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Zhu J, Zheng Z, Yin Z, Ding L, Li C, Wang X, Shu P, Zhou J, Liu W, Liu J. MiR-146b overexpression promotes bladder cancer cell growth via the SMAD4/C-MYC/Cyclin D1 axis. Front Oncol 2025; 15:1565638. [PMID: 40224178 PMCID: PMC11985428 DOI: 10.3389/fonc.2025.1565638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Accepted: 03/03/2025] [Indexed: 04/15/2025] Open
Abstract
MiR-146b has been identified as being overexpressed in human bladder cancer (BCa) and implicated in promoting cancer cell invasion. However, its specific involvement in BCa cell growth remains unclear. In this study, we demonstrate that the downregulation of miR-146b significantly suppresses tumorigenic growth of human BCa cells both in vitro and in vivo by inducing G0/G1 cell cycle arrest. Specifically, miR-146b inhibition resulted in a significant reduction in colony formation (p < 0.05) and anchorage-independent growth in both UMUC3 and T24T cells, as measured by soft agar assays, with three independent replicates for each experiment. Notably, Cyclin D1 protein plays a crucial role in miR-146b-induced BCa cell proliferation, as confirmed by Western blotting (p < 0.05), with each experiment performed in triplicate. Mechanistic investigations reveal that miR-146b reduces mothers against decapentaplegic homolog 4 (SMAD4) mRNA stability by directly binding to its 3' untranslated region (3'-UTR), leading to decreased SMAD4 expression. This reduction in SMAD4 levels promotes cellular myelocytomatosis (C-MYC) transcription, which in turn enhances Cyclin D1 transcription, ultimately facilitating BCa cell proliferation. The findings unveil a novel regulatory axis involving SMAD4/C-MYC/Cyclin D1 in mediating the oncogenic role of miR-146b in BCa cells. Statistical significance was determined using Student's t-test, with p-values <0.05 considered significant. Together with its previously established function in BCa invasion, the results highlight the potential for developing miR-146b-based therapeutic strategies for treating human BCa patients.
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Affiliation(s)
- Junlan Zhu
- Precision Medicine Laboratory, Beilun People’s Hospital, Beilun Branch of the First Affiliated Hospital, School of Medicine, Zhejiang University, Ningbo, Zhejiang, China
| | - Zhijian Zheng
- Department of Medical Oncology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Zhangya Yin
- Precision Medicine Laboratory, Beilun People’s Hospital, Beilun Branch of the First Affiliated Hospital, School of Medicine, Zhejiang University, Ningbo, Zhejiang, China
| | - Linchao Ding
- Department of Scientific Research, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Congya Li
- Precision Medicine Laboratory, Beilun People’s Hospital, Beilun Branch of the First Affiliated Hospital, School of Medicine, Zhejiang University, Ningbo, Zhejiang, China
| | - Xuyao Wang
- Precision Medicine Laboratory, Beilun People’s Hospital, Beilun Branch of the First Affiliated Hospital, School of Medicine, Zhejiang University, Ningbo, Zhejiang, China
| | - Peng Shu
- Precision Medicine Laboratory, Beilun People’s Hospital, Beilun Branch of the First Affiliated Hospital, School of Medicine, Zhejiang University, Ningbo, Zhejiang, China
| | - Jun Zhou
- Department of Urology, Beilun People’s Hospital, Beilun Branch of the First Affiliated Hospital, School of Medicine, Zhejiang University, Ningbo, Zhejiang, China
| | - Weihua Liu
- Department of Urology, Beilun People’s Hospital, Beilun Branch of the First Affiliated Hospital, School of Medicine, Zhejiang University, Ningbo, Zhejiang, China
| | - Jian Liu
- Precision Medicine Laboratory, Beilun People’s Hospital, Beilun Branch of the First Affiliated Hospital, School of Medicine, Zhejiang University, Ningbo, Zhejiang, China
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Ekramzadeh M, Kalantar-Zadeh K, Kopple JD. The Relevance of Phytate for the Treatment of Chronic Kidney Disease. Clin J Am Soc Nephrol 2024; 19:1341-1355. [PMID: 39110986 PMCID: PMC11469791 DOI: 10.2215/cjn.0000000000000558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 07/30/2024] [Indexed: 10/13/2024]
Abstract
Diets high in plant-based foods are commonly recommended for people with CKD. One putative advantage of these diets is reduced intestinal phosphate absorption. This effect has been ascribed to phytic acid (myoinositol hexaphosphoric acid) and its anion, phytate, that are present in many plant foods, particularly in the seeds, nuts, grains, and fruits of plants. This article reviews the structure and many actions of phytate with particular reference to its potential effects on people with CKD. Phytate binds avidly to and can reduce gastrointestinal absorption of the phosphate anion and many macrominerals and trace elements including iron, zinc, calcium, and magnesium. This has led some opinion leaders to label phytate as an anti-nutrient. The human intestine lacks phytase; hence, phytate is essentially not degraded in the small intestine. A small amount of phytate is absorbed from the small intestine, although phytate bound to phosphate is poorly absorbed. Clinical trials in maintenance hemodialysis patients indicate that intravenously administered phytate may decrease hydroxyapatite formation, vascular calcification, and calciphylaxis. Orally administered phytate or in vitro studies indicate that phytate may also reduce osteoporosis, urinary calcium calculi formation, and dental plaque formation. Phytate seems to have anti-inflammatory and antioxidant effects, at least partly because of its ability to chelate iron. Other potential therapeutic roles for phytate, not definitively established, include suppression of cancer formation, reduction in cognitive decline that occurs with aging, and amelioration of certain neurodegenerative diseases and several gastrointestinal and metabolic disorders. These latter potential benefits of phytate are supported by cell or animal research or observational studies in humans. Many of the above disorders are particularly common in patients with CKD. Definitive clinical trials to identify potential therapeutic benefits of phytate in patients with CKD are clearly warranted.
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Affiliation(s)
- Maryam Ekramzadeh
- David Geffen School of Medicine at UCLA and the UCLA Fielding School of Public Health, Los Angeles, CA
| | - Kamyar Kalantar-Zadeh
- David Geffen School of Medicine at UCLA and the UCLA Fielding School of Public Health, Los Angeles, CA
| | - Joel D. Kopple
- David Geffen School of Medicine at UCLA and the UCLA Fielding School of Public Health, Los Angeles, CA
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Kadhim IH, Oluremi AS, Chhetri BP, Ghosh A, Ali N. Encapsulation of Inositol Hexakisphosphate with Chitosan via Gelation to Facilitate Cellular Delivery and Programmed Cell Death in Human Breast Cancer Cells. Bioengineering (Basel) 2024; 11:931. [PMID: 39329673 PMCID: PMC11429465 DOI: 10.3390/bioengineering11090931] [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: 08/23/2024] [Revised: 09/08/2024] [Accepted: 09/11/2024] [Indexed: 09/28/2024] Open
Abstract
Inositol hexakisphosphate (InsP6) is the most abundant inositol polyphosphate both in plant and animal cells. Exogenous InsP6 is known to inhibit cell proliferation and induce apoptosis in cancerous cells. However, cellular entry of exogenous InsP6 is hindered due to the presence of highly negative charge on this molecule. Therefore, to enhance the cellular delivery of InsP6 in cancerous cells, InsP6 was encapsulated by chitosan (CS), a natural polysaccharide, via the ionic gelation method. Our hypothesis is that encapsulated InsP6 will enter the cell more efficiently to trigger its apoptotic effects. The incorporation of InsP6 into CS was optimized by varying the ratios of the two and confirmed by InsP6 analysis via polyacrylamide gel electrophoresis (PAGE) and atomic absorption spectrophotometry (AAS). The complex was further characterized by Scanning Electron Microscopy (SEM) and Fourier Transform Infrared Spectroscopy (FTIR) for physicochemical changes. The data indicated morphological changes and changes in the spectral properties of the complex upon encapsulation. The encapsulated InsP6 enters human breast cancer MCF-7 cells more efficiently than free InsP6 and triggers apoptosis via a mechanism involving the production of reactive oxygen species (ROS). This work has potential for developing cancer therapeutic applications utilizing natural compounds that are likely to overcome the severe toxic effects associated with synthetic chemotherapeutic drugs.
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Affiliation(s)
- Ilham H Kadhim
- Department of Biology, Donaghey College of Science, Engineering, Technology, and Mathematics, University of Arkansas at Little Rock, 2801 South University Avenue, Little Rock, AR 72204, USA
| | - Adeolu S Oluremi
- Department of Biology, Donaghey College of Science, Engineering, Technology, and Mathematics, University of Arkansas at Little Rock, 2801 South University Avenue, Little Rock, AR 72204, USA
| | - Bijay P Chhetri
- Department of Chemistry, Donaghey College of Science, Engineering, Technology, and Mathematics, University of Arkansas at Little Rock, 2801 South University Avenue, Little Rock, AR 72204, USA
| | - Anindya Ghosh
- Department of Chemistry, Donaghey College of Science, Engineering, Technology, and Mathematics, University of Arkansas at Little Rock, 2801 South University Avenue, Little Rock, AR 72204, USA
| | - Nawab Ali
- Department of Biology, Donaghey College of Science, Engineering, Technology, and Mathematics, University of Arkansas at Little Rock, 2801 South University Avenue, Little Rock, AR 72204, USA
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Pujol A, Sanchis P, Grases F, Masmiquel L. Phytate Intake, Health and Disease: "Let Thy Food Be Thy Medicine and Medicine Be Thy Food". Antioxidants (Basel) 2023; 12:antiox12010146. [PMID: 36671007 PMCID: PMC9855079 DOI: 10.3390/antiox12010146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 01/04/2023] [Accepted: 01/05/2023] [Indexed: 01/11/2023] Open
Abstract
Phytate (myo-inositol hexakisphosphate or InsP6) is the main phosphorus reservoir that is present in almost all wholegrains, legumes, and oilseeds. It is a major component of the Mediterranean and Dietary Approaches to Stop Hypertension (DASH) diets. Phytate is recognized as a nutraceutical and is classified by the Food and Drug Administration (FDA) as Generally Recognized As Safe (GRAS). Phytate has been shown to be effective in treating or preventing certain diseases. Phytate has been shown to inhibit calcium salt crystallization and, therefore, to reduce vascular calcifications, calcium renal calculi and soft tissue calcifications. Moreover, the adsorption of phytate to the crystal faces can inhibit hydroxyapatite dissolution and bone resorption, thereby playing a role in the treatment/prevention of bone mass loss. Phytate has a potent antioxidation and anti-inflammatory action. It is capable of inhibiting lipid peroxidation through iron chelation, reducing iron-related free radical generation. As this has the effect of mitigating neuronal damage and loss, phytate shows promise in the treatment/prevention of neurodegenerative disease. It is reported that phytate improves lipid and carbohydrate metabolism, increases adiponectin, decreases leptin and reduces protein glycation, which is linked with macrovascular and microvascular diabetes complications. In this review, we summarize the benefits of phytate intake as seen in in vitro, animal model, epidemiological and clinical trials, and we also identify questions to answer in the future.
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Affiliation(s)
- Antelm Pujol
- Vascular and Metabolic Diseases Research Group, Endocrinology Department, Son Llàtzer University Hospital, Health Research Institute of the Balearic Islands (IdISBa), 07198 Palma de Mallorca, Spain
- Correspondence: (A.P.); (L.M.)
| | - Pilar Sanchis
- Laboratory of Renal Lithiasis Research, Deptartment of Chemistry, University of Balearic Islands, Health Research Institute of Balearic Islands, (IdISBa), 07122 Palma de Mallorca, Spain
| | - Felix Grases
- Laboratory of Renal Lithiasis Research, Deptartment of Chemistry, University of Balearic Islands, Health Research Institute of Balearic Islands, (IdISBa), 07122 Palma de Mallorca, Spain
| | - Luis Masmiquel
- Vascular and Metabolic Diseases Research Group, Endocrinology Department, Son Llàtzer University Hospital, Health Research Institute of the Balearic Islands (IdISBa), 07198 Palma de Mallorca, Spain
- Correspondence: (A.P.); (L.M.)
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Lou N, Zheng C, Wang Y, Liang C, Tan Q, Luo R, Zhang L, Xie T, Shi Y, Han X. Identification of novel serological autoantibodies in Chinese prostate cancer patients using high-throughput protein arrays. Cancer Immunol Immunother 2023; 72:235-247. [PMID: 35831618 DOI: 10.1007/s00262-022-03242-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Accepted: 06/13/2022] [Indexed: 01/07/2023]
Abstract
Autoantibody (AAb) has a prominent role in prostate cancer (PCa), with few studies profiling the AAb landscape in Chinese patients. Therefore, the AAb landscape in Chinese patients was characterized using protein arrays. First, in the discovery phase, Huprot arrays outlined autoimmune profiles against ~ 21,888 proteins from 57 samples. In the verification phase, the PCa-focused arrays detected 25 AAbs selected from the discovery phase within 178 samples. Then, PCa was detected using a backpropagation artificial neural network (BPANN) model. In the validation phase, an enzyme-linked immunosorbent assay (ELISA) was used to validate four AAb biomarkers from 196 samples. Huprot arrays profiled distinct PCa, benign prostate diseases (BPD), and health AAb landscapes. PCa-focused array depicted that IFIT5 and CPOX AAbs could distinguish PCa from health with an area under curve (AUC) of 0.71 and 0.70, respectively. PAH and FCER2 AAbs had AUCs of 0.86 and 0.88 in discriminating PCa from BPD. Particularly, PAH AAb detected patients in the prostate-specific antigen (PSA) gray zone with an AUC of 0.86. Meanwhile, the BPANN model of 4-AAb (IFIT5, PAH, FCER2, CPOX) panel attained AUC of 0.83 among the two cohorts for detecting patients with gray-zone PSA. In the validation cohort, the IFIT5 AAb was upregulated in PCa compared to health (p < 0.001). Compared with BPD, PAH and FCER2 AAbs were significantly elevated in PCa (p = 0.012 and 0.039). We have demonstrated the first extensive profiling of autoantibodies in Chinese PCa patients, identifying novel diagnostic AAb biomarkers, especially for identification of gray-zone-PSA patients.
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Affiliation(s)
- Ning Lou
- Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China.,Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of Clinical Study On Anticancer Molecular Targeted Drugs, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Cuiling Zheng
- Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Yanrong Wang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of Clinical Study On Anticancer Molecular Targeted Drugs, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Caixia Liang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of Clinical Study On Anticancer Molecular Targeted Drugs, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Qiaoyun Tan
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of Clinical Study On Anticancer Molecular Targeted Drugs, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Rongrong Luo
- Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Lei Zhang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of Clinical Study On Anticancer Molecular Targeted Drugs, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Tongji Xie
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of Clinical Study On Anticancer Molecular Targeted Drugs, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Yuankai Shi
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of Clinical Study On Anticancer Molecular Targeted Drugs, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China.
| | - Xiaohong Han
- Clinical Pharmacology Research Center, Peking Union Medical College Hospital, State Key Laboratory of Complex Severe and Rare Diseases, NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing Key Laboratory of Clinical PK and PD Investigation for Innovative Drugs, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China.
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Raina K, Kandhari K, Jain AK, Ravichandran K, Maroni P, Agarwal C, Agarwal R. Stage-Specific Effect of Inositol Hexaphosphate on Cancer Stem Cell Pool during Growth and Progression of Prostate Tumorigenesis in TRAMP Model. Cancers (Basel) 2022; 14:4204. [PMID: 36077751 PMCID: PMC9455012 DOI: 10.3390/cancers14174204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 08/23/2022] [Accepted: 08/27/2022] [Indexed: 11/16/2022] Open
Abstract
Herein, we assessed the stage-specific efficacy of inositol hexaphosphate (IP6, phytic acid), a bioactive food component, on prostate cancer (PCa) growth and progression in a transgenic mouse model of prostate cancer (TRAMP). Starting at 4, 12, 20, and 30 weeks of age, male TRAMP mice were fed either regular drinking water or 2% IP6 in water for ~8-15 weeks. Pathological assessments at study endpoint indicated that tumor grade is arrested at earlier stages by IP6 treatment; IP6 also prevented progression to more advanced forms of the disease (~55-70% decrease in moderately and poorly differentiated adenocarcinoma incidence was observed in advanced stage TRAMP cohorts). Next, we determined whether the protective effects of IP6 are mediated via its effect on the expansion of the cancer stem cells (CSCs) pool; results indicated that the anti-PCa effects of IP6 are associated with its potential to eradicate the PCa CSC pool in TRAMP prostate tumors. Furthermore, in vitro assays corroborated the above findings as IP6 decreased the % of floating PC-3 prostaspheres (self-renewal of CSCs) by ~90%. Together, these findings suggest the multifaceted chemopreventive-translational potential of IP6 intervention in suppressing the growth and progression of PCa and controlling this malignancy at an early stage.
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Affiliation(s)
- Komal Raina
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
- Department of Pharmaceutical Sciences, South Dakota State University, Brookings, SD 57007, USA
| | - Kushal Kandhari
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Anil K. Jain
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Kameswaran Ravichandran
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Paul Maroni
- Department of Surgery, Division of Urology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Chapla Agarwal
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
- University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Rajesh Agarwal
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
- University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
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Effects of Inositol Hexaphosphate and Myo-Inositol Administration in Breast Cancer Patients during Adjuvant Chemotherapy. J Pers Med 2021; 11:jpm11080756. [PMID: 34442400 PMCID: PMC8400775 DOI: 10.3390/jpm11080756] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 07/27/2021] [Accepted: 07/28/2021] [Indexed: 01/20/2023] Open
Abstract
Background: Treatment of breast cancer (BC) includes locoregional and systemic therapies depending on tumor and patient’s characteristics. Inositol hexaphosphate (IP6) is known as a strong antioxidant agent, able to improve local (i.e., breast region) side effects, functional status and quality-of-life. We investigated some potential beneficial effects, including hematological and local, of the combined therapy with oral myo-inositol administration and topical IP6 application in patients undergoing surgery for BC and eligible to adjuvant chemotherapy. Methods: We considered BC patients randomly assigned to the Inositol Group (oral myo-inositol + IP6 local application for the entire neoadjuvant treatment period) and to the Control Group (standard of care). The EORTC QLQ-BR23 and QLQ-C30 questionnaires were administered to both groups and blood parameters were assessed as per clinical routine practice at baseline (before starting adjuvant chemotherapy), T1 (after the first two doses of epirubicin-cyclophosphamide regimen), T2 (at the end of epirubicin-cyclophosphamide regimen), T3 (after the first six doses of paclitaxel regimen), and T4 (at the end of the paclitaxel treatment). Results: A total of 36 BC patients were considered, 18 in the Inositol Group and 18 in the Control Group. The Inositol Group showed a lower decrease in red blood cells, hemoglobin levels and white blood cells with respect to controls (p ≤ 0.02), as well as amelioration in scores related to breast and arm local symptoms (p ≤ 0.02), body image (p = 0.04) and quality-of-life related symptoms (p ≤ 0.04). Conclusions: In our cohort of BC patients, a combined treatment with oral myo-inositol + IP6 local application was able to improve local symptoms and quality-of-life related symptoms which represent clinically relevant aspects associated with patient’s prognosis.
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Kumon M, Nakae S, Murayama K, Kato T, Ohba S, Inamasu J, Yamada S, Abe M, Sasaki H, Ohno Y, Hasegawa M, Kurahashi H, Hirose Y. Myoinositol to Total Choline Ratio in Glioblastomas as a Potential Prognostic Factor in Preoperative Magnetic Resonance Spectroscopy. Neurol Med Chir (Tokyo) 2021; 61:453-460. [PMID: 34078827 PMCID: PMC8365238 DOI: 10.2176/nmc.oa.2020-0312] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Isocitrate dehydrogenase (IDH) wild-type diffuse astrocytic tumors tend to be pathologically diagnosed as glioblastomas (GBMs). We previously reported that myoinositol to total choline (Ins/Cho) ratio in GBMs on magnetic resonance (MR) spectroscopy was significantly lower than that in IDH-mutant gliomas. We then hypothesized that a low Ins/Cho ratio is a poor prognosis factor in patients with GBMs, IDH-wild-type. In the present study, we calculated the Ins/Cho ratios of patients with GBMs and investigated their progression-free survival (PFS) and overall survival (OS) to determine their utility as prognostic marker. We classified patients with GBMs harboring wild-type IDH (n = 27) into two groups based on the Ins/Cho ratio, and compared patient backgrounds, pathological findings, PFS, OS, and copy number aberrations between the high and low Ins/Cho groups. Patients with GBMs in the low Ins/Cho ratio group indicated shorter PFS (P = 0.021) and OS (P = 0.048) than those in the high Ins/Cho group. Multivariate analysis demonstrated that the Ins/Cho ratio was significantly correlated with PFS (hazard ratio 0.24, P = 0.028). In conclusion, the preoperative Ins/Cho ratio can be used as a novel potential prognostic factor for GBM, IDH-wild-type.
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Affiliation(s)
| | | | - Kazuhiro Murayama
- Joint Research Laboratory of Advanced Medical Imaging, Fujita Health University
| | - Takema Kato
- Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University
| | - Shigeo Ohba
- Department of Neurosurgery, Fujita Health University
| | - Joji Inamasu
- Department of Neurosurgery, Fujita Health University
| | - Seiji Yamada
- Department of Pathology, Fujita Health University
| | - Masato Abe
- Department of Pathology, Fujita Health University
| | - Hikaru Sasaki
- Department of Neurosurgery, Keio University School of Medicine
| | | | | | - Hiroki Kurahashi
- Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University
| | - Yuichi Hirose
- Department of Neurosurgery, Fujita Health University
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Qi JC, Yang Z, Lin T, Ma L, Wang YX, Zhang Y, Gao CC, Liu KL, Li W, Zhao AN, Shi B, Zhang H, Wang DD, Wang XL, Wen JK, Qu CB. CDK13 upregulation-induced formation of the positive feedback loop among circCDK13, miR-212-5p/miR-449a and E2F5 contributes to prostate carcinogenesis. J Exp Clin Cancer Res 2021; 40:2. [PMID: 33390186 PMCID: PMC7780414 DOI: 10.1186/s13046-020-01814-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 12/13/2020] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Both E2F transcription factor and cyclin-dependent kinases (CDKs), which increase or decrease E2F activity by phosphorylating E2F or its partner, are involved in the control of cell proliferation, and some circRNAs and miRNAs regulate the expression of E2F and CDKs. However, little is known about whether dysregulation among E2Fs, CDKs, circRNAs and miRNAs occurs in human PCa. METHODS The expression levels of CDK13 in PCa tissues and different cell lines were determined by quantitative real-time PCR and Western blot analysis. In vitro and in vivo assays were preformed to explore the biological effects of CDK13 in PCa cells. Co-immunoprecipitation anlysis coupled with mass spectrometry was used to identify E2F5 interaction with CDK13. A CRISPR-Cas9 complex was used to activate endogenous CDK13 and circCDK13 expression. Furthermore, the mechanism of circCDK13 was investigated by using loss-of-function and gain-of-function assays in vitro and in vivo. RESULTS Here we show that CDK13 is significantly upregulated in human PCa tissues. CDK13 depletion and overexpression in PCa cells decrease and increase, respectively, cell proliferation, and the pro-proliferation effect of CDK13 is strengthened by its interaction with E2F5. Mechanistically, transcriptional activation of endogenous CDK13, but not the forced expression of CDK13 by its expression vector, remarkably promotes E2F5 protein expression by facilitating circCDK13 formation. Further, the upregulation of E2F5 enhances CDK13 transcription and promotes circCDK13 biogenesis, which in turn sponges miR-212-5p/449a and thus relieves their repression of the E2F5 expression, subsequently leading to the upregulation of E2F5 expression and PCa cell proliferation. CONCLUSIONS These findings suggest that CDK13 upregulation-induced formation of the positive feedback loop among circCDK13, miR-212-5p/miR-449a and E2F5 is responsible for PCa development. Targeting this newly identified regulatory axis may provide therapeutic benefit against PCa progression and drug resistance.
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Affiliation(s)
- Jin-Chun Qi
- Department of Urology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang, 050000, China
| | - Zhan Yang
- Department of Urology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang, 050000, China
| | - Tao Lin
- Department of Urology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang, 050000, China
| | - Long Ma
- Department of Urology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang, 050000, China
| | - Ya-Xuan Wang
- Department of Urology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang, 050000, China
| | - Yong Zhang
- Department of Urology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang, 050000, China
| | - Chun-Cheng Gao
- Department of Urology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang, 050000, China
| | - Kai-Long Liu
- Department of Urology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang, 050000, China
| | - Wei Li
- Department of Urology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang, 050000, China
| | - An-Ning Zhao
- Department of Urology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang, 050000, China
| | - Bei Shi
- Department of Urology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang, 050000, China
| | - Hong Zhang
- Department of Urology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang, 050000, China
| | - Dan-Dan Wang
- Department of Urology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang, 050000, China
| | - Xiao-Lu Wang
- Department of Urology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang, 050000, China
| | - Jin-Kun Wen
- Department of Biochemistry and Molecular Biology, Ministry of Education of China, Hebei Medical University, No. 361 Zhongshan E Rd, Shijiazhuang, 050017, China
| | - Chang-Bao Qu
- Department of Urology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang, 050000, China.
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10
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Vucenik I, Druzijanic A, Druzijanic N. Inositol Hexaphosphate (IP6) and Colon Cancer: From Concepts and First Experiments to Clinical Application. Molecules 2020; 25:E5931. [PMID: 33333775 PMCID: PMC7765177 DOI: 10.3390/molecules25245931] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 12/07/2020] [Accepted: 12/12/2020] [Indexed: 12/14/2022] Open
Abstract
Multiple human health-beneficial effects have been related to highly phosphorylated inositol hexaphosphate (IP6). This naturally occurring carbohydrate and its parent compound, myo-inositol (Ins), are abundantly present in plants, particularly in certain high-fiber diets, but also in mammalian cells, where they regulate important cellular functions. However, the striking and broad-spectrum anticancer activity of IP6, consistently demonstrated in different experimental models, has been in a spotlight of the scientific community dealing with the nutrition and cancer during the last several decades. First experiments were performed in colon cancer 30 years ago. Since then, it has been shown that IP6 reduces cell proliferation, induces apoptosis and differentiation of malignant cells with reversion to normal phenotype, affecting several critical molecular targets. Enhanced immunity and antioxidant properties also contribute to the tumor cell destruction. Although Ins possesses a modest anticancer potential, the best anticancer results were obtained from the combination of IP6 + Ins. Here we review the first experimental steps in colon cancer, when concepts and hypotheses were put together almost without real knowledge and present clinical studies, that were initiated in colon cancer patients. Available as a dietary supplement, IP6 + Ins has been shown to enhance the anticancer effect of conventional chemotherapy, controls cancer metastases, and improves quality of life in cancer patients. Emerging clinical and still vast amount of experimental data suggest its role either as an adjuvant or as an "alternative" to current chemotherapy for cancer.
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Affiliation(s)
- Ivana Vucenik
- Department of Medical and Research Technology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Department of Pathology, School of Medicine, University of Maryland, Baltimore, MD 21201, USA
| | - Ana Druzijanic
- Department of Oral Medicine and Periodontology, School of Medicine, Dental Medicine, University of Split, 21000 Split, Croatia;
| | - Nikica Druzijanic
- Department of Surgery, University Hospital Split, School of Medicine, University of Split, 21000 Split, Croatia;
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11
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Maffucci T, Falasca M. Signalling Properties of Inositol Polyphosphates. Molecules 2020; 25:molecules25225281. [PMID: 33198256 PMCID: PMC7696153 DOI: 10.3390/molecules25225281] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 11/02/2020] [Accepted: 11/04/2020] [Indexed: 12/16/2022] Open
Abstract
Several studies have identified specific signalling functions for inositol polyphosphates (IPs) in different cell types and have led to the accumulation of new information regarding their cellular roles as well as new insights into their cellular production. These studies have revealed that interaction of IPs with several proteins is critical for stabilization of protein complexes and for modulation of enzymatic activity. This has not only revealed their importance in regulation of several cellular processes but it has also highlighted the possibility of new pharmacological interventions in multiple diseases, including cancer. In this review, we describe some of the intracellular roles of IPs and we discuss the pharmacological opportunities that modulation of IPs levels can provide.
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Affiliation(s)
- Tania Maffucci
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK
- Correspondence: (T.M.); (M.F.); Tel.: +61-08-92669712 (M.F.)
| | - Marco Falasca
- School of Pharmacy and Biomedical Sciences, CHIRI, Curtin University, Perth 6102, Australia
- Correspondence: (T.M.); (M.F.); Tel.: +61-08-92669712 (M.F.)
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12
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Regulation of MicroRNA-155 and Its Related Genes Expression by Inositol Hexaphosphate in Colon Cancer Cells. Molecules 2019; 24:molecules24224153. [PMID: 31744065 PMCID: PMC6891702 DOI: 10.3390/molecules24224153] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 11/06/2019] [Accepted: 11/14/2019] [Indexed: 12/12/2022] Open
Abstract
Inositol hexaphosphate (IP6), a natural dietary component, has been found as an antitumor agent by stimulating apoptosis and inhibiting cancer cell proliferation, their migration, and metastasis in diverse cancers including colon cancer. However, molecular mechanisms of its action have not been well understood. In recent years, microRNAs (miRNAs) have been reported to play important roles in a broad range of biologic processes, such as cell growth, proliferation, apoptosis, or autophagy. These small noncoding molecules regulate post-transcriptional expression of targets genes via degradation of transcript or inhibition of protein synthesis. Aberrant expression and/or dysregulation of miRNAs have been characterized during tumor development and progression, thus, they are potential molecular targets for cancer prevention. The aim of this study was to investigate the effect of IP6 on the miRNAs expression profile in Caco-2 colon cancer cells. 84 miRNAs were analyzed in Caco-2 cells treated with 2.5 mM and 5 mM IP6 by the use of PCR (Polymerase Chain Reaction) array. The effect of 5 mM IP6 on selected potential miR-155 targets was determined by real-time (RT)-qPCR and ELISA (quantitative Polymerase Chain Reaction and Enzyme-Linked Immunosorbent Assay )method. The results indicated alteration in the specific 10 miRNA expression in human colon cancer cells following their treatment with 5 mM IP6. It down-regulated 8 miRNAs (miR-155, miR-210, miR-144, miR-194, miR-26b, miR-126, miR-302c, and miR-29a) and up-regulated 2 miRNAs (miR-223 and miR-196b). In silico analysis revealed that FOXO3a, HIF-1α, and ELK3 mRNAs are those of predicted targets of miR-155. IP6 at the concentration of 5 mM markedly induced FOXO3a and HIF-1a genes’ expression at both mRNA and protein level and decreased the amount of ELK3 mRNA as well as protein concentration in comparison to the control. In conclusion, the present study indicates that one of the mechanisms of antitumor potential of IP6 is down-regulation of the miR-155 expression in human colon cancer cells. Moreover, the expression of genes that are targeted by miRNA are also modulated by IP6.
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13
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Arya M, Mishra N, Singh P, Tripathi CB, Parashar P, Singh M, Gupta KP, Saraf SA. In vitro and in silico molecular interaction of multiphase nanoparticles containing inositol hexaphosphate and jacalin: Therapeutic potential against colon cancer cells (HCT-15). J Cell Physiol 2019; 234:15527-15536. [PMID: 30697733 DOI: 10.1002/jcp.28200] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 01/16/2019] [Indexed: 02/06/2023]
Abstract
Inositol hexaphosphate (IP6) is a natural constituent found in almost all cereals and legumes. It is known to cause numerous antiangiogenic manifestations. Notwithstanding its great potential, it is underutilized due to the chelation and rapid excretion from the body. Jacalin is another natural constituent obtained from seeds of jackfruit and can target disaccharides overexpressed in tumor cells. The current study was in-quested to develop and evaluate a surface-modified gold nanoparticulate system containing IP6 and jacalin which may maximize the apoptotic effect of IP6 against HCT-15 cell lines. IP6 loaded jacalin-pectin-gold nanoparticles (IJP-GNPs) were developed through reduction followed by incubation method. The developed formulation was tested for various in vitro and in silico studies to investigate its potential. HCT-15 cells when exposed to IJP-GNP resulted in significant apoptotic effects in dose as well as time-dependent manner, as measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, micronucleus, and reactive oxygen species assay. IJP-GNP displayed cell cycle arrest at the G0/G1 phase. To further explore the mechanism of chemoprevention, in silico studies were performed. The docking results revealed that the interactive behavior of IP6, P-GNP, and jacalin could target and inhibit the tumor formation activity, supported by in vitro studies. Taken together, all the findings suggested that IP6 loaded nanoparticles may increase the hope of future drug delivery strategy for targeting colon cancer.
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Affiliation(s)
- Malti Arya
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University (A Central University), Lucknow, India
| | - Nidhi Mishra
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University (A Central University), Lucknow, India
| | - Pooja Singh
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University (A Central University), Lucknow, India
| | - Chandra B Tripathi
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University (A Central University), Lucknow, India
| | - Poonam Parashar
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University (A Central University), Lucknow, India
| | - Mahendra Singh
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University (A Central University), Lucknow, India
| | - Krishna P Gupta
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University (A Central University), Lucknow, India
| | - Shubhini A Saraf
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University (A Central University), Lucknow, India
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14
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Armah SM. Association between Phytate Intake and C-Reactive Protein Concentration among People with Overweight or Obesity: A Cross-Sectional Study Using NHANES 2009/2010. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:E1549. [PMID: 31052485 PMCID: PMC6539023 DOI: 10.3390/ijerph16091549] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 04/24/2019] [Accepted: 04/30/2019] [Indexed: 12/12/2022]
Abstract
Phytic acid has anti-oxidant properties, which are useful in addressing inflammation. This study investigated the relationship between dietary phytate intake and C-reactive protein (CRP) levels among individuals that are overweight or obese. The study used cross-sectional data from the 2009/2010 National Health and Nutrition Examination Survey (NHANES) for 3152 subjects. Phytate intake was estimated using phytate content of foods reported by the International Zinc Nutrition Consultative Group (IZiNCG). Logistic regression was used to determine the associations between phytate intake and odds of elevated CRP concentration (CRP >3 mg/L), adjusting for confounders. Medians (and 95% CIs) for phytate intake and CRP concentration were 0.66 (0.64, 0.68) g/d and 1.4 (1.2, 1.5) mg/L, respectively. Phytate intake was higher in males than females, higher in non-Hispanic Whites than non-Hispanic Blacks and Mexican Americans, and lower in current smokers than former smokers and nonsmokers. Higher phytate intake was associated with lower odds of elevated CRP (OR = 0.66; 95% CI = 0.52, 0.84). Women, as well as current and former smokers with overweight or obesity, had higher odds of elevated CRP concentration. These results imply that individuals with high phytate intake, particularly among those with overweight or obesity, have lower risk for inflammation-related chronic diseases such as cardiovascular diseases.
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Affiliation(s)
- Seth M Armah
- Department of Nutrition, University of North Carolina at Greensboro, Greensboro, NC 27412, USA.
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15
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Brehm MA, Windhorst S. New options of cancer treatment employing InsP 6. Biochem Pharmacol 2019; 163:206-214. [PMID: 30797871 DOI: 10.1016/j.bcp.2019.02.024] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Accepted: 02/19/2019] [Indexed: 12/21/2022]
Abstract
Many mechanistic studies have been performed to analyze the cellular functions of the highly phosphorylated molecule inositol hexakisphosphate (InsP6) in health and disease. While the physiological intracellular functions are well described, the mechanism of potential pharmacological effects on cancer cell proliferation is still controversial. There are numerous studies demonstrating that a high InsP6 concentration (≥75 µM) inhibits growth of cancer cells in vitro and in vivo. Thus, there is no doubt that InsP6 exhibits anticancer activity but the mechanism underlying the cellular effects of extracellular InsP6 on cancer cells is far from being understood. In addition, studies on the inhibitory effect of InsP6 on cancer progression in animal models ignore aspects of its bioavailability. Here, we review and critically discuss the uptake mechanism and the intracellular involvement in signaling pathways of InsP6 in cancer cells. We take into account the controversial findings on InsP6 plasma concentration, which is a critical aspect of pharmacological accessibility of InsP6 for cancer treatment. Further, we discuss novel findings with respect to the effect of InsP6 on normal and immune cells as well as on platelet aggregate size. Our goal is to stimulate further mechanistic studies into novel directions considering previously disregarded aspects of InsP6. Only when we fully understand the mechanism underlying the anticancer activity of InsP6 novel and more efficient treatment options can be developed.
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Affiliation(s)
- Maria A Brehm
- Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sabine Windhorst
- Department of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany.
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16
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The Role of RB in Prostate Cancer Progression. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1210:301-318. [PMID: 31900914 DOI: 10.1007/978-3-030-32656-2_13] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The RB tumor suppressor is one of the most commonly deleted/mutated genes in human cancers. In prostate cancer specifically, mutation of RB is most frequently observed in aggressive, metastatic disease. As one of the earliest tumor suppressors to be identified, the molecular functions of RB that are lost in tumor development have been studied for decades. Earlier work focused on the canonical RB pathway connecting mitogenic signaling to the cell cycle via Cyclin/CDK inactivation of RB, thereby releasing the E2F transcription factors. More in-depth analysis revealed that RB-E2F complexes regulate cellular processes beyond proliferation. Most recently, "non-canonical" roles for RB function have been expanded beyond its E2F interactions, which may play a particular role in advanced prostate cancer. For example, in mouse models of prostate cancer, loss of RB has been shown to induce lineage plasticity, which enables resistance to androgen deprivation therapy. This increased understanding of the potential downstream functions of RB in prostate cancer may lead the way to identifying therapeutic vulnerabilities in cells following RB loss.
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17
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Inositol Hexaphosphate Inhibits Proliferation and Induces Apoptosis of Colon Cancer Cells by Suppressing the AKT/mTOR Signaling Pathway. Molecules 2017; 22:molecules22101657. [PMID: 28972559 PMCID: PMC6151581 DOI: 10.3390/molecules22101657] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Revised: 09/29/2017] [Accepted: 09/29/2017] [Indexed: 01/22/2023] Open
Abstract
AKT, a serine/threonine protein kinase and mammalian target of rapamycin (mTOR) plays a critical role in the proliferation and resistance to apoptosis that are essential to the development and progression of colon cancer. Therefore, AKT/mTOR signaling pathway has been recognized as an attractive target for anticancer therapy. Inositol hexaphosphate (InsP6), a natural occurring phytochemical, has been shown to have both preventive and therapeutic effects against various cancers, however, its exact molecular mechanisms of action are not fully understood. The aim of the in vitro study was to investigate the anticancer activity of InsP6 on colon cancer with the focus on inhibiting the AKT1 kinase and p70S6K1 as mTOR effector, in relation to proliferation and apoptosis of cells. The colon cancer Caco-2 cells were cultured using standard techniques and exposed to InsP6 at different concentrations (1 mM, 2.5 mM and 5 mM). Cellular proliferative activity was monitored by 5-bromo-2′-deoxyuridine (BrdU) incorporation into cellular DNA. Flow cytometric analysis was performed for cell cycle progression and apoptosis studies. Real-time RT-qPCR was used to validate mRNA levels of CDNK1A, CDNK1B, CASP3, CASP9, AKT1 and S6K1 genes. The concentration of p21 protein as well as the activities of caspase 3, AKT1 and p70S6K1 were determined by the ELISA method. The results revealed that IP6 inhibited proliferation and stimulated apoptosis of colon cancer cells. This effect was mediated by an increase in the expression of genes encoding p21, p27, caspase 3, caspase 9 as well a decrease in transcription of AKT1 and S6K1. InsP6 suppressed phosphorylation of AKT1 and p70S6K1, downstream effector of mTOR. Based on these studies it may be concluded that InsP6 can reduce proliferation and induce apoptosis through inhibition of the AKT/mTOR pathway and mTOR effector followed by modulation of the expression and activity of several key components of these pathways in colon cancer cells.
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18
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Irshad M, Asgher M, Bhatti KH, Zafar M, Anwar Z. Anticancer and Nutraceutical Potentialities of Phytase/Phytate. INT J PHARMACOL 2017. [DOI: 10.3923/ijp.2017.808.817] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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19
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Cytotoxic mechanism of Baccharis milleflora (Less.) DC. essential oil. Toxicol In Vitro 2017; 42:214-221. [DOI: 10.1016/j.tiv.2017.04.031] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Revised: 04/23/2017] [Accepted: 04/29/2017] [Indexed: 11/23/2022]
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20
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Guo X, Li R, Liu J, Chen R, Zhang H, Liu Q, Li Z, Wang J. Design of multifunctional phytate coated magnetic composites for combined therapy with antitumor drugs. NEW J CHEM 2017. [DOI: 10.1039/c7nj03258g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
A multifunctional phytate coated magnetic nanocomposite was successfully synthesized with Zn ions via self-assembly route for combined therapy with antitumor drug.
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Affiliation(s)
- Xuejie Guo
- Key Laboratory of Superlight Material and Surface Technology
- Ministry of Education
- Harbin Engineering University
- Harbin 150001
- China
| | - Rumin Li
- Key Laboratory of Superlight Material and Surface Technology
- Ministry of Education
- Harbin Engineering University
- Harbin 150001
- China
| | - Jingyuan Liu
- Key Laboratory of Superlight Material and Surface Technology
- Ministry of Education
- Harbin Engineering University
- Harbin 150001
- China
| | - Rongrong Chen
- College of Materials Science and Chemical Engineering
- Harbin Engineering University
- P. R. China
- Institute of Advanced Marine Materials
- Harbin Engineering University
| | - Hongsen Zhang
- Key Laboratory of Superlight Material and Surface Technology
- Ministry of Education
- Harbin Engineering University
- Harbin 150001
- China
| | - Qi Liu
- Key Laboratory of Superlight Material and Surface Technology
- Ministry of Education
- Harbin Engineering University
- Harbin 150001
- China
| | - Zhanshuang Li
- Key Laboratory of Superlight Material and Surface Technology
- Ministry of Education
- Harbin Engineering University
- Harbin 150001
- China
| | - Jun Wang
- Key Laboratory of Superlight Material and Surface Technology
- Ministry of Education
- Harbin Engineering University
- Harbin 150001
- China
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21
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Bizzarri M, Dinicola S, Bevilacqua A, Cucina A. Broad Spectrum Anticancer Activity of Myo-Inositol and Inositol Hexakisphosphate. Int J Endocrinol 2016; 2016:5616807. [PMID: 27795708 PMCID: PMC5067332 DOI: 10.1155/2016/5616807] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Accepted: 09/06/2016] [Indexed: 02/06/2023] Open
Abstract
Inositols (myo-inositol and inositol hexakisphosphate) exert a wide range of critical activities in both physiological and pathological settings. Deregulated inositol metabolism has been recorded in a number of diseases, including cancer, where inositol modulates different critical pathways. Inositols inhibit pRB phosphorylation, fostering the pRB/E2F complexes formation and blocking progression along the cell cycle. Inositols reduce PI3K levels, thus counteracting the activation of the PKC/RAS/ERK pathway downstream of PI3K activation. Upstream of that pathway, inositols disrupt the ligand interaction between FGF and its receptor as well as with the EGF-transduction processes involving IGF-II receptor and AP-1 complexes. Additionally, Akt activation is severely impaired upon inositol addition. Downregulation of both Akt and ERK leads consequently to NF-kB inhibition and reduced expression of inflammatory markers (COX-2 and PGE2). Remarkably, inositol-induced downregulation of presenilin-1 interferes with the epithelial-mesenchymal transition and reduces Wnt-activation, β-catenin translocation, Notch-1, N-cadherin, and SNAI1 release. Inositols interfere also with the cytoskeleton by upregulating Focal Adhesion Kinase and E-cadherin and decreasing Fascin and Cofilin, two main components of pseudopodia, leading hence to invasiveness impairment. This effect is reinforced by the inositol-induced inhibition on metalloproteinases and ROCK1/2 release. Overall, these effects enable inositols to remodel the cytoskeleton architecture.
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Affiliation(s)
- Mariano Bizzarri
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
- Systems Biology Group Lab, Sapienza University of Rome, Rome, Italy
- *Mariano Bizzarri:
| | - Simona Dinicola
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 336, 00161 Rome, Italy
- Department of Surgery “Pietro Valdoni”, Sapienza University of Rome, Via A. Scarpa 14, 00161 Rome, Italy
| | - Arturo Bevilacqua
- Department of Psychology, Section of Neuroscience, Sapienza University of Rome, Via dei Marsi 78, 00185 Rome, Italy
| | - Alessandra Cucina
- Department of Surgery “Pietro Valdoni”, Sapienza University of Rome, Via A. Scarpa 14, 00161 Rome, Italy
- Azienda Policlinico Umberto I, Viale del Policlinico 155, 00161 Rome, Italy
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Li Q, Ren FQ, Yang CL, Zhou LM, Liu YY, Xiao J, Zhu L, Wang ZG. Anti-proliferation effects of isorhamnetin on lung cancer cells in vitro and in vivo. Asian Pac J Cancer Prev 2015; 16:3035-42. [PMID: 25854402 DOI: 10.7314/apjcp.2015.16.7.3035] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Isorhamnetin (Iso), a novel and essential monomer derived from total flavones of Hippophae rhamnoides that has long been used as a traditional Chinese medicine for angina pectoris and acute myocardial infarction, has also shown a spectrum of antitumor activity. However, little is known about the mechanisms of action Iso on cancer cells. OBJECTIVES To investigate the effects of Iso on A549 lung cancer cells and underlying mechanisms. MATERIALS AND METHODS A549 cells were treated with 10~320 μg/ml Iso. Their morphological and cellular characteristics were assessed by light and electronic microscopy. Growth inhibition was analyzed by MTT, clonogenic and growth curve assays. Apoptotic characteristics of cells were determined by flow cytometry (FCM), DNA fragmentation, single cell gel electrophoresis (comet) assay, immunocytochemistry and terminal deoxynucleotidyl transferase nick end labeling (TUNEL) . Tumor models were setup by transplanting Lewis lung carcinoma cells into C57BL/6 mice, and the weights and sizes of tumors were measured. RESULTS Iso markedly inhibited the growth of A549 cells with induction of apoptotic changes. Iso at 20 μg/ml, could induce A549 cell apoptosis, up-regulate the expression of apoptosis genes Bax, Caspase-3 and P53, and down-regulate the expression of Bcl-2, cyclinD1 and PCNA protein. The tumors in tumor-bearing mice treated with Iso were significantly smaller than in the control group. The results of apoptosis-related genes, PCNA, cyclinD1 and other protein expression levels of transplanted Lewis cells were the same as those of A549 cells in vitro. CONCLUSIONS Iso, a natural single compound isolated from total flavones, has antiproliferative activity against lung cancer in vitro and in vivo. Its mechanisms of action may involve apoptosis of cells induced by down-regulation of oncogenes and up-regulation of apoptotic genes.
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Affiliation(s)
- Qiong Li
- School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, China E-mail :
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23
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Xu Z, Zeng X, Xu J, Xu D, Li J, Jin H, Jiang G, Han X, Huang C. Isorhapontigenin suppresses growth of patient-derived glioblastoma spheres through regulating miR-145/SOX2/cyclin D1 axis. Neuro Oncol 2015; 18:830-9. [PMID: 26681767 DOI: 10.1093/neuonc/nov298] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2015] [Accepted: 11/11/2015] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Glioblastoma (GBM) is the most common malignant brain tumor, and glioma stem cells (GSCs) are considered a major source of treatment resistance for glioblastoma. Identifying new compounds that inhibit the growth of GSCs and understanding their underlying molecular mechanisms are therefore important for developing novel therapy for GBM. METHODS We investigated the potential inhibitory effect of isorhapontigenin (ISO), an anticancer compound identified in our recent investigations, on anchorage-independent growth of patient-derived glioblastoma spheres (PDGS) and its mechanism of action. RESULTS ISO treatment resulted in significant anchorage-independent growth inhibition, accompanied with cell cycle G0-G1 arrest and cyclin D1 protein downregulation in PDGS. Further studies established that cyclin D1 was downregulated by ISO at transcription levels in a SOX2-dependent manner. In addition, ISO attenuated SOX2 expression by specific induction of miR-145, which in turn suppressed 3'UTR activity of SOX2 mRNA without affecting its mRNA stability. Moreover, ectopic expression of exogenous SOX2 rendered D456 cells resistant to induction of cell cycle G0-G1 arrest and anchorage-independent growth inhibition upon ISO treatment, whereas inhibition of miR-145 resulted in D456 cells resistant to ISO inhibition of SOX2 and cyclin D1 expression. In addition, overexpression of miR-145 mimicked ISO treatment in D456 cells. CONCLUSIONS ISO induces miR-145 expression, which binds to the SOX2 mRNA 3'UTR region and inhibits SOX2 protein translation. Inhibition of SOX2 leads to cyclin D1 downregulation and PDGS anchorage-independent growth inhibition. The elucidation of the miR-145/SOX2/cyclin D1 axis in PDGS provides a significant insight into understanding the anti-GBM effect of ISO compound.
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Affiliation(s)
- Zhou Xu
- Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York (Z.X., X.Z., J.X., D.X., J.L., H.J., G.J., C.H.); Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China (Z.X.); Division of Neuro-Oncology, Department of Neurology, University of Alabama, Birmingham, Alabama (X.H.)
| | - Xingruo Zeng
- Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York (Z.X., X.Z., J.X., D.X., J.L., H.J., G.J., C.H.); Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China (Z.X.); Division of Neuro-Oncology, Department of Neurology, University of Alabama, Birmingham, Alabama (X.H.)
| | - Jiawei Xu
- Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York (Z.X., X.Z., J.X., D.X., J.L., H.J., G.J., C.H.); Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China (Z.X.); Division of Neuro-Oncology, Department of Neurology, University of Alabama, Birmingham, Alabama (X.H.)
| | - Derek Xu
- Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York (Z.X., X.Z., J.X., D.X., J.L., H.J., G.J., C.H.); Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China (Z.X.); Division of Neuro-Oncology, Department of Neurology, University of Alabama, Birmingham, Alabama (X.H.)
| | - Jingxia Li
- Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York (Z.X., X.Z., J.X., D.X., J.L., H.J., G.J., C.H.); Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China (Z.X.); Division of Neuro-Oncology, Department of Neurology, University of Alabama, Birmingham, Alabama (X.H.)
| | - Honglei Jin
- Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York (Z.X., X.Z., J.X., D.X., J.L., H.J., G.J., C.H.); Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China (Z.X.); Division of Neuro-Oncology, Department of Neurology, University of Alabama, Birmingham, Alabama (X.H.)
| | - Guosong Jiang
- Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York (Z.X., X.Z., J.X., D.X., J.L., H.J., G.J., C.H.); Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China (Z.X.); Division of Neuro-Oncology, Department of Neurology, University of Alabama, Birmingham, Alabama (X.H.)
| | - Xiaosi Han
- Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York (Z.X., X.Z., J.X., D.X., J.L., H.J., G.J., C.H.); Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China (Z.X.); Division of Neuro-Oncology, Department of Neurology, University of Alabama, Birmingham, Alabama (X.H.)
| | - Chuanshu Huang
- Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York (Z.X., X.Z., J.X., D.X., J.L., H.J., G.J., C.H.); Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China (Z.X.); Division of Neuro-Oncology, Department of Neurology, University of Alabama, Birmingham, Alabama (X.H.)
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Cheng YL, Andrew DJ. Extracellular Mipp1 Activity Confers Migratory Advantage to Epithelial Cells during Collective Migration. Cell Rep 2015; 13:2174-88. [PMID: 26628373 DOI: 10.1016/j.celrep.2015.10.071] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Revised: 10/12/2015] [Accepted: 10/24/2015] [Indexed: 12/13/2022] Open
Abstract
Multiple inositol polyphosphate phosphatase (Mipp), a highly conserved but poorly understood histidine phosphatase, dephosphorylates higher-order IPs (IP4-IP6) to IP3. To gain insight into the biological roles of these enzymes, we have characterized Drosophila mipp1. mipp1 is dynamically expressed in the embryonic trachea, specifically in the leading cells of migrating branches at late stages, where Mipp1 localizes to the plasma membrane and filopodia. FGF signaling activates mipp1 expression in these cells, where extensive filopodia form to drive migration and elongation by cell intercalation. We show that Mipp1 facilitates formation and/or stabilization of filopodia in leading cells through its extracellular activity. mipp1 loss decreases filopodia number, whereas mipp1 overexpression increases filopodia number in a phosphatase-activity-dependent manner. Importantly, expression of Mipp1 gives cells a migratory advantage for the lead position in elongating tracheal branches. Altogether, these findings suggest that extracellular pools of inositol polyphosphates affect cell behavior during development.
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Affiliation(s)
- Yim Ling Cheng
- Department of Cell Biology, The Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, MD 21205, USA
| | - Deborah J Andrew
- Department of Cell Biology, The Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, MD 21205, USA.
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25
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de Lima EM, Kanunfre CC, de Andrade LF, Granato D, Rosso ND. Cytotoxic effect of inositol hexaphosphate and its Ni(II) complex on human acute leukemia Jurkat T cells. Toxicol In Vitro 2015; 29:2081-8. [PMID: 26335902 DOI: 10.1016/j.tiv.2015.08.018] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Revised: 08/26/2015] [Accepted: 08/28/2015] [Indexed: 01/22/2023]
Abstract
Inositol hexaphosphate (InsP6) is present in cereals, legumes, nuts and seed oils and is biologically active against some tumor and cancer cells. Herein, this study aimed at evaluating the cellular toxicity, antiproliferative activity and effects on cell cycle progression of free InsP6 and InsP6-Ni(II) of leukemic T (Jurkat) and normal human cells. Treatments with InsP6 at concentrations between 1.0 and 4.0mM significantly decreased the viability of Jurkat cells, but showed no cytotoxic effect on normal human lymphocytes. Treatment with InsP6-Ni(II) complex at concentrations between 0.05 and 0.30 mM showed an anti-proliferative dose and a time-dependent effect, with significantly reduced cell viability of Jurkat cells but showed no cytotoxic effect on normal human lymphocytes as compared to the control. Ni(II) free ion was toxic to normal cells while InsP6-Ni(II) had no cytotoxic effect. The InsP6-Ni(II) complex potentiated (up to 10×) the antiproliferative effect of free InsP6 on Jurkat cells. The cytometric flow assay showed that InsP6 led to an accumulation of cells in the G0/G1 phase of the cell cycle, accompanied by a decrease in the number of cells in S and G2/M phases, whereas InsP6-Ni(II) has led to an accumulation of cells in the S and G2/M phases. Our findings showed that InsP6-Ni(II) potentiates cytotoxic effects of InsP6 on Jurkat cells and may be a potential adjuvant in the treatment of cancer.
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Affiliation(s)
- Eliane May de Lima
- Departamento de Química, Universidade Estadual de Ponta Grossa, Av. Carlos Cavalcanti, 4748, 84030-900 Ponta Grossa, Brazil
| | - Carla Cristine Kanunfre
- Departamento de Biologia Celular, Universidade Estadual de Ponta Grossa, Av. Carlos Cavalcanti, 4748, 84030-900 Ponta Grossa, Brazil
| | - Lucas Ferrari de Andrade
- Departamento de Biologia Celular, Universidade Federal do Paraná, Rua Francisco H. dos Santos, s/n, 81531-990 Curitiba, Brazil
| | - Daniel Granato
- Departamento de Engenharia de Alimentos, Universidade Estadual de Ponta Grossa, Brazil. Av. Carlos Cavalcanti, 4748, 84030-900 Ponta Grossa, Brazil
| | - Neiva Deliberali Rosso
- Departamento de Química, Universidade Estadual de Ponta Grossa, Av. Carlos Cavalcanti, 4748, 84030-900 Ponta Grossa, Brazil.
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26
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Cai Y, Tan X, Liu J, Shen Y, Wu D, Ren M, Huang P, Yu D. Inhibition of PI3K/Akt/mTOR signaling pathway enhances the sensitivity of the SKOV3/DDP ovarian cancer cell line to cisplatin in vitro. Chin J Cancer Res 2014; 26:564-72. [PMID: 25400422 DOI: 10.3978/j.issn.1000-9604.2014.08.20] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2014] [Accepted: 08/08/2014] [Indexed: 11/14/2022] Open
Abstract
The activation of the PI3K/AKT/mTOR pathway plays a key role in ovarian cancer tumorigenesis, progression and chemotherapy resistance. This study aimed to explore the possible mechanism that PI-103, a dual inhibitor of phosphatidylinositide 3-kinase and mTOR, enhances the sensitivity of SKOV3/DDP ovarian cancer cell line to cisplatin chemotherapy. The results showed that PI-103 could significantly increase the sensitivity of SKVO3/DDP cells to cisplatin through inhibiting the activation of PI3K/Akt/mTOR signaling pathway and inducing cell cycle arrest and apoptosis.
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Affiliation(s)
- Yunlang Cai
- 1 Department of Obstetrics & Gynecology, Zhongda Hospital, Southeast University, Nanjing 210009, China ; 2 Medical College, Southeast University, Nanjing 210009, China
| | - Xiaoqiang Tan
- 1 Department of Obstetrics & Gynecology, Zhongda Hospital, Southeast University, Nanjing 210009, China ; 2 Medical College, Southeast University, Nanjing 210009, China
| | - Jun Liu
- 1 Department of Obstetrics & Gynecology, Zhongda Hospital, Southeast University, Nanjing 210009, China ; 2 Medical College, Southeast University, Nanjing 210009, China
| | - Yang Shen
- 1 Department of Obstetrics & Gynecology, Zhongda Hospital, Southeast University, Nanjing 210009, China ; 2 Medical College, Southeast University, Nanjing 210009, China
| | - Di Wu
- 1 Department of Obstetrics & Gynecology, Zhongda Hospital, Southeast University, Nanjing 210009, China ; 2 Medical College, Southeast University, Nanjing 210009, China
| | - Mulan Ren
- 1 Department of Obstetrics & Gynecology, Zhongda Hospital, Southeast University, Nanjing 210009, China ; 2 Medical College, Southeast University, Nanjing 210009, China
| | - Peilin Huang
- 1 Department of Obstetrics & Gynecology, Zhongda Hospital, Southeast University, Nanjing 210009, China ; 2 Medical College, Southeast University, Nanjing 210009, China
| | - Dandan Yu
- 1 Department of Obstetrics & Gynecology, Zhongda Hospital, Southeast University, Nanjing 210009, China ; 2 Medical College, Southeast University, Nanjing 210009, China
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27
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Shang D, Li C, Yao Q, Yang H, Xu Y, Han J, Li J, Su F, Zhang Y, Zhang C, Li D, Li X. Prioritizing candidate disease metabolites based on global functional relationships between metabolites in the context of metabolic pathways. PLoS One 2014; 9:e104934. [PMID: 25153931 PMCID: PMC4143229 DOI: 10.1371/journal.pone.0104934] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2014] [Accepted: 07/14/2014] [Indexed: 11/18/2022] Open
Abstract
Identification of key metabolites for complex diseases is a challenging task in today's medicine and biology. A special disease is usually caused by the alteration of a series of functional related metabolites having a global influence on the metabolic network. Moreover, the metabolites in the same metabolic pathway are often associated with the same or similar disease. Based on these functional relationships between metabolites in the context of metabolic pathways, we here presented a pathway-based random walk method called PROFANCY for prioritization of candidate disease metabolites. Our strategy not only takes advantage of the global functional relationships between metabolites but also sufficiently exploits the functionally modular nature of metabolic networks. Our approach proved successful in prioritizing known metabolites for 71 diseases with an AUC value of 0.895. We also assessed the performance of PROFANCY on 16 disease classes and found that 4 classes achieved an AUC value over 0.95. To investigate the robustness of the PROFANCY, we repeated all the analyses in two metabolic networks and obtained similar results. Then we applied our approach to Alzheimer's disease (AD) and found that a top ranked candidate was potentially related to AD but had not been reported previously. Furthermore, our method was applicable to prioritize the metabolites from metabolomic profiles of prostate cancer. The PROFANCY could identify prostate cancer related-metabolites that are supported by literatures but not considered to be significantly differential by traditional differential analysis. We also developed a freely accessible web-based and R-based tool at http://bioinfo.hrbmu.edu.cn/PROFANCY.
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Affiliation(s)
- Desi Shang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, P. R. China
| | - Chunquan Li
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, P. R. China
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, P. R. China
| | - Qianlan Yao
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, P. R. China
| | - Haixiu Yang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, P. R. China
| | - Yanjun Xu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, P. R. China
| | - Junwei Han
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, P. R. China
| | - Jing Li
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, P. R. China
| | - Fei Su
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, P. R. China
| | - Yunpeng Zhang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, P. R. China
| | - Chunlong Zhang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, P. R. China
| | - Dongguo Li
- School of Biomedical Engineering, Capital Medical University, No. 10 You An Men Wai Xi Tou Tiao, Beijing, P.R. China
- * E-mail: (DL); (XL)
| | - Xia Li
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, P. R. China
- * E-mail: (DL); (XL)
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Jin G, Cao Z, Sun X, Wang K, Huang T, Shen B. Protein O-glucosyltransferase 1 overexpression downregulates p16 in BT474 human breast cancer cells. Oncol Lett 2014; 8:594-600. [PMID: 25009645 PMCID: PMC4081438 DOI: 10.3892/ol.2014.2197] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2013] [Accepted: 05/07/2014] [Indexed: 01/16/2023] Open
Abstract
Protein O-glucosyltransferase 1 (POGLUT1) is a novel gene that was initially isolated and identified from the bone marrow cells of patients with myelodysplastic syndrome/acute myeloid leukemia. Previous findings have suggested that POGLUT1 promotes the proliferation of U937 human tissue lymphoma cells. Furthermore, POGLUT1 has been identified in other tissues, including the mammary glands, lymph nodes, intestine, liver and spleen. In the present study, in order to investigate the function and target of POGLUT1 in BT474 breast cancer cells, the effect of POGLUT1 on cell proliferation, differentiation, apoptosis and key proteins in the transforming growth factor (TGF)-β1 signaling pathway was investigated in BT474 cells. The overexpression of POGLUT1 in the presence of TGF-β1 was found to significantly enhance cell viability. Flow cytometric and quantitative polymerase chain reaction analyses revealed that POGLUT1 had an effect on the cell cycle and inhibited the TGF-β1-induced transcriptional upregulation of p16, a major cyclin-dependent kinase inhibitor (CDKI). Furthermore, phosphorylated (p)-Smad3, which has a key role in mediating the TGF-β antiproliferative response, was greatly inhibited by exogenous POGLUT1, suggesting a role for POGLUT1 in the TGF-β1-mediated signaling pathway in the BT474 cell cycle. However, no significant changes were observed in the expression of other CDKIs or in cell apoptosis. The findings of the present study show that the increase in BT474 cell viabilty induced by POGLUT1 is associated with POGLUT1-induced inhibition of the transcriptional upregulation of p16 by TGF-β1, which may be a result of the inhibition of p-Smad3.
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Affiliation(s)
- Gang Jin
- Department of Medical Imaging, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China ; The No. 211 Hospital of the People's Liberation Army, Harbin, Heilongjiang 150086, P.R. China
| | - Zhigang Cao
- The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Xilin Sun
- Department of Medical Imaging, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Kai Wang
- Department of Medical Imaging, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Tao Huang
- Department of Medical Imaging, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Baozhong Shen
- Department of Medical Imaging, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
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29
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Tailor D, Hahm ER, Kale RK, Singh SV, Singh RP. Sodium butyrate induces DRP1-mediated mitochondrial fusion and apoptosis in human colorectal cancer cells. Mitochondrion 2013; 16:55-64. [PMID: 24177748 DOI: 10.1016/j.mito.2013.10.004] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2013] [Revised: 10/21/2013] [Accepted: 10/22/2013] [Indexed: 12/12/2022]
Abstract
Sodium butyrate (NaBt) is the byproduct of anaerobic microbial fermentation inside the gastro-intestinal tract that could reach up to 20mM, and has been shown to inhibit the growth of various cancers. Herein, we evaluated its effect on mitochondrial fusion and associated induction of apoptosis in colorectal cancer cells (CRC). NaBt treatment at physiological (1-5mM) concentrations for 12 and 24h decreased the cell viability and induced G2-M phase cell cycle arrest in HCT116 (12h) and SW480 human CRC cells. This cell cycle arrest was associated with mitochondria-mediated apoptosis accompanied by a decrease in survivin and Bcl-2 expression, and generation of reactive oxygen species (ROS). Furthermore, NaBt treatment resulted in a significant decrease in the mitochondrial mass which is an indicator of mitochondrial fusion. Level of dynamin-related protein 1 (DRP1), a key regulator of mitochondrial fission and fusion where its up-regulation correlates with fission, was found to be decreased in CRC cells. Further, at early treatment time, DRP1 down-regulation was noticed in mitochondria which later became drastically reduced in both mitochondria as well as cytosol. DRP1 is activated by cyclin B1-CDK1 complex by its ser616 phosphorylation in which both cyclin B1-CDK1 complex and phospho-DRP1 (ser616) were strongly reduced by NaBt treatment. DRP1 was observed to be regulated by apoptosis as pan-caspase inhibitor showing rescue from NaBt-induced apoptosis also caused the reversal of DRP1 to the normal level as in control proliferating cells. Together, these findings suggest that NaBt can modulate mitochondrial fission and fusion by regulating the level of DRP1 and induce cell cycle arrest and apoptosis in human CRC cells.
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Affiliation(s)
- Dhanir Tailor
- School of Life Sciences, Central University of Gujarat, Gandhinagar, Gujarat, India
| | - Eun-Ryeong Hahm
- Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, USA; University of Pittsburgh Cancer Institute, Pittsburgh, USA
| | - Raosaheb K Kale
- School of Life Sciences, Central University of Gujarat, Gandhinagar, Gujarat, India; University of Pittsburgh Cancer Institute, Pittsburgh, USA
| | - Shivendra V Singh
- Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, USA; University of Pittsburgh Cancer Institute, Pittsburgh, USA
| | - Rana P Singh
- School of Life Sciences, Central University of Gujarat, Gandhinagar, Gujarat, India; Cancer and Radiation Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.
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30
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Vundru SS, Kale RK, Singh RP. β-Sitosterol induces G1 arrest and causes depolarization of mitochondrial membrane potential in breast carcinoma MDA-MB-231 cells. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2013; 13:280. [PMID: 24160369 PMCID: PMC3819702 DOI: 10.1186/1472-6882-13-280] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Accepted: 09/24/2013] [Indexed: 11/10/2022]
Abstract
BACKGROUNDS It is suggested that dietary phytosterols, such as β-sitosterol (ST), have cancer chemopreventive effects; however, studies are limited to support such claims. Here, we evaluated the efficacy of ST on three different human cancer cell lines including skin epidermoid carcinoma A431 cells, lung epithelial carcinoma A549 cells and breast adenocarcinoma MDA-MB-231. METHODS Cell growth assay, cell cycle analysis, FACS, JC-1 staining, annexin V staining and immunoblotting were used to study the efficacy of ST on cancer cells. RESULTS ST (30-90 μM) treatments for 48 h and 72 h did not show any significant effect on cell growth and death in A431 cells. Whereas similar ST treatments moderately inhibited the growth of A549 cells by up to 13% (p ≤ 0.05) in 48 h and 14% (p ≤ 0.05-0.0001) in 72 h. In MDA-MB-231 cells, ST caused a significant dose-dependent cell growth inhibition by 31- 63% (p ≤ 0.0001) in 48 h and 40-50% (p ≤ 0.0001) in 72 h. While exploring the molecular changes associated with strong ST efficacy in breast cancer cells, we observed that ST induced cell cycle arrest as well as cell death. ST caused G0/G1 cell cycle arrest which was accompanied by a decrease in CDK4 and cyclin D1, and an increase in p21/Cip1and p27/Kip1 protein levels. Further, cell death effect of ST was associated with induction of apoptosis. ST also caused the depolarization of mitochondrial membrane potential and increased Bax/Bcl-2 protein ratio. CONCLUSIONS These results suggest prominent in vitro anti-proliferative and pro-apoptotic effects of ST in MDA-MB-231 cells. This study provides valuable insight into the chemopreventive efficacy and associated molecular alterations of ST in breast cancer cells whereas it had only moderate efficacy on lung cancer cells and did not show any considerable effect on skin cancer cells. These findings would form the basis for further studies to understand the mechanisms and assess the potential utility of ST as a cancer chemopreventive agent against breast cancer.
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Affiliation(s)
- Shanthi Sri Vundru
- School of Life Sciences, Central University of Gujarat, Gandhinagar, Gujarat, India
| | - Raosaheb K Kale
- School of Life Sciences, Central University of Gujarat, Gandhinagar, Gujarat, India
- Cancer and Radiation Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Rana P Singh
- School of Life Sciences, Central University of Gujarat, Gandhinagar, Gujarat, India
- Cancer and Radiation Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
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31
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Wu YH, Hu CW, Chien CW, Chen YJ, Huang HC, Juan HF. Quantitative proteomic analysis of human lung tumor xenografts treated with the ectopic ATP synthase inhibitor citreoviridin. PLoS One 2013; 8:e70642. [PMID: 23990911 PMCID: PMC3749231 DOI: 10.1371/journal.pone.0070642] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2013] [Accepted: 06/20/2013] [Indexed: 01/08/2023] Open
Abstract
ATP synthase is present on the plasma membrane of several types of cancer cells. Citreoviridin, an ATP synthase inhibitor, selectively suppresses the proliferation and growth of lung cancer without affecting normal cells. However, the global effects of targeting ectopic ATP synthase in vivo have not been well defined. In this study, we performed quantitative proteomic analysis using isobaric tags for relative and absolute quantitation (iTRAQ) and provided a comprehensive insight into the complicated regulation by citreoviridin in a lung cancer xenograft model. With high reproducibility of the quantitation, we obtained quantitative proteomic profiling with 2,659 proteins identified. Bioinformatics analysis of the 141 differentially expressed proteins selected by their relative abundance revealed that citreoviridin induces alterations in the expression of glucose metabolism-related enzymes in lung cancer. The up-regulation of enzymes involved in gluconeogenesis and storage of glucose indicated that citreoviridin may reduce the glycolytic intermediates for macromolecule synthesis and inhibit cell proliferation. Using comprehensive proteomics, the results identify metabolic aspects that help explain the antitumorigenic effect of citreoviridin in lung cancer, which may lead to a better understanding of the links between metabolism and tumorigenesis in cancer therapy.
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Affiliation(s)
- Yi-Hsuan Wu
- Institute of Molecular and Cellular Biology, Department of Life Science, National Taiwan University, Taipei, Taiwan
| | - Chia-Wei Hu
- Institute of Molecular and Cellular Biology, Department of Life Science, National Taiwan University, Taipei, Taiwan
| | | | - Yu-Ju Chen
- Institute of Chemistry, Academia Sinica, Taipei, Taiwan
| | - Hsuan-Cheng Huang
- Institute of Biomedical Informatics, Center for Systems and Synthetic Biology, National Yang-Ming University, Taipei, Taiwan
- * E-mail: (H-CH); (H-FJ)
| | - Hsueh-Fen Juan
- Institute of Molecular and Cellular Biology, Department of Life Science, National Taiwan University, Taipei, Taiwan
- * E-mail: (H-CH); (H-FJ)
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Fang Y, Cao Z, Hou Q, Ma C, Yao C, Li J, Wu XR, Huang C. Cyclin d1 downregulation contributes to anticancer effect of isorhapontigenin on human bladder cancer cells. Mol Cancer Ther 2013; 12:1492-503. [PMID: 23723126 DOI: 10.1158/1535-7163.mct-12-0922] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Isorhapontigenin (ISO) is a new derivative of stilbene compound that was isolated from the Chinese herb Gnetum Cleistostachyum and has been used for treatment of bladder cancers for centuries. In our current studies, we have explored the potential inhibitory effect and molecular mechanisms underlying isorhapontigenin anticancer effects on anchorage-independent growth of human bladder cancer cell lines. We found that isorhapontigenin showed a significant inhibitory effect on human bladder cancer cell growth and was accompanied with related cell cycle G(0)-G(1) arrest as well as downregulation of cyclin D1 expression at the transcriptional level in UMUC3 and RT112 cells. Further studies identified that isorhapontigenin downregulated cyclin D1 gene transcription via inhibition of specific protein 1 (SP1) transactivation. Moreover, ectopic expression of GFP-cyclin D1 rendered UMUC3 cells resistant to induction of cell-cycle G(0)-G(1) arrest and inhibition of cancer cell anchorage-independent growth by isorhapontigenin treatment. Together, our studies show that isorhapontigenin is an active compound that mediates Gnetum Cleistostachyum's induction of cell-cycle G(0)-G(1) arrest and inhibition of cancer cell anchorage-independent growth through downregulating SP1/cyclin D1 axis in bladder cancer cells. Our studies provide a novel insight into understanding the anticancer activity of the Chinese herb Gnetum Cleistostachyum and its isolate isorhapontigenin.
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Affiliation(s)
- Yong Fang
- Department of Medical Oncology, Sir Run Run Shaw Hospital, ZheJiang University, Hangzhou, Zhejiang, China
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Kandzari SJ, Riggs D, Jackson B, Luchey A, Oliver C, Zaslau S. In vitro regulation of cell growth and angiogenesis by inositol hexaphosphate in bladder cancer. Curr Urol 2013; 6:199-204. [PMID: 24917743 DOI: 10.1159/000343539] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2012] [Accepted: 10/29/2012] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Inositol Hexaphosphate (IP6) is a naturally occurring polyphosphorylated carbohydrate that is found in food sources high in fiber content. We hypothesized that IP6 would inhibit the cell growth rate of bladder cancer in vitro. METHODS T24 and TCCSUP bladder cancer cell lines were treated with titrating doses of IP6 (0.3, 0.6 and 0.9 mM/well). Cell viability and vascular endothelial growth factor levels were measured. RESULTS Significant reductions (p < 0.001) in cellular growth were noted in both cell lines at all doses and time points tested, with the exception of 0.3 mM IP6 at 24 hours in the T24 cell line. The percent inhibition of vascular endothelial growth factor was significantly higher than that observed in the TCCSUP cell line at 48 and 72 hours with 0.3 mM IP6 (p < 0.001). The T24 cells exhibited the same level of inhibition at 24 and 48 hours with 0.6 mM dose of IP6 and at 72 hours with the 0.3 mM dose (p < 0.001). CONCLUSIONS In vitro treatment of bladder cancer with the common dietary polyphosphorylated carbohydrate IP6 significantly decreased cellular growth by anti-angiogenic mechanisms. We feel that this data warrants further investigation and consideration for initiation of clinical trials to evaluate the safety and clinical utility of this agent.
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Affiliation(s)
- Stanley J Kandzari
- Section of Urology, Department Of Surgery, Robert C. Byrd Health Science Center, West Virginia University, Morgantown, W. Va., USA
| | - Dale Riggs
- Section of Urology, Department Of Surgery, Robert C. Byrd Health Science Center, West Virginia University, Morgantown, W. Va., USA
| | - Barbara Jackson
- Section of Urology, Department Of Surgery, Robert C. Byrd Health Science Center, West Virginia University, Morgantown, W. Va., USA
| | - Adam Luchey
- Section of Urology, Department Of Surgery, Robert C. Byrd Health Science Center, West Virginia University, Morgantown, W. Va., USA
| | - Claire Oliver
- Section of Urology, Department Of Surgery, Robert C. Byrd Health Science Center, West Virginia University, Morgantown, W. Va., USA
| | - Stanley Zaslau
- Section of Urology, Department Of Surgery, Robert C. Byrd Health Science Center, West Virginia University, Morgantown, W. Va., USA
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Selimovic D, El-Khattouti A, Ghozlan H, Haikel Y, Abdelkader O, Hassan M. Hepatitis C virus-related hepatocellular carcinoma: An insight into molecular mechanisms and therapeutic strategies. World J Hepatol 2012; 4:342-55. [PMID: 23355912 PMCID: PMC3554798 DOI: 10.4254/wjh.v4.i12.342] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2012] [Revised: 11/17/2012] [Accepted: 11/24/2012] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infects more than 170 million people worldwide, and thereby becomes a series global health challenge. Chronic infection with HCV is considered one of the major causes of end-stage liver disease including cirrhosis and hepatocellular carcinoma. Although the multiple functions of the HCV proteins and their impacts on the modulation of the intracellular signaling transduction processes, the drive of carcinogenesis during the infection with HCV, is thought to result from the interactions of viral proteins with host cell proteins. Thus, the induction of mutator phenotype, in liver, by the expression of HCV proteins provides a key mechanism for the development of HCV-associated hepatocellular carcinoma (HCC). HCC is considered one of the most common malignancies worldwide with increasing incidence during the past decades. In many countries, the trend of HCC is attributed to several liver diseases including HCV infection. However, the development of HCC is very complicated and results mainly from the imbalance between tumor suppressor genes and oncogenes, as well as from the alteration of cellular factors leading to a genomic instability. Besides the poor prognosis of HCC patients, this type of tumor is quite resistance to the available therapies. Thus, understanding the molecular mechanisms, which are implicated in the development of HCC during the course of HCV infection, may help to design a general therapeutic protocol for the treatment and/or the prevention of this malignancy. This review summarizes the current knowledge of the molecular mechanisms, which are involved in the development of HCV-associated HCC and the possible therapeutic strategies.
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Affiliation(s)
- Denis Selimovic
- Denis Selimovic, Youssef Haikel, Mohamed Hassan, Institut National de la Santé et de la Recherche Médicale, U 977, 67000 Strasbourg, France
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Raina K, Ravichandran K, Rajamanickam S, Huber KM, Serkova NJ, Agarwal R. Inositol hexaphosphate inhibits tumor growth, vascularity, and metabolism in TRAMP mice: a multiparametric magnetic resonance study. Cancer Prev Res (Phila) 2012; 6:40-50. [PMID: 23213071 DOI: 10.1158/1940-6207.capr-12-0387] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Herein, employing anatomical and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI), we evaluated noninvasively, the in vivo, chemopreventive efficacy of inositol hexaphosphate (IP6), a major constituent of high-fiber diets, against prostate tumor growth and progression in transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Male TRAMP mice, beginning at 4 weeks of age, were fed with 1%, 2%, or 4% (w/v) IP6 in drinking water or only drinking water till 28 weeks of age and monitored using MRI over the course of study. Longitudinal assessment of prostate volumes by conventional MRI and tumor vascularity by gadolinium-based DCE-MRI showed a profound reduction in tumor size, partly due to antiangiogenic effects by IP6 treatment. As potential mechanisms of IP6 efficacy, decrease in the expression of glucose transporter GLUT-4 protein together with an increase in levels of phospho-AMP-activated kinase (AMPK(Th172)) were observed in prostate tissues of mice from IP6 fed-groups, suggesting that IP6 is interfering with the metabolic events occurring in TRAMP prostate. Investigative metabolomics study using quantitative high-resolution (1)H-NMR on prostate tissue extracts showed that IP6 significantly decreased glucose metabolism and membrane phospholipid synthesis, in addition to causing an increase in myoinositol levels in the prostate. Together, these findings show that oral IP6 supplement blocks growth and angiogenesis of prostate cancer in the TRAMP model in conjunction with metabolic events involved in tumor sustenance. This results in energy deprivation within the tumor, suggesting a practical and translational potential of IP6 treatment in suppressing growth and progression of prostate cancer in humans.
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Affiliation(s)
- Komal Raina
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
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Tomosugi M, Sowa Y, Yasuda S, Tanaka R, te Riele H, Ikawa H, Koyama M, Sakai T. Retinoblastoma gene-independent G1 phase arrest by flavone, phosphatidylinositol 3-kinase inhibitor, and histone deacetylase inhibitor. Cancer Sci 2012; 103:2139-43. [PMID: 22957647 DOI: 10.1111/cas.12012] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2012] [Revised: 08/16/2012] [Accepted: 08/30/2012] [Indexed: 11/28/2022] Open
Abstract
In most human malignant tumors, retinoblastoma tumor-suppressor gene (RB) product is inactivated by phosphorylation. Therefore, cancer preventive agents or molecular-targeting agents can inhibit the tumor growth at G(1) phase through RB reactivation. However, little is known about the effectiveness of RB reactivating agents against malignancies with mutated RB. We report here that chemopreventive agent flavone, phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002, and histone deacetylase (HDAC) inhibitor trichostatin A (TSA) also induce G(1) phase arrest in malignant tumor cells with mutated RB. In human prostate cancer DU145 cells with mutated RB, flavone increased cyclin-dependent kinase (CDK) inhibitors p21 and p27, and reduced cdk4 and cdk6, resulting in decrement of phosphorylated RB family proteins p130 and p107. LY294002 also dephosphorylated p107 and p130 proteins, whereas TSA dephosphorylated p130, but not p107. Furthermore, flavone induced G(1) phase arrest in both mouse embryo fibroblast (MEF) wild-type and MEF RB(-/-) cells, but did not do so in RB, p107, and p130 triple-knockout MEF cells. These results suggested that p130 and p107 contributed to G(1) phase arrest by flavone in RB-mutated cells. However, flavone induced tumor suppressor microRNA miR-34a with reduction of E2F1 and E2F3, known to be downregulated by miR-34a, raising the possibility that miR-34a might partially contribute to G(1) arrest by flavone. These results raise the possibility that RB reactivating chemopreventive agents or molecular targeting agents might also be effective against a variety of malignant tumor cells with mutant RB.
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Affiliation(s)
- Mitsuhiro Tomosugi
- Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Wu D, Sullards MC, Oldham CD, Gelbaum L, Lucrezi J, Pullman GS, May SW. Myo-inositol hexakisphosphate, isolated from female gametophyte tissue of loblolly pine, inhibits growth of early-stage somatic embryos. THE NEW PHYTOLOGIST 2012; 193:313-326. [PMID: 22023391 DOI: 10.1111/j.1469-8137.2011.03928.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
• Myo-inositol hexakisphosphate (InsP(6)), abundant in animals and plants, is well known for its anticancer activity. However, many aspects of InsP(6) function in plants remain undefined. We now report the first evidence that InsP(6) can inhibit cellular proliferation in plants under growth conditions where phosphorus is not limited. • A highly anionic molecule inhibitory to early-stage somatic embryo growth of loblolly pine (LP) was purified chromatographically from late-stage LP female gametophytes (FGs), and then characterized structurally using mass spectrometry (MS) and nuclear magnetic resonance (NMR) analyses. • Exact mass and mass spectrometry-mass spectrometry (MS-MS) fragmentation identified the bioactive molecule as an inositol hexakisphosphate. It was then identified as the myo-isomer (i.e. InsP(6)) on the basis of (1)H-, (31)P- and (13)C-NMR, (1)H-(1)H correlation spectroscopy (COSY), (1)H-(31)P heteronuclear single quantum correlation (HSQC) and (1)H-(13)C HSQC. Topical application of InsP(6) to early-stage somatic embryos indeed inhibits embryonic growth. • Recently evidence has begun to emerge that InsP(6) may also play a regulatory role in plant cells. We anticipate that our findings will help to stimulate additional investigations aimed at elucidating the roles of inositol phosphates in cellular growth and development in plants.
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Affiliation(s)
- Di Wu
- School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332, USA
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Stenman K, Stattin P, Stenlund H, Riklund K, Gröbner G, Bergh A. H HRMAS NMR Derived Bio-markers Related to Tumor Grade, Tumor Cell Fraction, and Cell Proliferation in Prostate Tissue Samples. Biomark Insights 2011; 6:39-47. [PMID: 21499438 PMCID: PMC3076017 DOI: 10.4137/bmi.s6794] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
A high-resolution magic angle spinning NMR spectroscopic approach is presented for evaluating the occurrence, amount and aggressiveness of cancer in human prostate tissue samples. Using this technique, key metabolites in malignant and non-malignant samples (n = 149) were identified, and patterns of their relative abundance were analyzed by multivariate statistical methods. Ratios of various metabolites – including (glycerophophorylcholine + phosphorylcholine)/creatine, myo-inositol/scyllo-inositol, scyllo-inositol/creatine, choline/creatine, and citrate/creatine – correlated with: i) for non-malignant tissue samples, the distance to the nearest tumor and its Gleason score and; ii) the fraction of tumor cells present in the sample; and iii) tumor cell proliferation (Ki67 labelling index). This NMR-based approach allows the extraction of information that could be useful for developing novel diagnostic methods for prostate cancer.
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Molecular characterization of apoptosis induced by CARF silencing in human cancer cells. Cell Death Differ 2010; 18:589-601. [PMID: 21052095 DOI: 10.1038/cdd.2010.129] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Collaborator of ARF (CARF) was cloned as an ARF-interacting protein and shown to regulate the p53-p21(WAF1)-HDM2 pathway, which is central to tumor suppression via senescence and apoptosis. We had previously reported that CARF inhibition in cancer cells led to polyploidy and caspase-dependent apoptosis, however, the mechanisms governing this phenomenon remained unknown. Thus, we examined various cell death and survival pathways including the mitochondrial stress, ataxia telangiectasia mutated (ATM)-ATR, Ras-MAP kinase and retinoblastoma cascades. We found that CARF is a pleiotropic regulator with widespread effects; its suppression affected all investigated pathways. Most remarkably, it protected the cells against genotoxicity; CARF knockdown elicited DNA damage response as evidenced by increased levels of phosphorylated ATM and γH2AX, leading to induction of mitotic arrest and eventual apoptosis. We also show that the CARF-silencing-induced apoptosis in vitro translates to in vivo. In a human tumor xenograft mouse model, treatment of developing tumors with short hairpin RNA (shRNA) against CARF via an adenovirus carrier induced complete suppression of tumor growth, suggesting that CARF shRNA is a strong candidate for an anticancer reagent. We demonstrate that CARF has a vital role in genome preservation and tumor suppression and CARF siRNA is an effective novel cancer therapeutic agent.
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Kang J, Badger TM, Ronis MJJ, Wu X. Non-isoflavone phytochemicals in soy and their health effects. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2010; 58:8119-33. [PMID: 20578706 DOI: 10.1021/jf100901b] [Citation(s) in RCA: 97] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2023]
Abstract
Epidemiological and clinical studies have linked consumption of soy foods with low incidences of a number of chronic diseases, such as cardiovascular diseases, cancer, and osteoporosis. Over the past decades, enormous research efforts have been made to identify bioactive components in soy. Isoflavones and soy protein have been suggested as the major bioactive components in soy and have received considerable attention. However, there are hundreds of phytochemical components in soybeans and soy-based foods. In recent years, accumulating evidence has suggested that the isoflavones or soy proteins stripped of phytochemicals only reflect certain aspects of health effects associated with soy consumption. Other phytochemicals, either alone or in combination with isoflavones or soy protein, may be involved in the health effects of soy. This review attempts to summarize major non-isoflavone phytochemicals in soy, as well as their bioavailability and health effects. In addition, a brief discussion of components formed during food processing is also included.
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Affiliation(s)
- Jie Kang
- USDA Arkansas Children's Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
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Kumar V, Sinha AK, Makkar HP, Becker K. Dietary roles of phytate and phytase in human nutrition: A review. Food Chem 2010. [DOI: 10.1016/j.foodchem.2009.11.052] [Citation(s) in RCA: 489] [Impact Index Per Article: 32.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Eberhard M, Föller M, Lang F. Effect of phytic acid on suicidal erythrocyte death. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2010; 58:2028-2033. [PMID: 20058927 DOI: 10.1021/jf903666b] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
Phytic acid, an anticarcinogenic food component, stimulates apoptosis of tumor cells. Similar to apoptosis, human erythrocytes may undergo suicidal death or eryptosis, characterized by cell membrane scrambling and cell shrinkage. Triggers of eryptosis include energy depletion. Phytate intake could cause anemia, an effect attributed to iron complexation. The present experiments explored whether phytic acid influences eryptosis. Supernatant hemoglobin concentration was determined to reveal hemolysis, annexin V-binding in FACS analysis was utilized to identify erythrocytes with scrambled cell membrane, forward scatter in FACS analysis was taken as a measure of cell volume, and a luciferin-luciferase assay was employed to determine erythrocyte ATP content. As a result, phytic acid (>or=1 mM) did not lead to significant hemolysis, but significantly increased the percentage of annexin V-binding erythrocytes, significantly decreased forward scatter, and significantly decreased cellular ATP content. In conclusion, phytic acid stimulates suicidal human erythrocyte death, an effect paralleling its proapoptotic effect on nucleated cells.
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Affiliation(s)
- Matthias Eberhard
- Department of Physiology, Eberhard-Karls-University of Tubingen, Gmelinstrasse 5, D-72076 Tuebingen, Germany
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Gu M, Raina K, Agarwal C, Agarwal R. Inositol hexaphosphate downregulates both constitutive and ligand-induced mitogenic and cell survival signaling, and causes caspase-mediated apoptotic death of human prostate carcinoma PC-3 cells. Mol Carcinog 2010; 49:1-12. [PMID: 19544333 DOI: 10.1002/mc.20560] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Constitutively active mitogenic and prosurvival signaling cascades due to aberrant expression and interaction of growth factors and their receptors are well documented in human prostate cancer (PCa). Epidermal growth factor (EGF) and insulin-like growth factor-1 (IGF-1) are potent mitogens that regulate proliferation and survival of PCa cells via autocrine and paracrine loops involving both mitogen-activated protein kinase (MAPK)- and Akt-mediated signaling. Accordingly, here we assessed the effect of inositol hexaphosphate (IP6) on constitutive and ligand (EGF and IGF-1)-induced biological responses and associated signaling cascades in advanced and androgen-independent human PCa PC-3 cells. Treatment of PC-3 cells with 2 mM IP6 strongly inhibited both growth and proliferation and decreased cell viability; similar effects were also observed in other human PCa DU145 and LNCaP cells. IP6 also caused a strong apoptotic death of PC-3 cells together with caspase 3 and PARP cleavage. Mechanistic studies showed that biological effects of IP6 were associated with inhibition of both constitutive and ligand-induced Akt phosphorylation together with a decrease in total Akt levels, but a differential inhibitory effect on MAPKs extra cellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase (JNK1/2), and p38 under constitutive and ligand-activated conditions. Under similar condition, IP6 also inhibited AP-1 DNA-binding activity and decreased nuclear levels of both phospho and total c-Fos and c-Jun. Together, these findings for the first time establish IP6 efficacy in inhibiting aberrant EGF receptor (EGFR) or IGF-1 receptor (IGF-1R) pathway-mediated sustained growth promoting and survival signaling cascades in advanced and androgen-independent human PCa PC-3 cells, which might have translational implications in advanced human PCa control and management.
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Affiliation(s)
- Mallikarjuna Gu
- Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, 80045, USA
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Gu M, Roy S, Raina K, Agarwal C, Agarwal R. Inositol hexaphosphate suppresses growth and induces apoptosis in prostate carcinoma cells in culture and nude mouse xenograft: PI3K-Akt pathway as potential target. Cancer Res 2010; 69:9465-72. [PMID: 19920184 DOI: 10.1158/0008-5472.can-09-2805] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Constitutive activation of phosphoinositide 3-kinase (PI3K)-Akt pathway transmits growth-regulatory signals that play a central role in promoting survival, proliferation, and angiogenesis in human prostate cancer cells. Here, we assessed the efficacy of inositol hexaphosphate (IP6) against invasive human prostate cancer PC-3 and C4-2B cells and regulation of PI3K-Akt pathway. IP6 treatment of cells suppressed proliferation, induced apoptosis along with caspase-3 and poly(ADP-ribose) polymerase (PARP) cleavage, and inhibited constitutive activation of Akt and its upstream regulators PI3K, phosphoinositide-dependent kinase-1 and integrin-linked kinase-1 (ILK1). Downstream of Akt, IP6 inhibited the phosphorylation of glycogen synthase kinase-3alpha/beta at Ser(21/9) and consequently reduced cyclin D1 expression. Efficacy studies employing PC-3 tumor xenograft growth in nude mice showed that 2% (w/v) IP6 feeding in drinking water inhibits tumor growth and weight by 52% to 59% (P < 0.001). Immunohistochemical analysis of xenografts showed that IP6 significantly reduces the expression of molecules associated with cell survival/proliferation (ILK1, phosphorylated Akt, cyclin D1, and proliferating cell nuclear antigen) and angiogenesis (platelet endothelial cell adhesion molecule-1 or CD31, vascular endothelial growth factor, endothelial nitric oxide synthase, and hypoxia-inducible factor-1alpha) together with an increase in apoptotic markers (cleaved caspase-3 and PARP). These findings suggest that, by targeting the PI3K-ILK1-Akt pathway, IP6 suppresses cell survival, proliferation, and angiogenesis but induces death in prostate cancer cells, which might have translational potential in preventing and controlling the growth of advanced and aggressive prostate cancer for which conventional chemotherapy is not effective.
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Affiliation(s)
- Mallikarjuna Gu
- Department of Pharmaceutical Sciences, School of Pharmacy, and University of Colorado Cancer Center, University of Colorado-Denver, Aurora, Colorado 80045, USA
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Roy S, Gu M, Ramasamy K, Singh RP, Agarwal C, Siriwardana S, Sclafani RA, Agarwal R. p21/Cip1 and p27/Kip1 Are essential molecular targets of inositol hexaphosphate for its antitumor efficacy against prostate cancer. Cancer Res 2009; 69:1166-73. [PMID: 19176374 DOI: 10.1158/0008-5472.can-08-3115] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Inositol hexaphosphate (IP6) causes G(1) arrest and increases cyclin-dependent kinase inhibitors p21/Cip1 and p27/Kip1 protein levels in human prostate cancer (PCa) DU145 cells lacking functional p53. However, whether cyclin-dependent kinase inhibitor I induction by IP6 plays any role in its antitumor efficacy is unknown. Herein, we observed that either p21 or p27 knockdown by small interfering RNA has no considerable effect on IP6-induced G(1) arrest, growth inhibition, and death in DU145 cells; however, the simultaneous knockdown of both p21 and p27 reversed the effects of IP6. To further confirm these findings both in vitro and in vivo, we generated DU145 cell variants with knockdown levels of p21 (DU-p21), p27 (DU-p27), or both (DU-p21+p27) via retroviral transduction of respective short hairpin RNAs. Knocking down p21 or p27 individually did not alter IP6-caused cell growth inhibition and G(1) arrest; however, their simultaneous ablation completely reversed the effects of IP6. In tumor xenograft studies, IP6 (2% w/v, in drinking water) caused a comparable reduction in tumor volume (40-46%) and tumor cell proliferation (26-28%) in DU-EV (control), DU-p21, and DU-p27 tumors but lost most of its effect in DU-p21+p27 tumors. IP6-caused apoptosis also occurred in a Cip/Kip-dependent manner because DU-p21+p27 cells were completely resistant to IP6-induced apoptosis both in cell culture and xenograft. Together, these results provide evidence, for the first time, of the critical role of p21 and p27 in mediating the anticancer efficacy of IP6, and suggest their redundant role in the antiproliferative and proapoptotic effects of IP6 in p53-lacking human PCa cells, both in vitro and in vivo.
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Affiliation(s)
- Srirupa Roy
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, University of Colorado Cancer Center, Denver, Colorado 80045, USA
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Enhanced killing of androgen-independent prostate cancer cells using inositol hexakisphosphate in combination with proteasome inhibitors. Br J Cancer 2008; 99:1613-22. [PMID: 18941459 PMCID: PMC2584963 DOI: 10.1038/sj.bjc.6604730] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Effective treatments for androgen-independent prostate cancer (AIPCa) are lacking. To address this, emerging therapeutics such as proteasome inhibitors are currently undergoing clinical trials. Inositol hexakisphosphate (IP6) is an orally non-toxic phytochemical that exhibits antitumour activity against several types of cancer including PCa. We have previously shown that treatment of PC3 cells with IP6 induces the transcription of a subset of nuclear factor-κB (NF-κB)-responsive and pro-apoptotic BCL-2 family genes. In this study, we report that although NF-κB subunits p50/p65 translocate to the nucleus of PC3 cells in response to IP6, inhibition of NF-κB-mediated transcription using non-degradable inhibitor of κB (IκB)-α does not modulate IP6 sensitivity. Treatment with IP6 also leads to increased protein levels of PUMA, BIK/NBK and NOXA between 4 and 8 h of treatment and decreased levels of MCL-1 and BCL-2 after 24 h. Although blocking transcription using actinomycin D does not modulate PC3 cell sensitivity to IP6, inhibition of protein translation using cycloheximide has a significant protective effect. In contrast, blocking proteasome-mediated protein degradation using MG-132 significantly enhances the ability of IP6 to reduce cellular metabolic activity in both PC3 and DU145 AIPCa cell lines. This effect of combined treatment on mitochondrial depolarisation is particularly striking and is also reproduced by another proteasome inhibitor (ALLN). The enhanced effect of combined MG132/IP6 treatment is almost completely inhibited by cycloheximide and correlates with changes in BCL-2 family protein levels. Altogether these results suggest a role for BCL-2 family proteins in mediating the combined effect of IP6 and proteasome inhibitors and warrant further pre-clinical studies for the treatment of AIPCa.
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Raina K, Rajamanickam S, Singh RP, Agarwal R. Chemopreventive efficacy of inositol hexaphosphate against prostate tumor growth and progression in TRAMP mice. Clin Cancer Res 2008; 14:3177-84. [PMID: 18483386 DOI: 10.1158/1078-0432.ccr-07-5275] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
PURPOSE Herein, for the first time, we evaluated the in vivo chemopreventive efficacy of inositol hexaphosphate (IP6), a major constituent of high-fiber diets, against prostate tumor growth and progression in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. EXPERIMENTAL DESIGN Beginning at 4 weeks of age, male TRAMP mice were fed 2% (w/v) IP6 in drinking water or only drinking water till 24 weeks of age, and then sacrificed. Prostate tissue was subjected to histopathologic analysis and to immunohistochemical analyses for proliferation and apoptosis. RESULTS IP6 feeding did not show any adverse effect on fluid and diet consumption and body weight. There was a significant reduction (40%; P < 0.01) in lower urogenital tract weight in IP6-fed mice. IP6 inhibited prostate cancer progression at prostatic intraepithelial neoplasia stage and strongly reduced the incidence of adenocarcinoma (prostatic intraepithelial neoplasia/adenocarcinoma, 75:25% in the IP6 group versus 39:61% in the control group; P < 0.05). The incidences of well-differentiated and poorly differentiated adenocarcinomas in the IP6-fed group were reduced by 44% and 62%, respectively. Immunohistochemical analysis of prostate tissue showed a 26% decrease (P < 0.05) in proliferation cell nuclear antigen-positive cells and a 3.5-fold increase in apoptotic cells with no effect on Tag expression by IP6. CONCLUSIONS These findings are both novel and highly significant in establishing for the first time that oral IP6, without any toxicity, suppresses prostate tumor growth and progression at the neoplastic stage, thereby reducing the incidence of adenocarcinoma through its antiproliferative and proapoptotic effects, and thus indicating that IP6 could have potential chemopreventive effects against human prostate cancer.
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Affiliation(s)
- Komal Raina
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, Denver, Colorado 80262, USA
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Partially saturated canthaxanthin purified from Aspergillus carbonarius induces apoptosis in prostrate cancer cell line. Appl Microbiol Biotechnol 2008; 80:467-73. [PMID: 18542946 DOI: 10.1007/s00253-008-1538-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2007] [Revised: 05/08/2008] [Accepted: 05/08/2008] [Indexed: 10/22/2022]
Abstract
A mutant Aspergillus carbonarius selected for temperature tolerance after UV treatment, when grown in shake flasks, produced mycelia bearing yellow pigment. Since the mutant was affected in sterol biosynthetic pathway, the pigment was apparently produced to maintain membrane fluidity and rigidity for growth sustenance in low-pH culture broth. Nuclear magnetic resonance analyses characterizing the pigment as a partially saturated canthaxanthin, containing beta-ionone end rings, suggested its application as a retinoid. When tested for this property in retinoic acid receptor expressing prostate cancer cell line, LNCaP, the fungal partially saturated canthaxanthin induced apoptosis. Low apoptosis percentage in DU145 prostrate cancer cells that does not express functional retinoic acid receptor-beta (RAR-beta) suggested binding specificity of the partially saturated canthaxanthin for RAR-beta.
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Rochfort S, Panozzo J. Phytochemicals for health, the role of pulses. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2007; 55:7981-94. [PMID: 17784726 DOI: 10.1021/jf071704w] [Citation(s) in RCA: 174] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2023]
Abstract
Pulses are the seeds of legumes that are used for human consumption and include peas, beans, lentils, chickpeas, and fava beans. Pulses are an important source of macronutrients, containing almost twice the amount of protein compared to cereal grains. In addition to being a source of macronutrients and minerals, pulses also contain plant secondary metabolites that are increasingly being recognised for their potential benefits for human health. The best-studied legume is the soybean, traditionally regarded as an oilseed crop rather than a pulse. The potential health benefits of soy, particularly with respect to isoflavone content, have been the subject of much research and the focus of several reviews. By comparison, less is known about pulses. This review investigates the health potential of pulses, examining the bioactivity of pulse isoflavones, phytosterols, resistant starch, bioactive carbohydrates, alkaloids and saponins. The evidence for health properties is considered, as is the effect of processing and cooking on these potentially beneficial phytochemicals.
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Affiliation(s)
- Simone Rochfort
- Department of Primary Industries, Werribee Centre, Werribee, Victoria, Australia.
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Kim HJ, Jang YM, Kim H, Kwon YH. Apoptotic effect of IP(6) was not enhanced by co-treatment with myo-inositol in prostate carcinoma PC3 cells. Nutr Res Pract 2007; 1:195-9. [PMID: 20368938 PMCID: PMC2849022 DOI: 10.4162/nrp.2007.1.3.195] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2007] [Revised: 09/02/2007] [Accepted: 09/13/2007] [Indexed: 12/30/2022] Open
Abstract
Inositol hexaphosphate (IP(6)) is a major constituent of most cereals, legumes, nuts, oil seeds and soybean. Previous studies reported the anticancer effect of IP(6) and suggested that co-treatment of IP(6) with inositol may enhance anticancer effect of IP(6). Although the anticancer effect of IP(6) has been intensively studied, the combinational effect of IP(6) and inositol and involved mechanisms are not well understood so far. In the present study, we investigated the effect of IP(6) and myo-inositol (MI) on cell cycle regulation and apoptosis using PC3 prostate cancer cell lines. When cells were co-treated with IP(6) and MI, the extent of cell growth inhibition was significantly increased than that by IP(6) alone. To identify the effect of IP(6) and MI on apoptosis, the activity of caspase-3 was measured. The caspase-3 activity was significantly increased when cells were treated with either IP(6) alone or both IP(6) and MI, with no significant enhancement by co-treatment. To investigate the effect of IP(6) and MI of cell cycle arrest, we measured p21 mRNA expression in PC3 cells and observed significant increase in p21 mRNA by IP(6). But synergistic regulation by co-treatment with IP(6) and MI was not observed. In addition, there was no significant effect by co-treatment compared to IP(6) treatment on the regulation of cell cycle progression although IP(6) significantly changed cell cycle distribution in the presence of MI or not. Therefore, these findings support that IP(6) has anticancer function by induction of apoptosis and regulation of cell cycle. However, synergistic effect by MI on cell cycle regulation and apoptosis was not observed in PC3 prostate cancer cells.
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Affiliation(s)
- Hyun-Jung Kim
- Department of Food and Nutrition, Seoul National University, Seoul 151-742, Korea
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