon tissue rapture and deters herbivores. We recently showed that indole-3-carbinol modulates auxin signaling in root tips. Here we present transcript profiling experiments which further reveal the influence of indole-3-carbinol on auxin signaling in root tips, and also show that I3C affects auxin transporters. Brief treatment with indole-3-carbinol led to a reduction in the amount of PIN1 and to mislocalization of PIN2.
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Affiliation(s)
- Ella Katz
- Molecular Biology and Ecology of Plants; Tel Aviv University; Ramat Aviv, Israel
| | - Sophia Nisani
- Molecular Biology and Ecology of Plants; Tel Aviv University; Ramat Aviv, Israel
| | - Mor Sela
- Molecular Biology and Ecology of Plants; Tel Aviv University; Ramat Aviv, Israel
| | - Hila Behar
- Molecular Biology and Ecology of Plants; Tel Aviv University; Ramat Aviv, Israel
| | - Daniel A Chamovitz
- Molecular Biology and Ecology of Plants; Tel Aviv University; Ramat Aviv, Israel
- Correspondence to: Daniel A Chamovitz;
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38
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Regulation of microRNAs by natural agents: new strategies in cancer therapies. BIOMED RESEARCH INTERNATIONAL 2014; 2014:804510. [PMID: 25254214 PMCID: PMC4165563 DOI: 10.1155/2014/804510] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/04/2014] [Accepted: 08/14/2014] [Indexed: 12/19/2022]
Abstract
MicroRNAs (miRNAs) are short noncoding RNA which regulate gene expression by messenger RNA (mRNA) degradation or translation repression. The plethora of published reports in recent years demonstrated that they play fundamental roles in many biological processes, such as carcinogenesis, angiogenesis, programmed cell death, cell proliferation, invasion, migration, and differentiation by acting as tumour suppressor or oncogene, and aberrations in their expressions have been linked to onset and progression of various cancers. Furthermore, each miRNA is capable of regulating the expression of many genes, allowing them to simultaneously regulate multiple cellular signalling pathways. Hence, miRNAs have the potential to be used as biomarkers for cancer diagnosis and prognosis as well as therapeutic targets. Recent studies have shown that natural agents such as curcumin, resveratrol, genistein, epigallocatechin-3-gallate, indole-3-carbinol, and 3,3′-diindolylmethane exert their antiproliferative and/or proapoptotic effects through the regulation of one or more miRNAs. Therefore, this review will look at the regulation of miRNAs by natural agents as a means to potentially enhance the efficacy of conventional chemotherapy through combinatorial therapies. It is hoped that this would provide new strategies in cancer therapies to improve overall response and survival outcome in cancer patients.
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Bell L, Wagstaff C. Glucosinolates, myrosinase hydrolysis products, and flavonols found in rocket (Eruca sativa and Diplotaxis tenuifolia). JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2014; 62:4481-92. [PMID: 24773270 DOI: 10.1021/jf501096x] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
Rocket species have been shown to have very high concentrations of glucosinolates and flavonols, which have numerous positive health benefits with regular consumption. This review highlights how breeders and processors of rocket species can utilize genomic and phytochemical research to improve varieties and enhance the nutritive benefits to consumers. Plant breeders are increasingly looking to new technologies such as HPLC, UPLC, LC-MS, and GC-MS to screen populations for their phytochemical content to inform plant selections. This paper collates the research that has been conducted to date in rocket and summarizes all glucosinolate and flavonol compounds identified in the species. The paper emphasizes the importance of the broad screening of populations for phytochemicals and myrosinase degradation products, as well as unique traits that may be found in underutilized gene bank resources. This review also stresses that collaboration with industrial partners is becoming essential for long-term plant breeding goals through research.
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Affiliation(s)
- Luke Bell
- Department of Food and Nutritional Sciences and the Centre for Food Security, University of Reading , Whiteknights, Reading, Berkshire RG6 6AH, United Kingdom
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40
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Indole-3-carbinol attenuates the deleterious gestational effects of bisphenol A exposure on the prostate gland of male F1 rats. Reprod Toxicol 2014; 43:56-66. [DOI: 10.1016/j.reprotox.2013.11.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2013] [Revised: 10/04/2013] [Accepted: 11/04/2013] [Indexed: 02/06/2023]
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Busbee PB, Nagarkatti M, Nagarkatti PS. Natural indoles, indole-3-carbinol and 3,3'-diindolymethane, inhibit T cell activation by staphylococcal enterotoxin B through epigenetic regulation involving HDAC expression. Toxicol Appl Pharmacol 2014; 274:7-16. [PMID: 24200994 PMCID: PMC3874587 DOI: 10.1016/j.taap.2013.10.022] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2013] [Revised: 10/24/2013] [Accepted: 10/25/2013] [Indexed: 12/13/2022]
Abstract
Staphylococcal enterotoxin B (SEB) is a potent exotoxin produced by the Staphylococcus aureus. This toxin is classified as a superantigen because of its ability to directly bind with MHC-II class molecules followed by activation of a large proportion of T cells bearing specific Vβ-T cell receptors. Commonly associated with classic food poisoning, SEB has also been shown to induce toxic shock syndrome, and is also considered to be a potential biological warfare agent because it is easily aerosolized. In the present study, we assessed the ability of indole-3-carbinol (I3C) and one of its byproducts, 3,3'-diindolylmethane (DIM), found in cruciferous vegetables, to counteract the effects of SEB-induced activation of T cells in mice. Both I3C and DIM were found to decrease the activation, proliferation, and cytokine production by SEB-activated Vβ8(+) T cells in vitro and in vivo. Interestingly, inhibitors of histone deacetylase class I (HDAC-I), but not class II (HDAC-II), showed significant decrease in SEB-induced T cell activation and cytokine production, thereby suggesting that epigenetic modulation plays a critical role in the regulation of SEB-induced inflammation. In addition, I3C and DIM caused a decrease in HDAC-I but not HDAC-II in SEB-activated T cells, thereby suggesting that I3C and DIM may inhibit SEB-mediated T cell activation by acting as HDAC-I inhibitors. These studies not only suggest for the first time that plant-derived indoles are potent suppressors of SEB-induced T cell activation and cytokine storm but also that they may mediate these effects by acting as HDAC inhibitors.
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Affiliation(s)
- Philip B Busbee
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29208, USA
| | - Mitzi Nagarkatti
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29208, USA
| | - Prakash S Nagarkatti
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29208, USA.
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Ahmad A, Biersack B, Li Y, Kong D, Bao B, Schobert R, Padhye SB, Sarkar FH. Targeted regulation of PI3K/Akt/mTOR/NF-κB signaling by indole compounds and their derivatives: mechanistic details and biological implications for cancer therapy. Anticancer Agents Med Chem 2013; 13:1002-13. [PMID: 23272910 DOI: 10.2174/18715206113139990078] [Citation(s) in RCA: 144] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Revised: 12/05/2012] [Accepted: 12/06/2012] [Indexed: 12/17/2022]
Abstract
Indole compounds, found in cruciferous vegetables, are potent anti-cancer agents. Studies with indole-3-carbinol (I3C) and its dimeric product, 3,3'-diindolylmethane (DIM) suggest that these compounds have the ability to deregulate multiple cellular signaling pathways, including PI3K/Akt/mTOR signaling pathway. These natural compounds are also effective modulators of downstream transcription factor NF-κB signaling which might help explain their ability to inhibit invasion and angiogenesis, and the reversal of epithelial-to-mesenchymal transition (EMT) phenotype and drug resistance. Signaling through PI3K/Akt/mTOR and NF-κB pathway is increasingly being realized to play important role in EMT through the regulation of novel miRNAs which further validates the importance of this signaling network and its regulations by indole compounds. Here we will review the available literature on the modulation of PI3K/Akt/mTOR/NF-κB signaling by both parental I3C and DIM, as well as their analogs/derivatives, in an attempt to catalog their anticancer activity.
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Affiliation(s)
- Aamir Ahmad
- Department of Pathology and Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA
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43
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Effect of storage on the content of indole-glucosinolate breakdown products and vitamin C of sauerkrauts treated by high hydrostatic pressure. Lebensm Wiss Technol 2013. [DOI: 10.1016/j.lwt.2013.01.015] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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44
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Wu TY, Khor TO, Su ZY, Saw CLL, Shu L, Cheung KL, Huang Y, Yu S, Kong ANT. Epigenetic modifications of Nrf2 by 3,3'-diindolylmethane in vitro in TRAMP C1 cell line and in vivo TRAMP prostate tumors. AAPS JOURNAL 2013; 15:864-74. [PMID: 23658110 DOI: 10.1208/s12248-013-9493-3] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 01/20/2013] [Accepted: 04/17/2013] [Indexed: 01/09/2023]
Abstract
3,3'-diindolylmethane (DIM) is currently being investigated in many clinical trials including prostate, breast, and cervical cancers and has been shown to possess anticancer effects in several in vivo and in vitro models. Previously, DIM has been reported to possess cancer chemopreventive effects in prostate carcinogenesis in TRAMP mice; however, the in vivo mechanism is unclear. The present study aims to investigate the in vitro and in vivo epigenetics modulation of DIM in TRAMP-C1 cells and in TRAMP mouse model. In vitro study utilizing TRAMP-C1 cells showed that DIM suppressed DNMT expression and reversed CpG methylation status of Nrf2 resulting in enhanced expression of Nrf2 and Nrf2-target gene NQO1. In vivo study, TRAMP mice fed with DIM-supplemented diet showed much lower incidence of tumorigenesis and metastasis than the untreated control group similar to what was reported previously. DIM increased apoptosis, decreased cell proliferation and enhanced Nrf2 and Nrf2-target gene NQO1 expression in prostate tissues. Importantly, immunohistochemical analysis showed that DIM reduced the global CpG 5-methylcytosine methylation. Focusing on one of the early cancer chemopreventive target gene Nrf2, bisulfite genomic sequencing showed that DIM decreased the methylation status of the first five CpGs of the Nrf2 promoter region, corroborating with the results of in vitro TRAMP-C1 cells. In summary, our current study shows that DIM is a potent cancer chemopreventive agent for prostate cancer and epigenetic modifications of the CpG including Nrf2 could be a potential mechanism by which DIM exerts its chemopreventive effects.
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Affiliation(s)
- Tien-Yuan Wu
- Center for Cancer Prevention Research, Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Room 228, 160 Frelinghuysen Road, Piscataway, New Jersey, 08854, USA
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45
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Beaver LM, Yu TW, Sokolowski EI, Williams DE, Dashwood RH, Ho E. 3,3'-Diindolylmethane, but not indole-3-carbinol, inhibits histone deacetylase activity in prostate cancer cells. Toxicol Appl Pharmacol 2012; 263:345-51. [PMID: 22800507 DOI: 10.1016/j.taap.2012.07.007] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2012] [Revised: 06/22/2012] [Accepted: 07/07/2012] [Indexed: 12/21/2022]
Abstract
Increased consumption of cruciferous vegetables is associated with a reduced risk of developing prostate cancer. Indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM) are phytochemicals derived from cruciferous vegetables that have shown promise in inhibiting prostate cancer in experimental models. Histone deacetylase (HDAC) inhibition is an emerging target for cancer prevention and therapy. We sought to examine the effects of I3C and DIM on HDACs in human prostate cancer cell lines: androgen insensitive PC-3 cells and androgen sensitive LNCaP cells. I3C modestly inhibited HDAC activity in LNCaP cells by 25% but no inhibition of HDAC activity was detected in PC-3 cells. In contrast, DIM significantly inhibited HDAC activity in both cell lines by as much as 66%. Decreases in HDAC activity correlated with increased expression of p21, a known target of HDAC inhibitors. DIM treatment caused a significant decrease in the expression of HDAC2 protein in both cancer cell lines but no significant change in the protein levels of HDAC1, HDAC3, HDAC4, HDAC6 or HDAC8 was detected. Taken together, these results show that inhibition of HDAC activity by DIM may contribute to the phytochemicals' anti-proliferative effects in the prostate. The ability of DIM to target aberrant epigenetic patterns, in addition to its effects on detoxification of carcinogens, may make it an effective chemopreventive agent by targeting multiple stages of prostate carcinogenesis.
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Affiliation(s)
- Laura M Beaver
- Linus Pauling Institute, Oregon State University, 307 Linus Pauling Science Center, Corvallis, OR 97331, USA.
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46
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Ralph JL, Von Ah D, Scheett AJ, Hoverson BS, Anderson CM. Diet assessment methods: a guide for oncology nurses. Clin J Oncol Nurs 2012; 15:E114-21. [PMID: 22119986 DOI: 10.1188/11.cjon.e114-e121] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Diet may play a significant role in cancer prevention, disease progression, and treatment tolerance. An in-depth search of the literature revealed limited information geared toward nurses about diet assessment methods used in research. The purpose of this review is to synthesize the evidence regarding diet assessment methods important in oncology studies. The method used varied based on the study size, duration, and research question. For example, studies focusing on mean nutrient intake of a group used a 24-hour dietary recall, estimated food diary or dietary record, or food frequency questionnaire. Studies investigating usual nutrient intake predominately used multiple 24-hour dietary recalls, dietary records, biomarkers, or food frequency questionnaires. Measuring dietary intake accurately in a cost-effective manner is a difficult task. Selection of the appropriate assessment tool is critical for the generation of quality data. Oncology nurses are increasing their involvement in nutrition research, and the findings from this review may promote a better understanding of the published and ongoing research in this important field of study.
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Affiliation(s)
- Jody L Ralph
- College of Nursing, University of North Dakota in Grand Forks, USA.
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47
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Sharma V, Kalia R, Raj T, Gupta VK, Suri N, Saxena AK, Sharma D, Bhella SS, Singh G, Ishar MPS. Synthesis and cytotoxic evaluation of substituted 3-(3′-indolyl-/3′-pyridyl)-isoxazolidines and bis-indoles. Acta Pharm Sin B 2012. [DOI: 10.1016/j.apsb.2011.12.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
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48
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Ho E, Beaver LM, Williams DE, Dashwood RH. Dietary factors and epigenetic regulation for prostate cancer prevention. Adv Nutr 2011; 2:497-510. [PMID: 22332092 PMCID: PMC3226387 DOI: 10.3945/an.111.001032] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The role of epigenetic alterations in various human chronic diseases has gained increasing attention and has resulted in a paradigm shift in our understanding of disease susceptibility. In the field of cancer research, e.g., genetic abnormalities/mutations historically were viewed as primary underlying causes; however, epigenetic mechanisms that alter gene expression without affecting DNA sequence are now recognized as being of equal or greater importance for oncogenesis. Methylation of DNA, modification of histones, and interfering microRNA (miRNA) collectively represent a cadre of epigenetic elements dysregulated in cancer. Targeting the epigenome with compounds that modulate DNA methylation, histone marks, and miRNA profiles represents an evolving strategy for cancer chemoprevention, and these approaches are starting to show promise in human clinical trials. Essential micronutrients such as folate, vitamin B-12, selenium, and zinc as well as the dietary phytochemicals sulforaphane, tea polyphenols, curcumin, and allyl sulfur compounds are among a growing list of agents that affect epigenetic events as novel mechanisms of chemoprevention. To illustrate these concepts, the current review highlights the interactions among nutrients, epigenetics, and prostate cancer susceptibility. In particular, we focus on epigenetic dysregulation and the impact of specific nutrients and food components on DNA methylation and histone modifications that can alter gene expression and influence prostate cancer progression.
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Affiliation(s)
- Emily Ho
- Linus Pauling Institute, Department of Nutrition and Exercise Sciences, Oregon State University, Corvallis, OR, USA.
| | - Laura M. Beaver
- Linus Pauling Institute,Department of Nutrition and Exercise Sciences, and
| | - David E. Williams
- Linus Pauling Institute,Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR
| | - Roderick H. Dashwood
- Linus Pauling Institute,Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR
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49
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Kim DJ, Reddy K, Kim MO, Li Y, Nadas J, Cho YY, Kim JE, Shim JH, Song NR, Carper A, Lubet RA, Bode AM, Dong Z. (3-Chloroacetyl)-indole, a novel allosteric AKT inhibitor, suppresses colon cancer growth in vitro and in vivo. Cancer Prev Res (Phila) 2011; 4:1842-51. [PMID: 21885813 PMCID: PMC3244047 DOI: 10.1158/1940-6207.capr-11-0158] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Indole-3-carbinol (I3C) is produced in Brassica vegetables such as broccoli and cabbage and has been shown to inhibit proliferation and induce apoptosis in various cancer cells, including breast, prostate, colon, and leukemia. However, only high doses of I3C were shown to inhibit cell proliferation (IC(50) = 200-300 μmol/L). Our goal here was to develop a more potent antitumor agent by modifying the structure of I3C. We created I3C derivatives and found that (3-chloroacetyl)-indole (3CAI) more strongly inhibited colon cancer cell growth than I3C. In addition, by screening 85 kinases in a competitive kinase assay, we found that 3CAI was a specific AKT inhibitor. AKT is a serine/threonine kinase that plays a pivotal role in promoting transformation and chemoresistance by inducing proliferation and inhibiting apoptosis. Therefore, AKT is regarded as a critical target for cancer therapy. 3ICA, a derivative of I3C, is a potent and specific AKT inhibitor. This compound showed significant inhibition of AKT in an in vitro kinase assay and suppressed expression of AKT direct downstream targets such as mTOR and GSK3β as well as induced growth inhibition and apoptosis in colon cancer cells. In addition, oral administration of this potent AKT inhibitor suppressed cancer cell growth in an in vivo xenograft mouse model.
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Affiliation(s)
- Dong Joon Kim
- The Hormel Institute, University of Minnesota, MN 55912, USA
| | - Kanamata Reddy
- The Hormel Institute, University of Minnesota, MN 55912, USA
| | - Myoung Ok Kim
- The Hormel Institute, University of Minnesota, MN 55912, USA
| | - Yan Li
- The Hormel Institute, University of Minnesota, MN 55912, USA
| | - Janos Nadas
- The Hormel Institute, University of Minnesota, MN 55912, USA
| | - Yong-Yeon Cho
- The Hormel Institute, University of Minnesota, MN 55912, USA
- Department of Pharmacology, College of Pharmacy, The Catholic University of Korea, Bucheon 420-102, Republic of Korea
| | - Jong-Eun Kim
- The Hormel Institute, University of Minnesota, MN 55912, USA
| | - Jung-Hyun Shim
- Department of Biochemistry, College of Medicine, Soonchunhyang University, Cheonan 330-090, Republic of Korea
| | - Nu Ry Song
- Department of Agricultural Biotechnology, Seoul National University, Seoul 151-921, Republic of Korea
| | - Andria Carper
- The Hormel Institute, University of Minnesota, MN 55912, USA
| | | | - Ann M Bode
- The Hormel Institute, University of Minnesota, MN 55912, USA
| | - Zigang Dong
- The Hormel Institute, University of Minnesota, MN 55912, USA
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50
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Richman EL, Carroll PR, Chan JM. Vegetable and fruit intake after diagnosis and risk of prostate cancer progression. Int J Cancer 2011; 131:201-10. [PMID: 21823116 DOI: 10.1002/ijc.26348] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2011] [Accepted: 07/29/2011] [Indexed: 11/05/2022]
Abstract
Cruciferous vegetables, tomato sauce and legumes have been associated with reduced risk of incident advanced prostate cancer. In vitro and animal studies suggest these foods may inhibit progression of prostate cancer, but there are limited data in men. Therefore, we prospectively examined whether intake of total vegetables, and specifically cruciferous vegetables, tomato sauce and legumes, after diagnosis reduce risk of prostate cancer progression among 1,560 men diagnosed with non-metastatic prostate cancer and participating in the Cancer of the Prostate Strategic Urologic Research Endeavor, a United States prostate cancer registry. As a secondary analysis, we also examined other vegetable subgroups, total fruit and subgroups of fruits. The participants were diagnosed primarily at community-based clinics and followed from 2004 to 2009. We assessed vegetable and fruit intake via a semi-quantitative food frequency questionnaire, and ascertained prostate cancer outcomes via urologist report and medical records. We observed 134 events of progression (53 biochemical recurrences, 71 secondary treatments likely due to recurrence, 6 bone metastases and 4 prostate cancer deaths) during 3,171 person-years. Men in the fourth quartile of post-diagnostic cruciferous vegetable intake had a statistically significant 59% decreased risk of prostate cancer progression compared to men in the lowest quartile (hazard ratio (HR): 0.41; 95% confidence interval (CI): 0.22, 0.76; p-trend: 0.003). No other vegetable or fruit group was statistically significantly associated with risk of prostate cancer progression. In conclusion, cruciferous vegetable intake after diagnosis may reduce risk of prostate cancer progression.
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Affiliation(s)
- Erin L Richman
- Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
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