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El-Masry TA, El-Nagar MMF, Oriquat GA, Alotaibi BS, Saad HM, El Zahaby EI, Ibrahim HA. Therapeutic efficiency of Tamoxifen/Orlistat nanocrystals against solid ehrlich carcinoma via targeting TXNIP/HIF1-α/MMP-9/P27 and BAX/Bcl2/P53 signaling pathways. Biomed Pharmacother 2024; 180:117429. [PMID: 39293373 DOI: 10.1016/j.biopha.2024.117429] [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: 06/27/2024] [Revised: 09/04/2024] [Accepted: 09/05/2024] [Indexed: 09/20/2024] Open
Abstract
BACKGROUND Orlistat (Orli) is an anti-obesity medication that has been approved by the US Food and Drug Administration. It has relatively limited oral bioavailability with promising inhibitory effects on cell proliferation as well as reducing the growth of tumors. AIMS This investigation was done to evaluate the potential protective effect of Tamoxifen/Orlistat nanocrystals alone or in combination against Solid Ehrlich Carcinoma (SEC) and to clarify the possible underlying influences. MATERIALS AND METHODS The liquid antisolvent precipitation technique (bottom-up technology) was utilized to manufacture Orlistat Nanocrystals. To explore potential causes for the anti-tumor action, female Swiss Albino mice bearing SEC were randomly assigned into five equal groups (n = 6). Group 1: Tumor control group, group 2: Tam group: tamoxifen (0.01 g/kg, IP), group 3: Free-Orli group: orlistat (0.24 g/kg, IP), group 4: Nano-Orli: orlistat nanocrystals (0.24 g/kg, IP), group 5: Tam-Nano-Orli: Both doses of Tam and Nano-Orli. All treatments were administered for 16 days. KEY FINDINGS The untreated mice showed development in the tumor volume and weight. As well as histopathology results from these mice revealed many tumor large cells as well as solid sheets of malignant cells. Also, untreated mice showed raised VEGF and TGF-1beta content. Moreover, results of gene expression in the SEC-bearing mice noted upregulation in HIF-1α, MMP-9, Bcl-2, and P27 gene expression and downregulation of TXNIP, BAX, and P53 gene expression. On the other hand, administrated TAM, Free-Orli, Nano-Orli, and a combination of Tam-Nano-Orli distinctly suppressed the tumor effects on estimated parameters with special reference to Tam-Nano-Orli. SIGNIFICANCE The developed Tamoxifen/Orlistat nanocrystals combination could be considered a promising approach to augment antitumor effects.
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Affiliation(s)
- Thanaa A El-Masry
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt.
| | - Maysa M F El-Nagar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt.
| | - Ghaleb Ali Oriquat
- Faculty of Allied Medical Sciences, Al-Ahliyya Amman University, Amman 19328, Jordan.
| | - Badriyah S Alotaibi
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia.
| | - Hebatallah M Saad
- Department of Pathology, Faculty of Veterinary Medicine, Matrouh University, Cairo 51511, Egypt.
| | - Enas I El Zahaby
- Department of Pharmaceutics, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 35712, Egypt.
| | - Hanaa A Ibrahim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt.
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Kotani H, Oshima H, Boucher JC, Yamano T, Sakaguchi H, Sato S, Fukuda K, Nishiyama A, Yamashita K, Ohtsubo K, Takeuchi S, Nishiuchi T, Oshima M, Davila ML, Yano S. Dual inhibition of SUMOylation and MEK conquers MYC-expressing KRAS-mutant cancers by accumulating DNA damage. J Biomed Sci 2024; 31:68. [PMID: 38992694 PMCID: PMC11238369 DOI: 10.1186/s12929-024-01060-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Accepted: 06/22/2024] [Indexed: 07/13/2024] Open
Abstract
BACKGROUND KRAS mutations frequently occur in cancers, particularly pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer. Although KRASG12C inhibitors have recently been approved, effective precision therapies have not yet been established for all KRAS-mutant cancers. Many treatments for KRAS-mutant cancers, including epigenome-targeted drugs, are currently under investigation. Small ubiquitin-like modifier (SUMO) proteins are a family of small proteins covalently attached to and detached from other proteins in cells via the processes called SUMOylation and de-SUMOylation. We assessed whether SUMOylation inhibition was effective in KRAS-mutant cancer cells. METHODS The efficacy of the first-in-class SUMO-activating enzyme E inhibitor TAK-981 (subasumstat) was assessed in multiple human and mouse KRAS-mutated cancer cell lines. A gene expression assay using a TaqMan array was used to identify biomarkers of TAK-981 efficacy. The biological roles of SUMOylation inhibition and subsequent regulatory mechanisms were investigated using immunoblot analysis, immunofluorescence assays, and mouse models. RESULTS We discovered that TAK-981 downregulated the expression of the currently undruggable MYC and effectively suppressed the growth of MYC-expressing KRAS-mutant cancers across different tissue types. Moreover, TAK-981-resistant cells were sensitized to SUMOylation inhibition via MYC-overexpression. TAK-981 induced proteasomal degradation of MYC by altering the balance between SUMOylation and ubiquitination and promoting the binding of MYC and Fbxw7, a key factor in the ubiquitin-proteasome system. The efficacy of TAK-981 monotherapy in immunocompetent and immunodeficient mouse models using a mouse-derived CMT167 cell line was significant but modest. Since MAPK inhibition of the KRAS downstream pathway is crucial in KRAS-mutant cancer, we expected that co-inhibition of SUMOylation and MEK might be a good option. Surprisingly, combination treatment with TAK-981 and trametinib dramatically induced apoptosis in multiple cell lines and gene-engineered mouse-derived organoids. Moreover, combination therapy resulted in long-term tumor regression in mouse models using cell lines of different tissue types. Finally, we revealed that combination therapy complementally inhibited Rad51 and BRCA1 and accumulated DNA damage. CONCLUSIONS We found that MYC downregulation occurred via SUMOylation inhibition in KRAS-mutant cancer cells. Our findings indicate that dual inhibition of SUMOylation and MEK may be a promising treatment for MYC-expressing KRAS-mutant cancers by enhancing DNA damage accumulation.
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Affiliation(s)
- Hiroshi Kotani
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, 13-1 Takara-Machi, Kanazawa, Ishikawa, 920-0934, Japan.
| | - Hiroko Oshima
- Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
- Nano Life Science Institute, Kanazawa University, Kanazawa, Japan
| | - Justin C Boucher
- Department of Blood and Marrow Transplant and Cellular Immunotherapy, Division of Clinical Science, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Tomoyoshi Yamano
- Nano Life Science Institute, Kanazawa University, Kanazawa, Japan
- Department of Immunology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Hiroyuki Sakaguchi
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, 13-1 Takara-Machi, Kanazawa, Ishikawa, 920-0934, Japan
| | - Shigeki Sato
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, 13-1 Takara-Machi, Kanazawa, Ishikawa, 920-0934, Japan
| | - Koji Fukuda
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, 13-1 Takara-Machi, Kanazawa, Ishikawa, 920-0934, Japan
- Nano Life Science Institute, Kanazawa University, Kanazawa, Japan
| | - Akihiro Nishiyama
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, 13-1 Takara-Machi, Kanazawa, Ishikawa, 920-0934, Japan
| | - Kaname Yamashita
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, 13-1 Takara-Machi, Kanazawa, Ishikawa, 920-0934, Japan
| | - Koushiro Ohtsubo
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, 13-1 Takara-Machi, Kanazawa, Ishikawa, 920-0934, Japan
| | - Shinji Takeuchi
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, 13-1 Takara-Machi, Kanazawa, Ishikawa, 920-0934, Japan
- Nano Life Science Institute, Kanazawa University, Kanazawa, Japan
| | - Takumi Nishiuchi
- Research Center for Experimental Modeling of Human Disease, Kanazawa University, Kanazawa, Japan
| | - Masanobu Oshima
- Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
- Nano Life Science Institute, Kanazawa University, Kanazawa, Japan
| | - Marco L Davila
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Seiji Yano
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, 13-1 Takara-Machi, Kanazawa, Ishikawa, 920-0934, Japan.
- Nano Life Science Institute, Kanazawa University, Kanazawa, Japan.
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
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Su Y, Zhang K. A novel cuproptosis-related gene prognostic signature in colon adenocarcinoma. Can J Physiol Pharmacol 2023; 101:589-598. [PMID: 37698225 DOI: 10.1139/cjpp-2023-0118] [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] [Indexed: 09/13/2023]
Abstract
Cuproptosis is the latest cell death type caused by enhanced mitochondrial-dependent energy metabolism. This study plans to establish a survival prognosis model for colon adenocarcinoma (COAD) patients based on cuproptosis-related genes (CRGs). We investigated the genetic alterations of CRGs in COAD based on The Cancer Genome Atlas database and validated in the GSE41328 dataset. Our results showed that LIPT1, PDHA1, GLS, and CDKN2A had significantly higher expression in COAD tissues than in normal tissues, while FDX1, DLD, and MTF1 had significantly lower expression in COAD tissues than in normal tissues (|(log2(fold change))| > 2, p < 0.05). DLD (hazard ratio (HR): 0.658; 95% confidence interval (CI): 0.445, 0.974; p = 0.037) and CDKN2A (HR: 1.785; 95% CI: 1.200, 2.654; p = 0.004) expressions were linked with overall survival throughout a log-rank test. CRG prognostic scores exhibited an area under the curve of 0.737, 0.646, and 0.633 at 1, 3, and 5 years. Patients with a high-risk factor suffered from poor prognosis (HR = 1.514; 95% CI: 1.022, 2.243; p = 0.0386). An independent validation dataset (GSE41328 (N = 20)) confirmed the above results. The CRGs' signature may be used as a prognostic predictor for COAD patients, providing unique insights into anticancer therapy.
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Affiliation(s)
- Yongqin Su
- General Practice Department, Heping Hospital Affiliated to Changzhi Medical College, Changzhi 46000, Shanxi, China
| | - Kun Zhang
- Department of Hepatobiliary Surgery, Heping Hospital Affiliated to Changzhi Medical College, Changzhi 046000, Shanxi, China
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Clapper ML, Chang WCL, Cooper HS. Dysplastic Aberrant Crypt Foci: Biomarkers of Early Colorectal Neoplasia and Response to Preventive Intervention. Cancer Prev Res (Phila) 2021; 13:229-240. [PMID: 32132117 DOI: 10.1158/1940-6207.capr-19-0316] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 10/04/2019] [Accepted: 10/25/2019] [Indexed: 12/15/2022]
Abstract
The discovery of aberrant crypt foci (ACF) more than three decades ago not only enhanced our understanding of how colorectal tumors form, but provided new opportunities to detect lesions prior to adenoma development and intervene in the colorectal carcinogenesis process even earlier. Because not all ACF progress to neoplasia, it is important to stratify these lesions based on the presence of dysplasia and establish early detection methods and interventions that specifically target dysplastic ACF (microadenomas). Significant progress has been made in characterizing the morphology and genetics of dysplastic ACF in both preclinical models and humans. Image-based methods have been established and new techniques that utilize bioactivatable probes and capture histologic abnormalities in vivo are emerging for lesion detection. Successful identification of agents that target dysplastic ACF holds great promise for intervening even earlier in the carcinogenesis process to maximize tumor inhibition. Future preclinical and clinical prevention studies should give significant attention to assessing the utility of dysplastic ACF as the earliest identifiable biomarker of colorectal neoplasia and response to therapy.See all articles in this Special Collection Honoring Paul F. Engstrom, MD, Champion of Cancer Prevention.
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Affiliation(s)
- Margie L Clapper
- Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
| | - Wen-Chi L Chang
- Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | - Harry S Cooper
- Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.,Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
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Krzystek-Korpacka M, Szczęśniak-Sięga B, Szczuka I, Fortuna P, Zawadzki M, Kubiak A, Mierzchała-Pasierb M, Fleszar MG, Lewandowski Ł, Serek P, Jamrozik N, Neubauer K, Wiśniewski J, Kempiński R, Witkiewicz W, Bednarz-Misa I. L-Arginine/Nitric Oxide Pathway Is Altered in Colorectal Cancer and Can Be Modulated by Novel Derivatives from Oxicam Class of Non-Steroidal Anti-Inflammatory Drugs. Cancers (Basel) 2020; 12:E2594. [PMID: 32932854 PMCID: PMC7564351 DOI: 10.3390/cancers12092594] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 09/05/2020] [Accepted: 09/10/2020] [Indexed: 12/14/2022] Open
Abstract
L-arginine/nitric oxide pathway metabolites are altered in colorectal cancer (CRC). We evaluated underlying changes in pathway enzymes in 55 paired tumor/tumor-adjacent samples and 20 normal mucosa using quantitative-PCR and assessed the impact of classic and novel oxicam analogues on enzyme expression and intracellular metabolite concentration (LC-MS/MS) in Caco-2, HCT116, and HT-29 cells. Compared to normal mucosa, ARG1, PRMT1, and PRMT5 were overexpressed in both tumor and tumor-adjacent tissue and DDAH2 solely in tumor-adjacent tissue. Tumor-adjacent tissue had higher expression of ARG1, DDAH1, and DDAH2 and lower NOS2 than patients-matched tumors. The ARG1 expression in tumors increased along with tumor grade and reflected lymph node involvement. Novel oxicam analogues with arylpiperazine moiety at the thiazine ring were more effective in downregulating DDAHs and PRMTs and upregulating ARG2 than piroxicam and meloxicam. An analogue distinguished by propylene linker between thiazine's and piperazine's nitrogen atoms and containing two fluorine substituents was the strongest inhibitor of DDAHs and PRMTs expression, while an analogue containing propylene linker but no fluorine substituents was the strongest inhibitor of ARG2 expression. Metabolic reprogramming in CRC includes overexpression of DDAHs and PRMTs in addition to ARG1 and NOS2 and is not restricted to tumor tissue but can be modulated by novel oxicam analogues.
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Affiliation(s)
- Małgorzata Krzystek-Korpacka
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.S.); (P.F.); (A.K.); (M.M.-P.); (M.G.F.); (Ł.L.); (P.S.); (N.J.); (J.W.); (I.B.-M.)
| | - Berenika Szczęśniak-Sięga
- Department of Medicinal Chemistry, Faculty of Pharmacy, Wroclaw Medical University, 50-556 Wroclaw, Poland;
| | - Izabela Szczuka
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.S.); (P.F.); (A.K.); (M.M.-P.); (M.G.F.); (Ł.L.); (P.S.); (N.J.); (J.W.); (I.B.-M.)
| | - Paulina Fortuna
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.S.); (P.F.); (A.K.); (M.M.-P.); (M.G.F.); (Ł.L.); (P.S.); (N.J.); (J.W.); (I.B.-M.)
| | - Marek Zawadzki
- Department of Oncological Surgery, Regional Specialist Hospital, 51-124 Wroclaw, Poland; (M.Z.); (W.W.)
- Department of Physiotherapy, Wroclaw Medical University, 51-618 Wroclaw, Poland
| | - Agnieszka Kubiak
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.S.); (P.F.); (A.K.); (M.M.-P.); (M.G.F.); (Ł.L.); (P.S.); (N.J.); (J.W.); (I.B.-M.)
| | - Magdalena Mierzchała-Pasierb
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.S.); (P.F.); (A.K.); (M.M.-P.); (M.G.F.); (Ł.L.); (P.S.); (N.J.); (J.W.); (I.B.-M.)
| | - Mariusz G. Fleszar
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.S.); (P.F.); (A.K.); (M.M.-P.); (M.G.F.); (Ł.L.); (P.S.); (N.J.); (J.W.); (I.B.-M.)
| | - Łukasz Lewandowski
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.S.); (P.F.); (A.K.); (M.M.-P.); (M.G.F.); (Ł.L.); (P.S.); (N.J.); (J.W.); (I.B.-M.)
| | - Paweł Serek
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.S.); (P.F.); (A.K.); (M.M.-P.); (M.G.F.); (Ł.L.); (P.S.); (N.J.); (J.W.); (I.B.-M.)
| | - Natalia Jamrozik
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.S.); (P.F.); (A.K.); (M.M.-P.); (M.G.F.); (Ł.L.); (P.S.); (N.J.); (J.W.); (I.B.-M.)
| | - Katarzyna Neubauer
- Department of Gastroenterology and Hepatology, Wroclaw Medical University, 50-556 Wroclaw, Poland; (K.N.); (R.K.)
| | - Jerzy Wiśniewski
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.S.); (P.F.); (A.K.); (M.M.-P.); (M.G.F.); (Ł.L.); (P.S.); (N.J.); (J.W.); (I.B.-M.)
| | - Radosław Kempiński
- Department of Gastroenterology and Hepatology, Wroclaw Medical University, 50-556 Wroclaw, Poland; (K.N.); (R.K.)
| | - Wojciech Witkiewicz
- Department of Oncological Surgery, Regional Specialist Hospital, 51-124 Wroclaw, Poland; (M.Z.); (W.W.)
- Research and Development Centre at Regional Specialist Hospital, 51-124 Wroclaw, Poland
| | - Iwona Bednarz-Misa
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.S.); (P.F.); (A.K.); (M.M.-P.); (M.G.F.); (Ł.L.); (P.S.); (N.J.); (J.W.); (I.B.-M.)
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Deol PK, Khare P, Bishnoi M, Kondepudi KK, Kaur IP. Coadministration of ginger extract-Lactobacillus acidophilus (cobiotic) reduces gut inflammation and oxidative stress via downregulation of COX-2, i-NOS, and c-Myc. Phytother Res 2018; 32:1950-1956. [PMID: 29876980 DOI: 10.1002/ptr.6121] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 04/24/2018] [Accepted: 04/26/2018] [Indexed: 12/11/2022]
Abstract
Aim of the study was to evaluate a combination of ginger extract (GE; antioxidant, anti-inflammatory) and Lactobacillus acidophilus (LAB; probiotic), in DMH-DSS-induced inflammation-driven colon cancer, in Wistar rats. Effect of varying GE concentration on growth of LAB was assessed in vitro. Colonic histology and permeability, oxidative stress, serum proinflammatory cytokines, expression of selected genes, gut bacteria, and SCFA determination of gut content was monitored after treatment with agents alone or in combination, postdisease induction. Significant increase in LAB CFU was observed following 48 and 96 hr of incubation with GE; 0.4% w/v GE showed the best results and was used in the cobiotic. Cobiotic administration significantly reversed the DMH-DSS-induced colonic histological alterations. Significant (p < .05) reduction in lipid peroxidation and increase in antioxidant levels (catalase and SOD) was observed in cobiotic group, whereas individual agents did not show any effect. Restoration of colonic permeability, decrease in serum inflammatory burden, and downregulation of COX-2, iNOS, and c-Myc expression on treatment with cobiotic was significantly (p < .05) better than individual agents. Neither LAB nor cobiotic administration produced any change in gut bacteria nor SCFA levels, probably due to loss of LAB viability under adverse gut conditions. Study concludes that presented cobiotic has a promising therapeutic potential, which can be improved by a smartly designed formulation.
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Affiliation(s)
- Parneet Kaur Deol
- University Institute of Pharmaceutical Sciences, Panjab University Chandigarh, Chandigarh, India
- G.H.G. Khalsa College of Pharmacy, Gurusar Sadhar, Ludhiana, Punjab, India
| | - Pragyanshu Khare
- National Agri-Food Biotechnology Institute, Mohali, Punjab, India
| | - Mahendra Bishnoi
- National Agri-Food Biotechnology Institute, Mohali, Punjab, India
| | | | - Indu Pal Kaur
- University Institute of Pharmaceutical Sciences, Panjab University Chandigarh, Chandigarh, India
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Deol PK, Khare P, Singh DP, Soman G, Bishnoi M, Kondepudi KK, Kaur IP. Managing colonic inflammation associated gut derangements by systematically optimised and targeted ginger extract-Lactobacillus acidophilus loaded pharmacobiotic alginate beads. Int J Biol Macromol 2017; 105:81-91. [PMID: 28690172 DOI: 10.1016/j.ijbiomac.2017.06.117] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2017] [Revised: 06/27/2017] [Accepted: 06/29/2017] [Indexed: 02/07/2023]
Abstract
Presently, we explore a cobiotic-ginger extract (GE; antioxidant-antiinflammatory) and Lactobacillus acidophilus (LAB, probiotic), for control of oxidative-stress, inflammation and dysbiosis mediated gut ailments. Since orally administered LAB looses viability while GE is a gastric irritant with poor ADME, we encapsulated them into calcium-alginate beads. Water-loving, viscolysing, and osmotic-building effects of polyethylene glycol were used to address poor probiotic encapsulation (≤10%) by effective sealing of numerous fine voids formed in the alginate gel. Beads were systematically optimized for maximum entrapment (92±2.3% for GE, and 30±1.2% for LAB) and sustained release, and were coated with eudragit-S100 for colonic-targetability, as established by in-vitro release. In-vivo evaluation in DMH-DSS induced colitis and precancerous lesions, in rats, indicated attenuation of oxidative stress (catalase, SOD, LPO) and inflammatory burden (IL-6 and TNF-α), and downregulation of COX-2, iNOS, and c-Myc by both GE and LAB; restoration of colonic permeability by GE; and modulation of gut bacteria and SCFAs by LAB as the mechanisms of action. Complementing activities of GE and LAB in cobiotic beads lead to better reversals. Histology (H&E and toluidine blue) confirmed healing of precancerous lesions.
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Affiliation(s)
- Parneet Kaur Deol
- University Institute of Pharmaceutical Sciences, Panjab University Chandigarh, India; G.H.G. Khalsa College of Pharmacy Gurusar Sadhar, Ludhiana, Punjab, India
| | - Pragyanshu Khare
- National Agri-Food Biotechnology Institute, Mohali, Punjab, India
| | | | | | - Mahendra Bishnoi
- National Agri-Food Biotechnology Institute, Mohali, Punjab, India
| | | | - Indu Pal Kaur
- University Institute of Pharmaceutical Sciences, Panjab University Chandigarh, India.
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Viral E6/E7 oncogene and cellular hexokinase 2 expression in HPV-positive cancer cell lines. Oncotarget 2017; 8:106342-106351. [PMID: 29290953 PMCID: PMC5739738 DOI: 10.18632/oncotarget.22463] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Accepted: 10/27/2017] [Indexed: 11/25/2022] Open
Abstract
Oncogenic types of human papillomaviruses (HPVs) are major human carcinogens. Cancer cells typically exhibit metabolic alterations which support their malignant growth. These include an enhanced rate of aerobic glycolysis (‘Warburg effect’) which in cancer cells is often linked to an increased expression of the rate-limiting glycolytic enzyme Hexokinase 2 (HK2). Intriguingly, recent studies indicate that the HPV E6/E7 oncogenes cause the metabolic reprogramming in HPV-positive cancer cells by directly upregulating HK2 expression. Notably, however, these results were obtained upon ectopic overexpression of E6/E7. Here, we investigated whether HK2 levels are affected by the endogenous E6/E7 amounts present in HPV-positive cancer cell lines. RNA interference analyses reveal that the sustained E6/E7 expression is critical to maintain HK2 expression levels in HeLa cells. Mechanistically, this effect is linked to the E6/E7-dependent upregulation of HK2-stimulatory MYC expression and the E6/E7-induced downregulation of the HK2-inhibitory micro(mi)RNA miR-143-3p. Importantly, however, a stimulatory effect of E6/E7 on HK2 expression was observed only in HeLa among a panel of 8 different HPV-positive cervical and head and neck cancer cell lines. Thus, whereas these results support the notion that E6/E7 can increase HK2 expression, they argue against the concept that the viral oncogenes, at endogenous expression levels, commonly induce the metabolic switch of HPV-positive cancer cells towards aerobic glycolysis by directly or indirectly stimulating HK2 expression.
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Ahmed HH, El-Abhar HS, Hassanin EAK, Abdelkader NF, Shalaby MB. Ginkgo biloba L. leaf extract offers multiple mechanisms in bridling N-methylnitrosourea – mediated experimental colorectal cancer. Biomed Pharmacother 2017; 95:387-393. [DOI: 10.1016/j.biopha.2017.08.103] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Revised: 08/19/2017] [Accepted: 08/23/2017] [Indexed: 12/11/2022] Open
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Ahmed HH, El-Abhar HS, Hassanin EAK, Abdelkader NF, Shalaby MB. Punica granatum suppresses colon cancer through downregulation of Wnt/β-Catenin in rat model. REVISTA BRASILEIRA DE FARMACOGNOSIA-BRAZILIAN JOURNAL OF PHARMACOGNOSY 2017. [DOI: 10.1016/j.bjp.2017.05.010] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Alexiou GA, Lianos GD, Ragos V, Galani V, Kyritsis AP. Difluoromethylornithine in cancer: new advances. Future Oncol 2017; 13:809-819. [PMID: 28125906 DOI: 10.2217/fon-2016-0266] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Difluoromethylornithine (DFMO; eflornithine) is an irreversible suicide inhibitor of the enzyme ornithine decarboxylase which is involved in polyamine synthesis. Polyamines are important for cell survival, thus DFMO was studied as an anticancer agent and as a chemoprevention agent. DFMO exhibited mainly cytostatic activity and had single agent efficacy as well as activity in combination with other chemotherapeutic drugs for some cancers and leukemias. Herewith, we summarize the current knowledge of the anticancer and chemopreventive properties of DFMO and assess the status of clinical trials.
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Affiliation(s)
- George A Alexiou
- Neurosurgical Institute, Ioannina University School of Medicine, Ioannina, GR 451 10, Greece
| | - Georgios D Lianos
- Neurosurgical Institute, Ioannina University School of Medicine, Ioannina, GR 451 10, Greece
| | - Vassileios Ragos
- Neurosurgical Institute, Ioannina University School of Medicine, Ioannina, GR 451 10, Greece
| | - Vasiliki Galani
- Department of Anatomy-Histology-Embryology, Medical School, University of Ioannina, 45110 Ioannina, Greece
| | - Athanassios P Kyritsis
- Neurosurgical Institute, Ioannina University School of Medicine, Ioannina, GR 451 10, Greece
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12
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Malekinejad H, Fani M, Shafiee-Roodbari SK, Delkhosh-Kasmaie F, Rezaei-Golmisheh A. Crosstalk between E2f1 and c-Myc mediates hepato-protective effect of royal jelly on taxol-induced damages. Hum Exp Toxicol 2016; 36:626-637. [PMID: 27496854 DOI: 10.1177/0960327116660752] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Previous histopathological studies have shown the hepatotoxicity of paclitaxel (TXL). However, there is little known about the molecular pathway(s) of TXL-induced hepatotoxicity. Therefore, this study aimed to uncover the role of two transcription factors in the TXL-induced hepatotoxicity. Moreover, the hepato-protective effect of royal jelly (RJ) on TXL-induced toxicity was investigated. Wistar rats were divided into control and test groups. The test groups along with TXL received various doses of RJ (0, 50, 100 and 150 mg/kg, body weight). Biochemical hepatic functional assays, histopathological studies and hepatic superoxide dismutase level were determined. Additionally, the expression of E2f1 and cellular-myelocytomatosis (c-Myc) at messenger RNA (mRNA) level in the liver was evaluated. The hepatic functional biomarkers showed a significant ( p < 0.05) elevation in the TXL-received animals, while RJ administration for 28 days resulted in a remarkable reduction in TXL-elevated alkaline phosphatase, alanine transaminase and lactate dehydrogenase levels. The TXL-treated animals showed a significant ( p < 0.05) up-regulation of E2f1 and down-regulation of c-Myc at mRNA level, respectively. RJ lowered the expression of E2f1 while enhanced the expression of c-Myc in a dose-dependent manner. Our data suggest the hepato-protective effects of RJ on TXL-induced toxicity, which may attribute to a clear crosstalk between E2f1 and c-Myc as two regulators of liver growth.
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Affiliation(s)
- H Malekinejad
- 1 Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Urmia University, Urmia, Islamic Republic of Iran.,2 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Urmia University of Medical Sciences, Urmia, Islamic Republic of Iran
| | - M Fani
- 2 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Urmia University of Medical Sciences, Urmia, Islamic Republic of Iran
| | - S Kh Shafiee-Roodbari
- 2 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Urmia University of Medical Sciences, Urmia, Islamic Republic of Iran
| | - F Delkhosh-Kasmaie
- 3 Department of Pathology, Faculty of Veterinary Medicine, Urmia University, Urmia, Islamic Republic of Iran
| | - A Rezaei-Golmisheh
- 4 Department of Embryology and Histology, Faculty of Veterinary Medicine, Urmia University, Urmia, Islamic Republic of Iran
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Mohammed A, Janakiram NB, Madka V, Ritchie RL, Brewer M, Biddick L, Patlolla JMR, Sadeghi M, Lightfoot S, Steele VE, Rao CV. Eflornithine (DFMO) prevents progression of pancreatic cancer by modulating ornithine decarboxylase signaling. Cancer Prev Res (Phila) 2014; 7:1198-209. [PMID: 25248858 PMCID: PMC4310684 DOI: 10.1158/1940-6207.capr-14-0176] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Ornithine decarboxylase (ODC) is the key rate-limiting enzyme in the polyamine synthesis pathway and it is overexpressed in a variety of cancers. We found that polyamine synthesis and modulation of ODC signaling occurs at early stages of pancreatic precursor lesions and increases as the tumor progresses in Kras-activated p48(Cre/+)-LSL-Kras(G12D/+) mice. Interest in use of the ODC inhibitor eflornithine (DFMO) as a cancer chemopreventive agent has increased in recent years since ODC was shown to be transactivated by the c-myc oncogene and to cooperate with the ras oncogene in malignant transformation of epithelial tissues. We tested the effects of DFMO on pancreatic intraepithelial neoplasias (PanIN) and their progression to pancreatic ductal adenocarcinoma (PDAC) in genetically engineered Kras mice. The Kras(G12D/+) mice fed DFMO at 0.1% and 0.2% in the diet showed a significant inhibition (P < 0.0001) of PDAC incidence compared with mice fed control diet. Pancreatic tumor weights were decreased by 31% to 43% (P < 0.03-0.001) with both doses of DFMO. DFMO at 0.1% and 0.2% caused a significant suppression (27% and 31%; P < 0.02-0.004) of PanIN 3 lesions (carcinoma in situ). DFMO-treated pancreas exhibited modulated ODC pathway components along with decreased proliferation and increased expression of p21/p27 as compared with pancreatic tissues derived from mice fed control diet. In summary, our preclinical data indicate that DFMO has potential for chemoprevention of pancreatic cancer and should be evaluated in other PDAC models and in combination with other drugs in anticipation of future clinical trials.
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Affiliation(s)
- Altaf Mohammed
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
| | - Naveena B Janakiram
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Venkateshwar Madka
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Rebekah L Ritchie
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Misty Brewer
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Laura Biddick
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Jagan Mohan R Patlolla
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Michael Sadeghi
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Stan Lightfoot
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Vernon E Steele
- Division of Cancer Prevention, Chemopreventive Agent Development Research Group, National Cancer Institute, Bethesda, Maryland
| | - Chinthalapally V Rao
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
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Cosimelli B, Laneri S, Ostacolo C, Sacchi A, Severi E, Porcù E, Rampazzo E, Moro E, Basso G, Viola G. Synthesis and biological evaluation of imidazo[1,2-a]pyrimidines and imidazo[1,2-a]pyridines as new inhibitors of the Wnt/β-catenin signaling. Eur J Med Chem 2014; 83:45-56. [DOI: 10.1016/j.ejmech.2014.05.071] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Revised: 05/19/2014] [Accepted: 05/30/2014] [Indexed: 01/08/2023]
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Barathidasan R, Pawaiya RS, Rai RB, Dhama K. Upregulated Myc expression in N-methyl nitrosourea (MNU)- induced rat mammary tumours. Asian Pac J Cancer Prev 2014; 14:4883-9. [PMID: 24083763 DOI: 10.7314/apjcp.2013.14.8.4883] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The most common incident cancer and cause of cancer-related deaths in women is breast cancer. The Myc gene is upregulated in many cancer types including breast cancer, and it is considered as a potential anti-cancer drug target. The present study was conducted to evaluate the Myc (gene and protein) expression pattern in an experimental mammary tumour model in rats. MATERIALS AND METHODS Thirty six Sprague Dawley rats were divided into: Experimental group (26 animals), which received the chemical carcinogen N-methyl nitrosourea (MNU) and a control group (10 animals), which received vehicle only. c-Myc oncoprotein and its mRNA expression pattern were evaluated using immunohistochemistry (IHC) and semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR), respectively, in normal rat mammary tissue and mammary tumours. The rat glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene was used as internal control for semi-quantitative RT-PCR. RESULTS Histopathological examination of mammary tissues and tumours from MNU treated animals revealed the presence of premalignant lesions, benign tumours, in situ carcinomas and invasive carcinomas. Immunohistochemical evaluation of tumour tissues showed upregulation and heterogeneous cellular localization of c-Myc oncoprotein. The expression levels of c-Myc oncoprotein were significantly elevated (75- 91%) in all the tumours. Semi-quantitative RT-PCR revealed increased expression of c-Myc mRNA in mammary tumours compared to normal mammary tissues. CONCLUSIONS Further large-scale investigation study is needed to adopt this experimental rat mammary tumour model as an in vivo model to study anti-cancer strategies directed against Myc or its downstream partners at the transcriptional or post-transcriptional level.
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Affiliation(s)
- Rajamani Barathidasan
- Division of Pathology, Indian Veterinary Research Institute, Izatnagar, India E-mail :
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Malekinejad H, Janbaz-Acyabar H, Razi M, Varasteh S. Preventive and protective effects of silymarin on doxorubicin-induced testicular damages correlate with changes in c-myc gene expression. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2012; 19:1077-84. [PMID: 22819302 DOI: 10.1016/j.phymed.2012.06.011] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2012] [Revised: 05/03/2012] [Accepted: 06/19/2012] [Indexed: 05/25/2023]
Abstract
This study aimed to investigate the preventive and protective effects of silymarin (SMN) on doxorubicin (DOX)-induced damages in the testis. Wistar rats were divided into six groups (n=8), including: control (C), DOX-treated (DOX, 15 mg/kg, i.p.), DOX- and SMN-treated and SMN-treated animals (SMN, 50 mg/kg, orally). Those groups, which received either compounds, were sub-grouped based on the preventive (PVT), protective (PTT) and/or therapeutic regimens (TPT) of SMN administration. The antioxidant status analyses, hormonal assay, and histopathological examinations in the testis were conducted. The expression of c-myc at mRNA level also was analyzed. SMN in preventive and protective forms significantly (p<0.05) improved the DOX-induced weight loss and lowered the alkaline phosphatase level. Pretreatment and co-treatment with SMN attenuated the DOX-induced carbonyl stress. The DOX-induced histopathological damages including negative TDI and IR were significantly (p<0.05) improved with SMN pretreatment and co-administration. SMN in preventive and protective forms prevented from DOX-induced DNA fragmentation in the testis. SMN ameliorated the DOX-reduced serum level of sexual hormones including testosterone, inhibin B, LH and FSH in PVT and PTT groups. The c-myc expression at mRNA level was completely and relatively down regulated in the testis of animals that received SMN as pretreatment and concurrent administration, respectively. Our data suggests that the DOX-induced biochemical and histopathological alterations could be prevented and/or protected by SMN. Moreover, the SMN protective and preventive effects attribute to its capacity in the reduction of DOX-induced carbonyl stress and DNA damage, which may be mediated by c-myc expression.
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Affiliation(s)
- H Malekinejad
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran
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17
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Perrone EE, Liu L, Turner DJ, Strauch ED. Bile salts increase epithelial cell proliferation through HuR-induced c-Myc expression. J Surg Res 2012; 178:155-64. [PMID: 22626558 DOI: 10.1016/j.jss.2012.02.029] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2011] [Revised: 01/05/2012] [Accepted: 02/16/2012] [Indexed: 10/28/2022]
Abstract
BACKGROUND Bile salts increase intestinal mucosal proliferation through an increase in c-Myc, a transcription factor that controls the expression of numerous translation regulatory proteins. HuR is an RNA-binding protein that regulates translation of target mRNAs. RNA-binding proteins can control mRNA stability by binding to AU- and U-rich elements located in the 3'-untranslated regions (3'-UTRs) of target mRNAs. AIM To determine how bile salt-induced c-Myc stimulates enterocyte proliferation. METHODS Enterocyte proliferation was measured both in vivo using C57Bl6 mice and in vitro using IEC-6 cells after taurodeoxycholate (TDCA) supplementation. HuR and c-Myc protein expression was determined by immunoblot. c-Myc mRNA expression was determined by PCR. HuR expression was inhibited using specific small interfering RNA. HuR binding to c-Myc mRNA was determined by immunoprecipitation. RESULTS TDCA increased enterocyte proliferation in vivo and in vitro. TDCA stimulates translocation of HuR from the nucleus to the cytoplasm. Cytoplasmic HuR regulates c-Myc translation by HuR binding to the 3'-UTR of c-Myc mRNA. Increased TDCA-induced c-Myc increases enterocyte proliferation. CONCLUSIONS Bile salts have beneficial effects on the intestinal epithelial mucosa, which are important in maintaining intestinal mucosal integrity and function. These data further support an important beneficial role of bile salts in regulation of mucosal growth and repair. Decreased enterocyte exposure to luminal bile salts, as occurs during critical illness, liver failure, starvation, and intestinal injury, may have a detrimental effect on mucosal integrity.
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Affiliation(s)
- Erin E Perrone
- Department of Pediatric Surgery, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA
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18
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Heijink DM, Jalving M, Oosterhuis D, Sloots IA, Koster R, Hollema H, Kleibeuker JH, Koornstra JJ, de Vries EGE, de Jong S. TNF-related apoptosis-inducing ligand cooperates with NSAIDs via activated Wnt signalling in (pre)malignant colon cells. J Pathol 2010; 223:378-89. [PMID: 21171083 DOI: 10.1002/path.2797] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2010] [Revised: 09/08/2010] [Accepted: 09/24/2010] [Indexed: 11/11/2022]
Abstract
TNF-related apoptosis-inducing ligand (TRAIL) receptor agonistic agents and non-steroidal anti-inflammatory drugs (NSAIDs) are interesting agents for the chemoprevention and treatment of colorectal cancer. We investigated whether NSAIDs sensitize colon cancer and adenoma cell lines and ex vivo cultured human adenomas to recombinant human (rh)TRAIL. Involvement of the crucial Wnt signalling pathway in the sensitization of colon cancer cells was examined. Five colon cancer and two adenoma cell lines, human ex vivo adenomas and normal colonic epithelium were treated with aspirin or sulindac combined with rhTRAIL. Apoptosis levels, expression of intracellular proteins and TRAIL receptor membrane expression were assessed. Ls174T cells stably transfected with an inducible dominant negative TCF-4 (dnTCF-4) construct served to analyse the role of Wnt pathway activation. Both rhTRAIL-sensitive and -resistant colon cancer cell lines were strongly sensitized to rhTRAIL by aspirin (maximum enhancement ratio, 7.1). Remarkably, in adenoma cell lines sulindac enhanced rhTRAIL-induced apoptosis most effectively (maximum enhancement ratio, 2.5). Although membrane TRAIL receptor expression was not affected by NSAIDs, caspase-8 activation was enhanced by combinational treatment. Several proteins from different biological pathways were affected by NSAIDs, indicating complex mechanisms of sensitization. Elimination of TCF-4 completely blocked the sensitizing effect in colon cancer cells. In ex vivo adenomas the combination of sulindac and rhTRAIL increased apoptosis from 18.4% (sulindac) and 17.8% (rhTRAIL) to 28.0% (p = 0.003 and p = 0.005, respectively). It was concluded that NSAID-induced sensitization to rhTRAIL requires TCF-4 activity. Thus, the combination of TRAIL-receptor agonistic agents and NSAIDs is a potentially attractive treatment option for (pre)malignant tumours with constitutively active Wnt signalling, such as colorectal tumours.
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Affiliation(s)
- Dianne M Heijink
- Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, The Netherlands
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Chakraborty P, Roy SS, Sk UH, Bhattacharya S. Amelioration of cisplatin-induced nephrotoxicity in mice by oral administration of diphenylmethyl selenocyanate. Free Radic Res 2010; 45:177-87. [PMID: 20942565 DOI: 10.3109/10715762.2010.521155] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Cisplatin is one of the most potent and active cytotoxic drug in the treatment of cancer. However, side-effects in normal tissues and organs, notably nephrotoxicity in the kidneys, limit the promising efficacy of cisplatin. The present study was designed to ascertain the possible in vivo protective potential of a synthetic organoselenium compound diphenylmethyl selenocyanate (3 mg/kg.b.w.) against the nephrotoxic damage induced by cisplatin (5 mg/kg.b.w. for 5 days) in Swiss albino mice. Treatment with diphenylmethyl selenocyanate markedly reduced cisplatin-induced lipid peroxidation, serum creatinine and blood urea nitrogen levels. Renal antioxidant defense systems, such as glutathione-S-transferase, glutathione peroxidase, superoxide dismutase, catalase, activities and reduced glutathione level, depleted by cisplatin therapy, were restored to normal by the selenium compound. The selenium compound also reduced renal tubular epithelial cell damage, nitric oxide levels and expression of COX-2, and iNOS in kidneys injured by cisplatin. These results demonstrate the protective effect of diphenylmethyl selenocyanate against cisplatin-induced nephrotoxicity in mice.
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Affiliation(s)
- Pramita Chakraborty
- Department of Cancer Chemoprevention, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata 700026, West Bengal, India
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Yang G, Fu H, Zhang J, Lu X, Yu F, Jin L, Bai L, Huang B, Shen L, Feng Y, Yao L, Lu Z. RNA-binding protein quaking, a critical regulator of colon epithelial differentiation and a suppressor of colon cancer. Gastroenterology 2010; 138:231-40.e1-5. [PMID: 19686745 PMCID: PMC2847771 DOI: 10.1053/j.gastro.2009.08.001] [Citation(s) in RCA: 108] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2009] [Revised: 06/20/2009] [Accepted: 08/06/2009] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS Colon cancer is one of the best understood neoplasms from a genetic perspective, yet it remains the second most common cause of cancer-related death. Post-transcriptional regulation mediated by RNA-binding proteins or microRNAs coordinately targets multiple genes, holding promise involved in colon cancer initiation and development. Here we studied the role of RNA-binding protein quaking (QKI) in colon cancer. METHODS We observed the expression pattern of QKI in normal colon and colon cancers through reverse-transcription polymerase chain reaction and Western blot. Bisulfite sequencing and methylation-specific PCR were applied for QKI promoter methylation analysis. We used enterocyte differentiation markers and soft agar assay to test the role of QKI in colon differentiation and colon cancer development. 3' Untranslated region (UTR) reporter assay and RNA-immunoprecipitation were used to confirm the interaction between QKI and beta-catenin or p27. RESULTS QKI is significantly down-regulated and even absent in some colon cancers, which is at least partially because of the promoter hypermethylation. Forced expression of QKI in the colon cancer cells increased the expression of enterocyte differentiation marker intestinal alkaline phosphatase and lactase, together with the enhancement of p27Kip1 protein level, and membrane localized beta-catenin. Finally, QKI overexpression reduced the proliferation and tumorigenesis ability. CONCLUSIONS Our study establishes that QKI functions as a principal regulator in the differentiation of colon epithelium and a suppressor of carcinogenesis through coordinately targeting multiple genes associated with cell growth and differentiation, whose deregulation by methylation is involved in colon cancer onset and progress.
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Affiliation(s)
- Guodong Yang
- Department of Biochemistry and Molecular Biology, the State Key Laboratory of Cancer Biology, the Fourth Military Medical University
| | - Haiyan Fu
- Department of Biochemistry and Molecular Biology, the State Key Laboratory of Cancer Biology, the Fourth Military Medical University
| | - Jie Zhang
- Department of Biochemistry and Molecular Biology, the State Key Laboratory of Cancer Biology, the Fourth Military Medical University
| | - Xiaozhao Lu
- Department of Biochemistry and Molecular Biology, the State Key Laboratory of Cancer Biology, the Fourth Military Medical University
| | - Fang Yu
- Department of Biochemistry and Molecular Biology, the State Key Laboratory of Cancer Biology, the Fourth Military Medical University
| | - Liang Jin
- Department of Biochemistry and Molecular Biology, the State Key Laboratory of Cancer Biology, the Fourth Military Medical University
| | - Liyuan Bai
- Department of Biochemistry and Molecular Biology, the State Key Laboratory of Cancer Biology, the Fourth Military Medical University
| | - Bo Huang
- Department of Biochemistry and Molecular Biology, the State Key Laboratory of Cancer Biology, the Fourth Military Medical University
| | - Lan Shen
- Department of Biochemistry and Molecular Biology, the State Key Laboratory of Cancer Biology, the Fourth Military Medical University
| | - Yue Feng
- Department of Pharmacology, Emory University, Atlanta, GA, 30322
| | - Libo Yao
- Department of Biochemistry and Molecular Biology, the State Key Laboratory of Cancer Biology, the Fourth Military Medical University,To whom correspondence should be addressed: Z Lu, NO.17 Changlexi Road, the Fourth Military Medical University, 710032 Xi’an PR China, , tel: 86-29-84774513, fax 86-29-84773947. L Yao, NO.17 Changlexi Road, the Fourth Military Medical University, 710032 Xi’an PR China, , tel: 86-29-84774513, fax 86-29-84773947
| | - Zifan Lu
- Department of Biochemistry and Molecular Biology, the State Key Laboratory of Cancer Biology, the Fourth Military Medical University,To whom correspondence should be addressed: Z Lu, NO.17 Changlexi Road, the Fourth Military Medical University, 710032 Xi’an PR China, , tel: 86-29-84774513, fax 86-29-84773947. L Yao, NO.17 Changlexi Road, the Fourth Military Medical University, 710032 Xi’an PR China, , tel: 86-29-84774513, fax 86-29-84773947
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Kumar A, Singh NK, Sinha PR, Kumar R. Intervention of Acidophilus-casei dahi and wheat bran against molecular alteration in colon carcinogenesis. Mol Biol Rep 2009; 37:621-7. [PMID: 19642015 DOI: 10.1007/s11033-009-9649-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2009] [Accepted: 07/21/2009] [Indexed: 02/07/2023]
Abstract
An in vivo trial was conducted on seventy five rats allocated to three groups, first group was DMH control group, second group was Wheat bran-DMH group (WB-DMH) in which wheat bran was given along with DMH (1,2-dimethylhydrazine) injection, third group was Wheat bran-DMH-Ac Dahi group in which both wheat bran and Acidophilus-casei dahi (a probiotic microorganisms fermented dairy product) was given along with DMH injections. Animals received subcutaneous injections of DMH at a dose rate of 20 mg/kg body weight, once weekly for 15 weeks. The rats were dissected at 40th week of experiment and comet assay was done in colonic cells to assess the DNA damage. The c-myc and cox-2 expression was studied in rat tumour. A significant reduction in DNA damage (48.2%) was observed in WB-DMH-Ac Dahi group as compared to DMH control group (87.8%). The c-myc and cox-2 mRNA level was found highest in DMH control group as compared to WB-DMH and WB-DMH-Ac Dahi group. The results of present study show the enhanced protective potential of Acidophilus-casei and wheat bran against DMH induced molecular alteration in colonic cells during carcinogenesis.
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Affiliation(s)
- Arvind Kumar
- Animal Biochemistry Division, National Dairy Research Institute, Haryana, India.
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Kuroiwa-Trzmielina J, de Conti A, Scolastici C, Pereira D, Horst MA, Purgatto E, Ong TP, Moreno FS. Chemoprevention of rat hepatocarcinogenesis with histone deacetylase inhibitors: efficacy of tributyrin, a butyric acid prodrug. Int J Cancer 2009; 124:2520-7. [PMID: 19195022 DOI: 10.1002/ijc.24212] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Hepatocellular carcinoma (HCC) ranks in prevalence and mortality among top 10 cancers worldwide. Butyric acid (BA), a member of histone deacetylase inhibitors (HDACi) has been proposed as an anticarcinogenic agent. However, its short half-life is a therapeutical limitation. This problem could be circumvented with tributyrin (TB), a proposed BA prodrug. To investigate TB effectiveness for chemoprevention, rats were treated with the compound during initial phases of "resistant hepatocyte" model of hepatocarcinogenesis, and cellular and molecular parameters were evaluated. TB inhibited (p < 0.05) development of hepatic preneoplastic lesions (PNL) including persistent ones considered HCC progression sites. TB increased (p < 0.05) PNL remodeling, a process whereby they tend to disappear. TB did not inhibit cell proliferation in PNL, but induced (p < 0.05) apoptosis in remodeling ones. Compared to controls, rats treated with TB presented increased (p < 0.05) hepatic levels of BA indicating its effectiveness as a prodrug. Molecular mechanisms of TB-induced hepatocarcinogenesis chemoprevention were investigated. TB increased (p < 0.05) hepatic nuclear histone H3K9 hyperacetylation specifically in PNL and p21 protein expression, which could be associated with inhibitory HDAC effects. Moreover, it reduced (p < 0.05) the frequency of persistent PNL with aberrant cytoplasmic p53 accumulation, an alteration associated with increased malignancy. Original data observed in our study support the effectiveness of TB as a prodrug of BA and as an HDACi in hepatocarcinogenesis chemoprevention. Besides histone acetylation and p21 restored expression, molecular mechanisms involved with TB anticarcinogenic actions could also be related to modulation of p53 pathways.
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Mazzantini RP, de Conti A, Moreno FS. Persistent and remodeling hepatic preneoplastic lesions present differences in cell proliferation and apoptosis, as well as in p53, Bcl-2 and NF-κB pathways. J Cell Biochem 2008; 103:538-46. [PMID: 17546582 DOI: 10.1002/jcb.21420] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
During rat hepatocarcinogenesis preneoplastic lesions (PNL) emerge which may persist (pPNL) and be sites of progress to cancer or suffer remodeling (rPNL) tending to disappear. Cellular and molecular mechanisms involved in both phenotypes are not sufficiently elucidated. pPNL and rPNL cellular proliferation and apoptosis were evaluated in rats submitted to the resistant hepatocyte (RH) model, and an adjusted growth index (AGI) was established. p53, Bcl-2, and NF-kappaB p65 subunit expression was evaluated by immunohistochemistry in pPNL and rPNL. p65 expression and NF-kappaB activation was evaluated by Western blot assays in whole livers. A lower number of BrdU-stained hepatocyte nuclei/mm(2) and higher number of apoptotic bodies (AB) per mm(2) were observed in remodeling compared to pPNL. Cytoplasmic p53 accumulation is related to increased hepatocarcinoma malignancy. We observed that 71.3% pPNL and 25.4% rPNL (P < 0.05) presented p53 staining in the cytoplasm. Similarly, 67.7% pPNL and 23.1 % rPNL (P < 0.05) presented increased Bcl-2 staining. Thirty-two percent pPNL and 15.6% rPNL (P < 0.05) presented p65 staining. Compared to normal rats, increase (P < 0.05) of hepatic p65 expression and NF-kappaB activation in rats submitted to the RH model was observed. In agreement to previous studies hepatic pPNL and rPNL differ regarding cell proliferation and apoptosis. Moreover, persistence and remodeling involve differences in p53, Bcl-2, and NF-kappaB pathways. These data point to molecular pathways that may direct preneoplastic lesions to spontaneously regress or to progress to cancer. J. Cell. Biochem. 103: 538-546, 2008. (c) 2007 Wiley-Liss, Inc.
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Affiliation(s)
- Rogério Pietro Mazzantini
- Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
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24
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Abstract
Owing to their high turnover, the intestinal mucosal cells have a particularly high requirement for polyamines. Therefore, they are an excellent charcol for the study of polyamine function in rapid physiological growth and differentiation. After a cursory introduction to the major aspects of polyamine metabolism, regulation, and mode of action, we discuss the contribution of the polyamines to the maintenance of normal gut function, the maturation of the intestinal mucosa, and its repair after injuries. Repletion of cellular polyamine pools with (D,L)-2-(difluoromethyl)ornithine has considerably improved our understanding of how the polyamines are involved in the regulation of normal and neoplastic growth. Unfortunately, the attempts to exploit polyamine metabolism as a cancer therapeutic target have not yet been successful. However, the selective inactivation of ornithine decarboxylase appears to be a promising chemopreventive method in familial adenomatous polyposis. Presumably, it relies on the fact that ornithine decarboxylase is a critical regulator of the proliferative response of the protooncogene c-myc, but not of its apoptotic response.
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Affiliation(s)
- Nikolaus Seiler
- INSERM U682, Université Louis Pasteur EA3430, Faculty of Medicine, Laboratory of Nutritional Cancer Prevention, IRCAD, Strasbourg, France
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25
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Abstract
In recent years, growing interest has been focused on the field of cancer prevention. Cancer prevention by chemopreventive agents offers significant promise for reducing the incidence and mortality of cancer. Chemopreventive agents may exert their effects either by blocking or metabolizing carcinogens or by inhibiting tumor cell growth. Another important benefit of chemopreventive agents is their nontoxic nature. Therefore, chemopreventive agents have recently been used for cancer treatment in combination with chemotherapeutics or radiotherapy, uncovering a novel strategy for cancer therapy. This strategy opens a new avenue from cancer prevention to cancer treatment. In vitro and in vivo studies have demonstrated that chemopreventive agents could enhance the antitumor activity of chemotherapeutics, improving the treatment outcome. Growing evidence has shown that chemopreventive agents potentiate the efficacy of chemotherapy and radiotherapy through the regulation of multiple signaling pathways, including Akt, NF-kappaB, c-Myc, cyclooxygenase-2, apoptosis, and others, suggesting a multitargeted nature of chemopreventive agents. However, further in-depth mechanistic studies, in vivo animal experiments, and clinical trials are needed to investigate the effects of chemopreventive agents in combination treatment of cancer with conventional cancer therapies. More potent natural and synthetic chemopreventive agents are also needed to improve the efficacy of mechanism-based and targeted therapeutic strategies against cancer, which are likely to make a significant impact on saving lives. Here, we have briefly reviewed the role of chemopreventive agents in cancer prevention, but most importantly, we have reviewed how they could be useful for cancer therapy in combination with conventional therapies.
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Affiliation(s)
- Fazlul H Sarkar
- Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
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26
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Femia AP, Caderni G, Bottini C, Salvadori M, Dolara P, Tessitore L. Mucin-depleted foci are modulated by dietary treatments and show deregulation of proliferative activity in carcinogen-treated rodents. Int J Cancer 2007; 120:2301-5. [PMID: 17294441 DOI: 10.1002/ijc.22145] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The correlation between mucin-depleted foci (MDF) and colon carcinogenesis was studied in F344 rats initiated with 1,2-dimethylhydrazine and treated with a chemopreventive regimen (polyethylene glycol, PEG) or with a promoting diet (high-corn oil). High corn oil diet increased MDF, while PEG reduced them. The expression of p27 and p16, inhibitors of cyclin-dependent kinases, which inhibit the progression of the cell cycle, was studied by immunohistochemistry in MDF and in aberrant crypt foci (ACF) of control rats. In both MDF and ACF, the nuclear expression of p27 was markedly reduced, while p16 was reduced to a lower extent. Mitotic activity was higher in MDF and ACF than in normal mucosa of control rats. MDF were also identified in azoxymethane-initiated SWR/J mice. These results further confirm that MDF are preneoplastic lesions and could be useful biomarkers of colon carcinogenesis.
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27
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Chu EC, Chai J, Ahluwalia A, Tarnawski AS. Mesalazine downregulates c-Myc in human colon cancer cells. A key to its chemopreventive action? Aliment Pharmacol Ther 2007; 25:1443-1449. [PMID: 17539984 DOI: 10.1111/j.1365-2036.2007.03336.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Dysplasia and malignant transformation of colonocytes in ulcerative colitis are associated with overexpression of c-Myc and genes regulating cell survival. 5-Aminosalicylates such as mesalazine may reduce the development of colorectal cancer in ulcerative colitis, but the mechanisms of its chemopreventive action are not clear. AIMS To examine whether mesalazine affects the expression of c-Myc in human colon cancer cell lines. METHODS Human colon cancer cells were treated with vehicle or mesalazine (4 mm or 40 mm). We examined: (i) mRNA expression by gene array, (ii) protein expression by Western blotting and immunohistochemistry and (iii) apoptosis by Annexin V labelling. RESULTS Mesalazine significantly reduced expression of c-Myc mRNA and protein. CONCLUSIONS Mesalazine downregulates gene and protein expression of c-Myc. The apoptotic and growth inhibitory effects of mesalazine are dose-dependent. Expression of c-Myc is significantly reduced by mesalazine 40 mm.
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Affiliation(s)
- E C Chu
- Department of Medicine, Division of Gastroenterology, VA Long Beach Healthcare System, Long Beach, CA, USA.
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28
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Aderogba MA, McGaw LJ, Ogundaini AO, Eloff JN. Antioxidant activity and cytotoxicity study of the flavonol glycosides fromBauhinia galpinii. Nat Prod Res 2007; 21:591-9. [PMID: 17613816 DOI: 10.1080/14786410701369557] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
The antioxidant activity of the crude extract and solvent fractions obtained from the leaves of Bauhinia galpinii was evaluated in terms of capacity to scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radicals. The crude extract and the more polar solvent fractions (ethyl acetate and butanol) showed considerable antioxidant activity. The antioxidant potential of the extracts, expressed as EC50, ranged between 28.85 +/- 1.28 microg mL(-1)and 118.16 +/- 6.41 microg mL(-1). L-Ascorbic acid was used as a standard (EC50 = 19.79 +/- 0.14 microM). Bioassay guided fractionation of the two active solvent fractions led to the isolation of three flavonoid glycosides, identified as: quercetin-3-O-galactopyranoside (1), myricetin-3-O-galactopyranoside (2), and 2''-O-rhamnosylvitexin (3). These compounds are reported for the first time from this species. The structures of the compounds were determined on the basis of spectral studies (1H NMR, 13C NMR and MS). Their antioxidant potential was evaluated using a DPPH spectrophotometric assay. Compound 2 had higher and 3 had lower antioxidant activity than L-ascorbic acid. No cytotoxic effects were displayed by compounds 1 and 3, but compound 2 was cytotoxic to Vero cells (LC50 = 74.68 microg mL(-1)) and bovine dermis cells (LC50 = 30.69 microg mL(-1)).
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Affiliation(s)
- M A Aderogba
- Department of Chemistry, Obafemi Awolowo University, Ile-Ife, Nigeria.
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29
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Sengupta A, Ghosh S, Das RK, Bhattacharjee S, Bhattacharya S. Chemopreventive potential of diallylsulfide, lycopene and theaflavin during chemically induced colon carcinogenesis in rat colon through modulation of cyclooxygenase-2 and inducible nitric oxide synthase pathways. Eur J Cancer Prev 2007; 15:301-5. [PMID: 16835502 DOI: 10.1097/00008469-200608000-00005] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Chemoprevention of colorectal cancer has become essential in the modern industrialized world as cancer of the large bowel has become one of the major causes of cancer mortality, second only to lung cancer. Colon cancer integrates lifestyle factors and multistep genetic alterations, and without preventive intervention, a substantial part of the population is likely to develop colorectal cancer at some point during their lives. Diet and nutrition clearly play a role in the etiology of colon cancer. Inhibitory activity of aqueous suspensions of garlic, tomato and black tea was tested on azoxymethane-induced colon carcinogenesis in Sprague-Dawley rats during earlier studies. In the present study, the protective activity of diallylsulfide and lycopene and theaflavin, important antioxidative ingredients of garlic, tomato and black tea, respectively, was assessed during colon carcinogenesis. The effect was observed on aberrant crypt foci, the preneoplastic lesion. As inhibition of cyclooxygenase-2 and inducible nitric oxide synthase activities is correlated with the prevention of colon cancer, the study continues with the determination of the change in the expression of these proteins. Following treatment, significant reduction in the incidences of aberrant crypt foci (by 43.65% in diallylsulfide, 57.39% in lycopene and 66.08% in theaflavin group) was observed, which was in accordance with the reduced expression of cyclooxygenase-2 and inducible nitric oxide synthase. The effect of the intact source was found to be more pronounced than their components used separately.
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Affiliation(s)
- Archana Sengupta
- Department of Cancer Chemoprevention, Chittaranjan National Cancer Institute, Kolkata, India.
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30
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Williamson L, Raess NA, Caldelari R, Zakher A, de Bruin A, Posthaus H, Bolli R, Hunziker T, Suter MM, Müller EJ. Pemphigus vulgaris identifies plakoglobin as key suppressor of c-Myc in the skin. EMBO J 2006; 25:3298-309. [PMID: 16871158 PMCID: PMC1523185 DOI: 10.1038/sj.emboj.7601224] [Citation(s) in RCA: 148] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2006] [Accepted: 06/09/2006] [Indexed: 12/12/2022] Open
Abstract
The autoimmune disease pemphigus vulgaris (PV) manifests as loss of keratinocyte cohesion triggered by autoantibody binding to desmoglein (Dsg)3, an intercellular adhesion molecule of mucous membranes, epidermis, and epidermal stem cells. Here we describe a so far unknown signaling cascade activated by PV antibodies. It extends from a transient enhanced turn over of cell surface-exposed, nonkeratin-anchored Dsg3 and associated plakoglobin (PG), through to depletion of nuclear PG, and as one of the consequences, abrogation of PG-mediated c-Myc suppression. In PV patients (6/6), this results in pathogenic c-Myc overexpression in all targeted tissues, including the stem cell compartments. In summary, these results show that PV antibodies act via PG to abolish the c-Myc suppression required for both maintenance of epidermal stem cells in their niche and controlled differentiation along the epidermal lineage. Besides a completely novel insight into PV pathogenesis, these data identify PG as a potent modulator of epithelial homeostasis via its role as a key suppressor of c-Myc.
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Affiliation(s)
- Lina Williamson
- Molecular Dermatology, Institute Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Natalia A Raess
- Molecular Dermatology, Institute Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Reto Caldelari
- Molecular Dermatology, Institute Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Anthony Zakher
- Molecular Dermatology, Institute Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Alain de Bruin
- Molecular Dermatology, Institute Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Horst Posthaus
- Molecular Dermatology, Institute Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | | | - Thomas Hunziker
- Department Dermatology, Medical Faculty, University of Bern, Bern, Switzerland
| | - Maja M Suter
- Molecular Dermatology, Institute Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Eliane J Müller
- Molecular Dermatology, Institute Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
- Molecular Dermatology, Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Postfach, Länggass-Str. 122, Bern 3001, Switzerland. Tel.: +41 31 631 24 03 or 631 23 98; Fax: +41 31 631 26 35; E-mail:
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31
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Topashka-Ancheva MN, Taskova RM, Handjieva NV. Mitogenic effect of Carthamus lanatus extracts, fractions and constituents. Fitoterapia 2006; 77:608-10. [PMID: 16962726 DOI: 10.1016/j.fitote.2006.06.014] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2005] [Accepted: 06/20/2006] [Indexed: 11/25/2022]
Abstract
Extracts, fractions and constituents of Carthamus lanatus were tested for their mitogenic effect on bone marrow cells in mice. Most of the studied samples inhibited cell proliferation and only the flavonoid glycoside rutin caused increasing of mitotic activity.
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32
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Ong TP, Heidor R, de Conti A, Dagli MLZ, Moreno FS. Farnesol and geraniol chemopreventive activities during the initial phases of hepatocarcinogenesis involve similar actions on cell proliferation and DNA damage, but distinct actions on apoptosis, plasma cholesterol and HMGCoA reductase. Carcinogenesis 2005; 27:1194-203. [PMID: 16332721 DOI: 10.1093/carcin/bgi291] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Chemopreventive activities of farnesol (FOH) and geraniol (GOH) were evaluated during the initial phases of hepatocarcinogenesis. Rats received during eight consecutive weeks 25 mg/100 g body weight FOH (FOH group) or GOH (GOH group), or only corn oil (CO group, controls). Incidence (%) and mean number of visible hepatocyte nodules/animal were inhibited in FOH group (13% and 4 +/- 1; P < 0.05), but not in GOH group (42% and 18 +/- 17, P > 0.05), compared to CO group (100% and 42 +/- 17). Mean area (mm2) and % liver section area occupied by total hepatic placental glutathione S-transferase positive preneoplastic lesions (PNLs) were reduced in FOH group (0.09 +/- 0.06; 2.8 +/- 1.3; P < 0.05) compared to CO group (0.18 +/- 0.12; 10.0 +/- 2.8), while in GOH group only the mean area of these PNL was reduced (0.11 +/- 0.09; P < 0.05), but not the % liver section area occupied by them (5.1 +/- 1.1; P > 0.05). Compared to CO group, FOH and GOH groups showed reduced (P < 0.05) PNL cell proliferation and DNA damage, but only GOH group showed increased PNL apoptosis (P < 0.05). FOH group, but not GOH group, presented reduced (P < 0.05) total plasma cholesterol levels and increased (P < 0.05) hepatic levels of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase mRNA, compared to CO group. No differences (P > 0.05) were observed between CO, FOH and GOH regarding hepatic levels of farnesoid X activated receptor (FXR) protein. Results indicate that FOH and GOH could represent promising chemopreventive agents against hepatocarcinogenesis. Inhibition of cell proliferation and DNA damage relate to both isoprenoids' anticarcinogenic actions while induction of apoptosis specifically relates to GOH protective actions. Inhibition of HMGCoA reductase activity could be associated with FOH, but not GOH anticarcinogenic actions. FXR does not seem to be involved in the isoprenoids' chemopreventive activities.
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Affiliation(s)
- Thomas Prates Ong
- Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
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33
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Yu L, Quinn DA, Garg HG, Hales CA. Cyclin-Dependent Kinase Inhibitor p27
Kip1
, But Not p21
WAF1/Cip1
, Is Required for Inhibition of Hypoxia-Induced Pulmonary Hypertension and Remodeling by Heparin in Mice. Circ Res 2005; 97:937-45. [PMID: 16195480 DOI: 10.1161/01.res.0000188211.83193.1a] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Heparin has growth inhibitory effects on pulmonary artery smooth muscle cell (PASMC) in vitro and in vivo. However, the mechanism has not been fully defined. In this study, we investigated the role of cyclin-dependent kinase inhibitors, p21(WAF1/cip1) (p21) and p27Kip1 (p27), in the inhibitory effect of heparin on PASMC proliferation in vitro and on hypoxia-induced pulmonary hypertension in vivo using p21 and p27-null mice. In vitro, loss of the p27 gene negated the inhibitory effect of heparin on PASMC proliferation, but p21 was not critical for this inhibition. In vivo, heparin significantly inhibited the development of hypoxia-induced pulmonary hypertension and remodeling, as evidenced by decreased right ventricular systolic pressure, ratio of right ventricular weight to left ventricle plus septum weight, and percent wall thickness of pulmonary artery, in p21(+/+), p21(-/-), p27(+/+), and p27(+/-), but not in p27(-/-) mice. We also observed that hypoxia decreased p27 expression significantly in mouse lung, which was restored by heparin. Heparin inhibited Ki67 proliferative index in terminal bronchial vessel walls in p27(+/+) and p27(+/-), but not in p27(-/-) mice exposed to hypoxia. Therefore, we conclude that the cyclin-dependent kinase inhibitor p27, but not p21, is required for the inhibition of hypoxic pulmonary vascular remodeling by heparin.
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Affiliation(s)
- Lunyin Yu
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114-2696, USA
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Doi K, Wanibuchi H, Salim EI, Morimura K, Kinoshita A, Kudoh S, Hirata K, Yoshikawa J, Fukushima S. Lack of large intestinal carcinogenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine at low doses in rats initiated with azoxymethane. Int J Cancer 2005; 115:870-8. [PMID: 15751028 DOI: 10.1002/ijc.20960] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), an abundant food-derived heterocyclic amine (HCA), has attracted particular attention as a human colon carcinogen. Humans are in fact exposed to continuous low doses of HCAs during lifetime. Therefore, we focused on rat large intestinal carcinogenicity of PhIP at levels that mimic practical human exposure. A total of 192 6-week-old male F344 rats were subcutaneously injected twice with 15 mg/kg body weight azoxymethane (AOM), then continuously fed various doses (0, 0.001, 0.01, 0.1, 1, 10, 50 and 200 ppm) of PhIP in the diet. At week 16, aberrant crypt foci (ACF) were quantitatively analyzed. At week 36, tumor occurrence was pathologically analyzed. Then immunohistochemical examinations were performed. PhIP was found to enhance strongly AOM-initiated rat large intestinal tumorigenesis at high doses (50 and 200 ppm), while lower doses (0.001-10 ppm) had no apparent effects. High doses also caused variation in tumor histologic types and their distribution throughout the large intestinal segments. Frequencies of ACF/cm(2) did not meaningfully vary between the groups. Cellular proliferation activity in normal-appearing colonic mucosa was significantly increased at high doses. These novel findings may provide evidence of a low-dose potential for PhIP, with a no-observed effect level speculated to be 10 ppm in the present initiation-promotion experimental model.
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Affiliation(s)
- Kenichiro Doi
- Department of Pathology, Osaka City University Medical School, Osaka, Japan
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35
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Volate SR, Davenport DM, Muga SJ, Wargovich MJ. Modulation of aberrant crypt foci and apoptosis by dietary herbal supplements (quercetin, curcumin, silymarin, ginseng and rutin). Carcinogenesis 2005; 26:1450-6. [PMID: 15831530 DOI: 10.1093/carcin/bgi089] [Citation(s) in RCA: 161] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
It is estimated that one-third of Americans use dietary herbal supplements on a regular basis. Diets rich in bioactive phytochemicals are associated with reduced risk of certain cancers, notably, colon cancer. Herbal supplements have not been directly tested as sources of bioactive cancer preventives. Hence, this study compares the ability of four herbal flavonoids (quercetin, curcumin, rutin and silymarin) and one whole herb mixture (ginseng powder) to suppress aberrant crypt foci (ACF) in an azoxymethane (AOM)-induced rat colon cancer model. Second, this study examines the effect of these herbal compounds on apoptosis and the mechanisms by which these compounds evoke apoptosis. The results of this study show that diets containing quercetin, curcumin, silymarin, ginseng and rutin decreased the number of ACFs by 4-, 2-, 1.8-, 1.5- and 1.2-fold, respectively compared with control. Histological analysis of the colon mucosa revealed that all the herbal supplements, except silymarin, induced apoptosis, with quercetin being the most potent (3x increase compared with control). Furthermore, ginseng and curcumin were region-specific in inducing apoptosis. The ability of quercetin and curcumin to modulate ACFs correlates well with their ability to induce apoptosis. Western blot analysis of caspase 9, Bax (proapoptotic) and Bcl-2 (antiapoptotic) proteins from the colon scraping suggests that quercetin and curcumin induce apoptosis via the mitochondrial pathway. Taken together, the results of this study suggest that these herbal supplements may exert significant and potentially beneficial effects on decreasing the amount of precancerous lesions and inducing apoptosis in the large intestine.
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Affiliation(s)
- Suresh R Volate
- Division of Basic Research, South Carolina Cancer Center, 14 Medical Park, Suite 500 Columbia, SC 29203, USA
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36
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de Moura Espíndola R, Mazzantini RP, Ong TP, de Conti A, Heidor R, Moreno FS. Geranylgeraniol and β-ionone inhibit hepatic preneoplastic lesions, cell proliferation, total plasma cholesterol and DNA damage during the initial phases of hepatocarcinogenesis, but only the former inhibits NF-κB activation. Carcinogenesis 2005; 26:1091-9. [PMID: 15718255 DOI: 10.1093/carcin/bgi047] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Chemopreventive activities of the isoprenoids geranylgeraniol (GGO) and beta-ionone (BI) were evaluated during initial phases of hepatocarcinogenesis. Rats received 8 or 16 mg/100 g body wt GGO (GGO8 and GGO16 groups) or BI (BI8 and BI16 groups), or only corn oil (CO group, controls) daily for 7 weeks. Incidence (%) and the mean number of visible hepatocyte nodules/animal were inhibited in the GGO8 (64% and 21 +/- 40), GGO16 (33% and 3 +/- 5), BI8 (50% and 13 +/- 34) and BI16 (42% and 9 +/- 19) groups compared with the CO group (100% and 34 +/- 51) (P < 0.05, except for the GGO8 group). Number/cm(2) liver section, mean area (mm(2)) and % liver section area occupied by persistent hepatic placental glutathione S-transferase positive preneoplastic lesions (PNL) were reduced in the GGO8 (11 +/- 9; 0.26 +/- 0.35; 2.7 +/- 3.0), GGO16 (6 +/- 6; 0.18 +/- 0.16; 0.9 +/- 0.9), BI8 (9 +/- 5; 0.13 +/- 0.20; 1.1 +/- 1.2) and BI16 (8 +/- 6; 0.08 +/- 0.09; 0.6 +/- 0.4) groups compared with the CO group (26 +/- 18; 0.29 +/- 0.34; 7.0 +/- 5.5) (P < 0.05). GGO16 and BI16 groups showed smaller visible hepatocyte nodules, reduced PNL cell proliferation and total plasma cholesterol levels compared with the CO group (P < 0.05), but did not show any differences (P > 0.05) in PNL apoptosis. DNA damage expressed as comet length (microm) was reduced in the GGO8 (96.7 +/- 1.5), GGO16 (94.2 +/- 1.5), BI8 (97.1 +/- 1.1) and BI16 (95.1 +/- 1.5) groups compared with the CO group (102.1 +/- 1.7) (P < 0.05). In comparison with normal animals, the CO group animals showed increased (P < 0.05) nuclear levels of nuclear factor kappa B (NF-kappaB) p65 subunit in hepatic cells, which were decreased (P < 0.05) in the GGO16 group animals. Anticarcinogenic actions of these isoprenoids seem to follow a dose-response relationship. Results indicate that GGO and BI could be represented as promising chemopreventive agents against hepatocarcinogenesis. Inhibition of cell proliferation and DNA damage seems to be important for the anticarcinogenic actions of isoprenoids, while the inhibition of NF-kappaB activation seems to be specifically related to GGO actions.
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Affiliation(s)
- Roseli de Moura Espíndola
- Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
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Wijnands MVW, van Erk MJ, Doornbos RP, Krul CAM, Woutersen RA. Do aberrant crypt foci have predictive value for the occurrence of colorectal tumours? Potential of gene expression profiling in tumours. Food Chem Toxicol 2004; 42:1629-39. [PMID: 15304309 DOI: 10.1016/j.fct.2004.05.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2004] [Accepted: 05/27/2004] [Indexed: 11/18/2022]
Abstract
The effects of different dietary compounds on the formation of aberrant crypt foci (ACF) and colorectal tumours and on the expression of a selection of genes were studied in rats. Azoxymethane-treated male F344 rats were fed either a control diet or a diet containing 10% wheat bran (WB), 0.2% curcumin (CUR), 4% rutin (RUT) or 0.04% benzyl isothiocyanate (BIT) for 8 months. ACF were counted after 7, 15 and 26 weeks. Tumours were scored after 26 weeks and 8 months. We found that the WB and CUR diets inhibited the development of colorectal tumours. In contrast, the RUT and BIT diets rather enhanced (although not statistically significantly) colorectal carcinogenesis. In addition, the various compounds caused different effects on the development of ACF. In most cases the number or size of ACF was not predictive for the ultimate tumour yield. The expression of some tumour-related genes was significantly different in tumours from the control group as compared to tumours from the treated groups. It was concluded that WB and CUR, as opposed to RUT and BIT, protects against colorectal cancer and that ACF are unsuitable as biomarker for colorectal cancer. Effects of the different dietary compounds on metalloproteinase 1 (TIMP-1) expression correlated well with the effects of the dietary compounds on the ultimate tumour yield.
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Affiliation(s)
- M V W Wijnands
- TNO Nutrition and Food Research, Department of Toxicology and Applied Pharmacology, Utrechtseweg 48, P.O. Box 360, Zeist, AJ 3700, The Netherlands.
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Pereira MA, Wang W, Kramer PM, Tao L. DNA hypomethylation induced by non-genotoxic carcinogens in mouse and rat colon. Cancer Lett 2004; 212:145-51. [PMID: 15279894 DOI: 10.1016/j.canlet.2004.03.024] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2003] [Revised: 03/18/2004] [Accepted: 03/22/2004] [Indexed: 12/31/2022]
Abstract
The ability of non-genotoxic colon carcinogens to induce DNA hypomethylation was evaluated. Administering 0, 0.2 and 0.4 mg/kg of 5-aza-2'-deoxycytidine to female mice for 5 days resulted in a dose-related decrease in 5-methylcytosine in colon DNA. Rutin (3.0 mg/kg) and five bile acids (4.0 mg/kg) were administered in the diet to male F344 rats for 14 days. Rutin and four bile acids that promote colon cancer, deoxycholic acid, chenodeoxycholic acid, cholic acid and lithocholic acid caused DNA hypomethylation, while ursodeoxycholic acid that prevents colon cancer did not. Bromodichloromethane (BDCM) was administered to male F344 rats and B6C3F1 mice by gavage at 0, 50 and 100 mg/kg or in their drinking water at 0, 350 and 700 mg/l for up to 28 days. In rats, BDCM decreased DNA methylation, being more effective when administered by gavage, correlating to its greater carcinogenic potency by this route. In mice, BDCM did not decrease DNA methylation, corresponding to its lack of carcinogenic activity in the colon of this species. In summary, the ability of non-genotoxic colon carcinogens to cause DNA hypomethylation correlated with their carcinogenic activity in the colon.
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Affiliation(s)
- Michael A Pereira
- Department of Pathology, Medical College of Ohio, 3055 Arlington Avenue, Toledo 43614-5806, USA.
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Tao L, Wang W, Kramer PM, Lubet RA, Steele VE, Pereira MA. Modulation of DNA hypomethylation as a surrogate endpoint biomarker for chemoprevention of colon cancer. Mol Carcinog 2004; 39:79-84. [PMID: 14750212 DOI: 10.1002/mc.20003] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Surrogate end-point biomarkers are being developed as indicators of the efficacy of chemopreventive agents. These biomarkers are molecular and biological end-points that can be modulated by chemopreventive agents in accordance with their efficacy to prevent cancer. DNA hypomethylation is a common alteration found in colon tumors that has the potential of being modulated by chemopreventive agents and thus being useful as a surrogate end-point biomarker. Agents that were either effective or ineffective in preventing colon cancer were evaluated for the ability to modulate DNA hypomethylation in azoxymethane-induced colon tumors in male F344 rats. DNA methylation was determined by Dot Blot Analysis using a mouse monoclonal anti-5-methylcytosine antibody. Colon tumors had a 70% reduction in DNA methylation relative to normal colonic mucosa. DNA methylation in the tumors was increased by 7 days of treatment with agents that have been shown to prevent colon cancer (calcium chloride, alpha-diflouromethylornithine [DFMO], piroxicam, and sulindac), whereas agents shown not to prevent colon cancer in rats (low dose aspirin, 2-carboxyphenyl retinamide [2-CPR], quercetin, 9-cis retinoic acid, and rutin) did not increase DNA methylation. The results suggest that the ability to reverse the DNA hypomethylation in colon tumors could be useful as a surrogate end-point biomarker for chemoprevention of colon cancer.
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Affiliation(s)
- Lianhui Tao
- Department of Pathology, Medical College of Ohio, Toledo, Ohio, USA
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Wei HB, Han XY, Fan W, Chen GH, Wang JF. Effect of retinoic acid on cell proliferation kinetics and retinoic acid receptor expression of colorectal mucosa. World J Gastroenterol 2003; 9:1725-8. [PMID: 12918108 PMCID: PMC4611531 DOI: 10.3748/wjg.v9.i8.1725] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of retinoic acid (RA) on cell proliferation kinetics and retinoic acid receptor (RAR) expression of colorectal mucosa.
METHODS: One hundred sixty healthy male Wistar rats were randomly divided into 4 groups. Rats in groups I and II were subcutaneously injected with dimethylhydrazine (DMH) (20 mg/kg, once a week,) for 7 to 13 weeks, while groups III and IV were injected with normal saline. Rats in groups II and III were also treated with RA (50 mg/kg, every day, orally) from 7th to 15th week, thus group IV was used as a control. The rats were killed in different batches. The expressions of proliferating cell nuclear antigen (PCNA), nucleolar organizer region-associated protein (AgNOR) and RAR were detected.
RESULTS: The incidence of colorectal carcinoma was different between groups I (100%) and II (15%) (P < 0.01). The PCNA indices and mean AgNOR count in group II were significantly lower than those in group I (F = 5.418 and 4.243, P < 0.01). The PCNA indices and mean AgNOR count in groups I and II were significantly higher than those in the groups III and IV (in which carcinogen was not used) (F = 5.927 and 4.348, P < 0.01). There was a tendency in group I that the longer the induction with DMH the higher PCNA index and AgNOR count expressed (F = 7.634 and 6.826, P < 0.05). However, there was no such tendency in groups II, III and IV (F = 1.662 and 1.984, P > 0.05). The levels of RAR in normal and cancerous tissues in groups treated with RA were significantly higher than those in groups not treated with RA (F = 6.343 and 6.024, P < 0.05).
CONCLUSION: RA decreases the incidence of colorectal carcinoma induced by DMH. Colorectal cancer tissue is associated with abnormal expression of PCNA, AgNOR and RAR. RA inhibits the expression of PCNA and AgNOR, and increases RAR concentration in colorectal tissues.
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Affiliation(s)
- Hong-Bo Wei
- Department of Gastrointestinal Surgery, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, China.
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