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Yin H, Gao Y, Chen W, Tang C, Zhu Z, Li K, Xia S, Han C, Ding X, Ruan F, Tian H, Zhu C, Xie S, Zuo Z, Liao L, He C. Topically applied fullerenols protect against radiation dermatitis by scavenging reactive oxygen species. DISCOVER NANO 2023; 18:101. [PMID: 37581715 PMCID: PMC10427596 DOI: 10.1186/s11671-023-03869-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 07/04/2023] [Indexed: 08/16/2023]
Abstract
Adverse skin reactions caused by ionizing radiation are collectively called radiation dermatitis (RD), and the use of nanomedicine is an attractive approach to this condition. Therefore, we designed and large-scale synthesized fullerenols that showed free radical scavenging ability in vitro. Next, we pretreated X-ray-exposed cells with fullerenols. The results showed that pretreatment with fullerenols significantly scavenged intracellular reactive oxygen species (ROS) produced and enhanced the antioxidant capacity, protecting skin cells from X-ray-induced DNA damage and apoptosis. Moreover, we induced RD in mice by applying 30 Gy of X-ray irradiation, followed by treatment with fullerenols. We found that after treatment, the RD scores dropped, and the histological results systematically demonstrated that topically applied fullerenols could reduce radiation-induced skin epidermal thickening, collagen deposition and skin appendage damage and promote hair regeneration after 35 days. Compared with Trolamine cream, a typical RD drug, fullerenols showed superior radiation protection. Overall, the in vitro and in vivo experiments proved that fullerenols agents against RD.
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Grants
- Nos. XDHT2020407A and 20213160A0471 Xiamen Funano New Materials Technology Co., Ltd.
- Nos. XDHT2020407A and 20213160A0471 Xiamen Funano New Materials Technology Co., Ltd.
- Nos. XDHT2020407A and 20213160A0471 Xiamen Funano New Materials Technology Co., Ltd.
- Nos. XDHT2020407A and 20213160A0471 Xiamen Funano New Materials Technology Co., Ltd.
- Nos. XDHT2020407A and 20213160A0471 Xiamen Funano New Materials Technology Co., Ltd.
- Nos. XDHT2020407A and 20213160A0471 Xiamen Funano New Materials Technology Co., Ltd.
- Nos. XDHT2020407A and 20213160A0471 Xiamen Funano New Materials Technology Co., Ltd.
- Nos. XDHT2020407A and 20213160A0471 Xiamen Funano New Materials Technology Co., Ltd.
- Nos. XDHT2020407A and 20213160A0471 Xiamen Funano New Materials Technology Co., Ltd.
- Nos. XDHT2020407A and 20213160A0471 Xiamen Funano New Materials Technology Co., Ltd.
- Nos. XDHT2020407A and 20213160A0471 Xiamen Funano New Materials Technology Co., Ltd.
- Nos. XDHT2020407A and 20213160A0471 Xiamen Funano New Materials Technology Co., Ltd.
- Nos. XDHT2020407A and 20213160A0471 Xiamen Funano New Materials Technology Co., Ltd.
- Nos. XDHT2020407A and 20213160A0471 Xiamen Funano New Materials Technology Co., Ltd.
- Nos. XDHT2020407A and 20213160A0471 Xiamen Funano New Materials Technology Co., Ltd.
- Nos. XDHT2020407A and 20213160A0471 Xiamen Funano New Materials Technology Co., Ltd.
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Affiliation(s)
- Hanying Yin
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, The Plastic and Aesthetic Burn Department, The First Affiliated Hospital, Xiamen University, Xiamen, People's Republic of China
| | - You Gao
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, The Plastic and Aesthetic Burn Department, The First Affiliated Hospital, Xiamen University, Xiamen, People's Republic of China
| | - Weiguang Chen
- School of Medicine and School of Biomedical Sciences, Huaqiao University, Xiamen, Fujian, China
| | - Chen Tang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, The Plastic and Aesthetic Burn Department, The First Affiliated Hospital, Xiamen University, Xiamen, People's Republic of China
| | - Zihan Zhu
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, The Plastic and Aesthetic Burn Department, The First Affiliated Hospital, Xiamen University, Xiamen, People's Republic of China
| | - Kun Li
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, The Plastic and Aesthetic Burn Department, The First Affiliated Hospital, Xiamen University, Xiamen, People's Republic of China
| | - Siyu Xia
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, The Plastic and Aesthetic Burn Department, The First Affiliated Hospital, Xiamen University, Xiamen, People's Republic of China
| | - Changshun Han
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, The Plastic and Aesthetic Burn Department, The First Affiliated Hospital, Xiamen University, Xiamen, People's Republic of China
| | - Xiaoyan Ding
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, The Plastic and Aesthetic Burn Department, The First Affiliated Hospital, Xiamen University, Xiamen, People's Republic of China
| | - Fengkai Ruan
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, The Plastic and Aesthetic Burn Department, The First Affiliated Hospital, Xiamen University, Xiamen, People's Republic of China
| | - Hanrui Tian
- State Key Laboratory for Physical Chemistry of Solid Surfaces, Collaborative Innovation Center of Chemistry for Energy Materials, Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China
| | - Changfeng Zhu
- Xiamen Funano New Materials Technology Co., Ltd., Xiamen, China
| | - Suyuan Xie
- State Key Laboratory for Physical Chemistry of Solid Surfaces, Collaborative Innovation Center of Chemistry for Energy Materials, Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China
| | - Zhenghong Zuo
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, The Plastic and Aesthetic Burn Department, The First Affiliated Hospital, Xiamen University, Xiamen, People's Republic of China
| | - Lixin Liao
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, The Plastic and Aesthetic Burn Department, The First Affiliated Hospital, Xiamen University, Xiamen, People's Republic of China.
| | - Chengyong He
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, The Plastic and Aesthetic Burn Department, The First Affiliated Hospital, Xiamen University, Xiamen, People's Republic of China.
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Kim YJ, Song J, Lee DH, Um SH, Bhang SH. Suppressing cancer by damaging cancer cell DNA using LED irradiation. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY. B, BIOLOGY 2023; 243:112714. [PMID: 37084656 DOI: 10.1016/j.jphotobiol.2023.112714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 04/09/2023] [Accepted: 04/13/2023] [Indexed: 04/23/2023]
Abstract
BACKGROUND High-energy irradiation eliminates cancer cells by destroying their genetic components. However, there are several side effects from doing this, such as fatigue, dermatitis, and hair loss, which remain obstacles to this treatment. Here, we propose a moderate method that uses low-energy white light from a light-emitting diode (LED) to selectively inhibit cancer cell proliferation without affecting normal cells. METHODS The association between LED irradiation and cancer cell growth arrest was evaluated based on cell proliferation, viability, and apoptotic activity. Immunofluorescence, polymerase chain reaction, and western blotting were performed in vitro and in vivo to identify the metabolism related to the inhibition of HeLa cell proliferation. RESULTS LED irradiation aggravated the defective p53 signaling pathway and induced cell growth arrest in cancer cells. Consequently, cancer cell apoptosis was induced by the increased DNA damage. Additionally, LED irradiation inhibited the proliferation of cancer cells by suppressing the MAPK pathway. Furthermore, the suppression of cancer growth by the regulation of p53 and MAPK was observed in cancer-bearing mice irradiated with LED. CONCLUSIONS Our findings suggest that LED irradiation can suppress cancer cell activity and may contribute to preventing the proliferation of cancer cells after medical surgery without causing side effects.
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Affiliation(s)
- Yu-Jin Kim
- School of Chemical Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea; Center for Biomaterials, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
| | - Jihun Song
- School of Chemical Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea; Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Republic of Korea
| | - Dong-Hyun Lee
- School of Chemical Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Soong Ho Um
- School of Chemical Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Suk Ho Bhang
- School of Chemical Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea.
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Iqubal A, Iqubal MK, Sharma S, Wasim M, Alfaleh MA, Md S, Baboota S, Ali J, Haque SE. Pathogenic mechanisms and therapeutic promise of phytochemicals and nanocarriers based drug delivery against radiotherapy-induced neurotoxic manifestations. Drug Deliv 2022; 29:1492-1511. [PMID: 35543534 PMCID: PMC9103628 DOI: 10.1080/10717544.2022.2064562] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Radiotherapy is one of the extensively used therapeutic modalities in glioblastoma and other types of cancers. Radiotherapy is either used as a first-line approach or combined with pharmacotherapy or surgery to manage and treat cancer. Although the use of radiotherapy significantly increased the survival time of patients, but its use has been reported with marked neuroinflammation and cognitive dysfunction that eventually reduced the quality of life of patients. Based on the preclinical and clinical investigations, the profound role of increased oxidative stress, nuclear translocation of NF-kB, production of proinflammatory cytokines such as TNF-α, IL-6, IL-β, increased level of MMPs, increased apoptosis, reduced angiogenesis, neurogenesis, and histological aberrations in CA1, CA2, CA3 and DG region of the hippocampus have been reported. Various pharmacotherapeutic drugs are being used as an adjuvant to counteract this neurotoxic manifestation. Still, most of these drugs suffer from systemic adverse effect, causes interference to ongoing chemotherapy, and exhibit pharmacokinetic limitations in crossing the blood-brain barrier. Therefore, various phytoconstituents, their nano carrier-based drug delivery systems and miRNAs have been explored to overcome the aforementioned limitations. The present review is focused on the mechanism and evidence of radiotherapy-induced neuroinflammation and cognitive dysfunction, pathological and molecular changes in the brain homeostasis, available adjuvants, their limitations. Additionally, the potential role and mechanism of neuroprotection of various nanocarrier based natural products and miRNAs have been discussed.
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Affiliation(s)
- Ashif Iqubal
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Mohammad Kashif Iqubal
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India.,Product Development Department, Sentiss Research Centre, Sentiss Pharma Pvt Ltd, Gurugram, India
| | - Sumit Sharma
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Mohd Wasim
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Mohamed A Alfaleh
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia.,Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Shadab Md
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia.,Center of Excellence for Drug Research & Pharmaceutical Industries, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Sanjula Baboota
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Javed Ali
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Syed Ehtaishamul Haque
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
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Zhang P, Yu B, Jin X, Zhao T, Ye F, Liu X, Li P, Zheng X, Chen W, Li Q. Therapeutic Efficacy of Carbon Ion Irradiation Enhanced by 11-MUA-Capped Gold Nanoparticles: An in vitro and in vivo Study. Int J Nanomedicine 2021; 16:4661-4674. [PMID: 34262274 PMCID: PMC8275145 DOI: 10.2147/ijn.s313678] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 06/07/2021] [Indexed: 12/19/2022] Open
Abstract
PURPOSE Gold nanoparticles (AuNPs) are widely studied as radiosensitizers, but their radiosensitization in carbon ion radiotherapy is unsatisfactory. There is a lack of in vivo data on the radiosensitization of AuNPs under carbon ion irradiation. This study focused on the radiosensitization effect of AuNPs in the mouse melanoma cell line B16-F10 in vitro and in vivo. MATERIALS AND METHODS 11-mercaptoundecanoic acid (11-MUA)-coated gold (Au) nanoparticles (mAuNPs) formulations were prepared and characterized. To verify the radiosensitization effect of mAuNPs, hydroxyl radicals were generated in aqueous solution, and the detection of intracellular reactive oxygen species (ROS) and clone survival were carried out in vitro. The tumor growth rate (TGR) and survival of mice were analyzed to verify the radiosensitization effect of mAuNPs in vivo. The apoptosis of tumor cells was detected, and the expression of key proteins in the apoptosis pathway was verified by immunohistochemistry. RESULTS The intracellular ROS level in B16-F10 cells was enhanced by mAuNPs under carbon ion irradiation. The sensitization rate of mAuNPs was 1.22 with a 10% cell survival rate. Compared with irradiation alone, the inhibitory effect of mAuNPs combined with carbon ion irradiation on tumor growth was 1.94-fold higher, the survival time of mice was prolonged by 1.75-fold, and the number of apoptotic cells was increased by 1.43-fold. The ratio of key proteins Bax and Bcl2 in the apoptosis pathway was up-regulated, and the expression of caspase-3, a key executor of the apoptosis pathway, was up-regulated. CONCLUSION In in vivo and in vitro experiments, mAuNPs showed radiosensitivity to carbon ion irradiation. The sensitization effect of mAuNPs on mice tumor may be achieved by activating the mitochondrial apoptosis pathway and increasing tumor tissue apoptosis. To our best knowledge, the present study is the first in vivo evidence for radiosensitization of mAuNPs in tumor-bearing mice exposed to carbon ion irradiation.
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Affiliation(s)
- Pengcheng Zhang
- Institute of Modern Physics, Chinese Academy of Sciences; Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, Gansu Province, 730000, People’s Republic of China
- University of Chinese Academy of Sciences, Beijing, 100049, People’s Republic of China
- The First Hospital of Lanzhou University, Lanzhou, 730000, People’s Republic of China
- Department of Radiation Oncology, The First Hospital of Lanzhou University, Lanzhou, 730000, People’s Republic of China
| | - Boyi Yu
- Institute of Modern Physics, Chinese Academy of Sciences; Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, Gansu Province, 730000, People’s Republic of China
- University of Chinese Academy of Sciences, Beijing, 100049, People’s Republic of China
| | - Xiaodong Jin
- Institute of Modern Physics, Chinese Academy of Sciences; Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, Gansu Province, 730000, People’s Republic of China
- University of Chinese Academy of Sciences, Beijing, 100049, People’s Republic of China
| | - Ting Zhao
- Institute of Modern Physics, Chinese Academy of Sciences; Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, Gansu Province, 730000, People’s Republic of China
| | - Fei Ye
- Institute of Modern Physics, Chinese Academy of Sciences; Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, Gansu Province, 730000, People’s Republic of China
- University of Chinese Academy of Sciences, Beijing, 100049, People’s Republic of China
| | - Xiongxiong Liu
- Institute of Modern Physics, Chinese Academy of Sciences; Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, Gansu Province, 730000, People’s Republic of China
- University of Chinese Academy of Sciences, Beijing, 100049, People’s Republic of China
| | - Ping Li
- Institute of Modern Physics, Chinese Academy of Sciences; Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, Gansu Province, 730000, People’s Republic of China
- University of Chinese Academy of Sciences, Beijing, 100049, People’s Republic of China
| | - Xiaogang Zheng
- Institute of Modern Physics, Chinese Academy of Sciences; Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, Gansu Province, 730000, People’s Republic of China
| | - Weiqiang Chen
- Institute of Modern Physics, Chinese Academy of Sciences; Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, Gansu Province, 730000, People’s Republic of China
- University of Chinese Academy of Sciences, Beijing, 100049, People’s Republic of China
| | - Qiang Li
- Institute of Modern Physics, Chinese Academy of Sciences; Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, Gansu Province, 730000, People’s Republic of China
- University of Chinese Academy of Sciences, Beijing, 100049, People’s Republic of China
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Visualization of Radiation-Induced Cell Cycle Kinetics with a Fluorescent Ubiquitination-Based Cell Cycle Indicator (Fucci). Methods Mol Biol 2021; 2329:223-236. [PMID: 34085226 DOI: 10.1007/978-1-0716-1538-6_16] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2022]
Abstract
Among the methods for detecting cell cycle kinetics in tumor cells, fluorescent ubiquitination-based cell cycle indicator (Fucci) is innovative because it allows observation in live cells without losing spatiotemporal information. We succeeded in using the Fucci system to visualize radiation-induced G2 arrest in tumor cells with deficient p53 function. Here we describe protocols for establishing Fucci-expressing cell lines and analyzing radiation-induced G2 arrest kinetics in three different models: monolayer cell cultures, spheroids, and xenografted solid tumors in mice.
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Gaillard B, Remy JS, Pons F, Lebeau L. Dual Gene Delivery Reagents From Antiproliferative Alkylphospholipids for Combined Antitumor Therapy. Front Chem 2020; 8:581260. [PMID: 33134279 PMCID: PMC7566913 DOI: 10.3389/fchem.2020.581260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 08/31/2020] [Indexed: 11/13/2022] Open
Abstract
Alkylphospholipids (APLs) have elicited great interest as antitumor agents due to their unique mode of action on cell membranes. However, their clinical applications have been limited so far by high hemolytic activity. Recently, cationic prodrugs of erufosine, a most promising APL, have been shown to mediate efficient intracellular gene delivery, while preserving the antiproliferative properties of the parent APL. Here, cationic prodrugs of the two APLs that are currently used in the clinic, miltefosine, and perifosine, are investigated and compared to the erufosine prodrugs. Their synthesis, stability, gene delivery and self-assembly properties, and hemolytic activity are discussed in detail. Finally, the potential of the pro-miltefosine and pro-perifosine compounds ME12 and PE12 in combined antitumor therapy is demonstrated using pUNO1-hTRAIL, a plasmid DNA encoding TRAIL, a member of the TNF superfamily. With these pro-APL compounds, we provide a proof of concept for a new promising strategy for cancer therapy combining gene therapy and APL-based chemotherapy.
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Affiliation(s)
- Boris Gaillard
- Laboratoire de Conception et Application de Molécules Bioactives, UMR 7199 CNRS-Université de Strasbourg, Faculté de Pharmacie, Illkirch, France
| | - Jean-Serge Remy
- Laboratoire de Conception et Application de Molécules Bioactives, UMR 7199 CNRS-Université de Strasbourg, Faculté de Pharmacie, Illkirch, France
| | - Françoise Pons
- Laboratoire de Conception et Application de Molécules Bioactives, UMR 7199 CNRS-Université de Strasbourg, Faculté de Pharmacie, Illkirch, France
| | - Luc Lebeau
- Laboratoire de Conception et Application de Molécules Bioactives, UMR 7199 CNRS-Université de Strasbourg, Faculté de Pharmacie, Illkirch, France
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Momeny M, Sankanian G, Hamzehlou S, Yousefi H, Esmaeili F, Alishahi Z, Karimi B, Zandi Z, Shamsaiegahkani S, Sabourinejad Z, Kashani B, Nasrollahzadeh A, Mousavipak SH, Mousavi SA, Ghaffari SH. Cediranib, an inhibitor of vascular endothelial growth factor receptor kinases, inhibits proliferation and invasion of prostate adenocarcinoma cells. Eur J Pharmacol 2020; 882:173298. [PMID: 32593665 DOI: 10.1016/j.ejphar.2020.173298] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Revised: 06/17/2020] [Accepted: 06/18/2020] [Indexed: 11/29/2022]
Abstract
Prostate Cancer is the second cause of cancer-related death in men and development of metastatic castration-resistant prostate cancer (mCRPC) is the major reason for its high mortality rate. Despite various treatments, all patients succumb to resistant disease, suggesting that there is a pressing need for novel and more efficacious treatments. Members of the vascular endothelial growth factor (VEGF) family play key roles in the tumorigenesis of mCRPC, indicating that VEGF-targeted therapies may have potential anti-tumor efficacy in this malignancy. However, due to compensatory activation of other family members, clinical trials with single-targeted VEGF inhibitors were discouraging. Here, we determined the anti-neoplastic activity of Cediranib, a pan-VEGF receptor inhibitor, in the mCRPC cell lines. Anti-growth effects of Cediranib were studied by MTT and BrdU cell proliferation assays and crystal violet staining. Annexin V/PI, radiation therapy and cell motility assays were carried out to examine the effects of Cediranib on apoptosis, radio-sensitivity and cell motility. Quantitative reverse transcription-PCR (qRT-PCR) and Western blot analyses were conducted to determine the molecular mechanisms underlying the anti-tumor activity of Cediranib. Cediranib decreased cell viability and induced apoptosis via inhibition of the anti-apoptotic proteins. Combination with Cediranib synergistically increased Docetaxel sensitivity and potentiated the effects of radiation therapy. Furthermore, Cediranib impaired cell motility via decrease in the expression of the epithelial-to-mesenchymal transition markers. These findings suggest that Cediranib may have anti-tumor activity in mCRPC cells and warrant further investigation on the therapeutic activity of this pan-VEGF receptor inhibitor in mCRPC.
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Affiliation(s)
- Majid Momeny
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
| | - Ghazaleh Sankanian
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Sepideh Hamzehlou
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hassan Yousefi
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, New Orleans, USA
| | - Fatemeh Esmaeili
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Zivar Alishahi
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Behnaz Karimi
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Zandi
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Sahar Shamsaiegahkani
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Sabourinejad
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Bahareh Kashani
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Nasrollahzadeh
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyyedeh H Mousavipak
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed A Mousavi
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed H Ghaffari
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran.
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H N, Gh H, M V J. The Effect of Vitamin C on Apoptosis and Bax/Bcl-2 Proteins Ratio in Peripheral Blood Lymphocytes of Patients during Cardiac Interventional Procedures. J Biomed Phys Eng 2020; 10:421-432. [PMID: 32802790 PMCID: PMC7416102 DOI: 10.31661/jbpe.v0i0.917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Accepted: 05/10/2018] [Indexed: 11/17/2022]
Abstract
Background: There is a close relationship between the effects of free radicals and apoptosis, and vitamin C is known as a potent scavenger of free radicals. Objective: The aim of this study was to evaluate the effect of vitamin C against the radiation-induced apoptosis and the ratio of Bax/Bcl-2 proteins in peripheral blood lymphocytes in patients undergoing cardiac procedures in vivo condition. Material and Methods: In this clinical intervention study, blood samples from 6 patients in the first group were taken to assess the effect of radiation on the apoptosis and Bax/Bcl-2 proteins ratio, and 5 patients as the second group to evaluate the effect of vitamin C on the apoptosis and Bax/Bcl-2 proteins ratio before and 24 hours after the examination. Flow cytometry was used to analyze the apoptosis and ELISA method to assess Bax and Bcl-2 proteins amount. Results: In the second group receiving 25 mg/kg vitamin C and a mean skin dose of 1001 mGy in the chest area, there was no significant difference (P <0.05)
in the percentage of early apoptosis in 24 hours after the examination than before it. This significant increase in the percentage of apoptosis in the first group (385.6 mGy)
was associated with a significant increase in the Bax/Bcl-2 ratio (P <0.05), while in the second group, it was not associated with a significant decrease in the Bax/Bcl-2 ratio in 24 hours after the examination than before it. Conclusion: Our results suggest that vitamin C may modulate Bax and Bcl-2 proteins expression, in maintaining peripheral blood lymphocytes in patients undergoing cardiology in radiation-induced apoptosis.
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Affiliation(s)
- Nematollahi H
- MSc, Department of Radiology, Paramedical School, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Haddadi Gh
- PhD, Associate Professor, Department of Radiology, Paramedical School, Shiraz University of Medical Sciences, Shiraz, Iran
- PhD, Associate Professor, Ionizing and Non-ionizing Radiation Protection Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Jorat M V
- MD, Associate Professor, Cardiovascular Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Zerp SF, Bibi Z, Verbrugge I, Voest EE, Verheij M. Enhancing radiation response by a second-generation TRAIL receptor agonist using a new in vitro organoid model system. Clin Transl Radiat Oncol 2020; 24:1-9. [PMID: 32577539 PMCID: PMC7303921 DOI: 10.1016/j.ctro.2020.05.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 05/27/2020] [Accepted: 05/29/2020] [Indexed: 02/07/2023] Open
Abstract
We evaluated the effect of the second-generation TRAIL receptor agonist APG-880 on radiation-induced cytotoxicity. The combined effect was studied in short-term and long-term cytotoxicity assays in established CRC cell lines, and tumor organoids derived from colon cancer patients. We observed a supra-additive effect on cytotoxicity when APG-880 and radiation were combined simultaneously, with combination indices around 0.7. In long-term survival assays, we demonstrated a radiosensitizing effect of APG-880 with dose enhancement factors between 1.3 and 1.5. Background For many cancer types, including colorectal carcinoma (CRC), combined modality treatments have shown to improve outcome, but are frequently associated with significant toxicity, illustrating the need for new therapeutic approaches. Based on preclinical data, TRAIL receptor agonists appeared to be promising agents for cancer therapy especially in combination with DNA damaging regimens. Here, we present the combination of the second-generation TRAIL receptor agonist APG-880 with radiation in a new and clinically relevant 3D model system. Methods To investigate the effect of APG-880 in combination with radiation we performed short-term cytotoxicity and long-term clonogenic survival assays in established CRC cell lines, and in tumor organoids derived from colon cancer patients. Results APG-880 is a potent inducer of apoptosis in CRC cell lines and in patient-derived CRC organoids. Furthermore, a supra-additive effect on cytotoxicity was found when APG-880 and radiation were combined simultaneously, with combination indices around 0.7. Lastly, in the long-term survival assays, we demonstrated a radiosensitizing effect of APG-880 with dose enhancement factors between 1.3 and 1.5. Conclusions In a new, clinically relevant CRC-organoid model system we demonstrated a more than additive combined effect between the second-generation TRAIL receptor agonist APG-880 and radiation.
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Affiliation(s)
- Shuraila F. Zerp
- Division of Cell Biology, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
| | - Zainab Bibi
- Division of Cell Biology, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
| | - Inge Verbrugge
- Division of Tumor Biology and Immunology, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
| | - Emile E. Voest
- Division of Oncogenomics, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
| | - Marcel Verheij
- Division of Cell Biology, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
- Department of Radiation Oncology, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
- Corresponding author at: The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
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10
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Motallebzadeh E, Tameh AA, Zavareh SAT, Farhood B, Aliasgharzedeh A, Mohseni M. Neuroprotective effect of melatonin on radiation-induced oxidative stress and apoptosis in the brainstem of rats. J Cell Physiol 2020; 235:8791-8798. [PMID: 32324264 DOI: 10.1002/jcp.29722] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 04/07/2020] [Accepted: 04/07/2020] [Indexed: 02/06/2023]
Abstract
This study aimed to determine the effects of melatonin on irradiation-induced apoptosis and oxidative stress in the brainstem region of Wistar rats. Therefore, the animals underwent whole-brain X-radiation with a single dose of 25 Gy in the presence or absence of melatonin pretreatment at a concentration of 100 mg/kg BW. The rats were allocated into four groups (10 rats in each group): namely, vehicle control (VC), 100 mg/kg of melatonin alone (MLT), irradiation-only (RAD), and irradiation plus 100 mg/kg of melatonin (RAM). An hour before irradiation, the animals received intraperitoneal (IP) melatonin and then were killed after 6 hr, followed by measurement of nitric oxide (NO), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), and total antioxidant capacity (TAC) in the brainstem region. Furthermore, the western blot analysis technique was performed to assess the caspase-3 expression level. Results showed significantly higher MDA and NO levels in the brainstem tissues for the RAD group when compared with the VC group (p < .001). Moreover, the irradiated rats exhibited a significant decrease in the levels of CAT, SOD, GPx, and TAC (p < .01, p < .001, p < .001, and p < .001, respectively) in comparison to the VC group. The results of apoptosis assessment revealed that the expression level of caspase-3 significantly rose in the RAD group in comparison with the VC group (p < .001). Pretreatment with melatonin ameliorated the radiation-induced adverse effects by decreasing the MDA and NO levels (p < .001) and increasing the antioxidant enzyme activities (p < .001). Consequently, the caspase-3 protein expression level in the RAM group showed a significant reduction in comparison with the RAD group (p < .001). In conclusion, melatonin approximately showed a capacity for neuroprotective activity in managing irradiation-induced oxidative stress and apoptosis in the brainstem of rats; however, the use of melatonin as a neuroprotective agent in humans requires further study, particularly clinical trials.
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Affiliation(s)
- Elham Motallebzadeh
- Department of Medical Physics and Radiology, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran.,Anatomical Sciences Research Center, Kashan University of Medical Sciences, Kashan, Iran
| | - Abolfazl Azami Tameh
- Anatomical Sciences Research Center, Kashan University of Medical Sciences, Kashan, Iran
| | | | - Bagher Farhood
- Department of Medical Physics and Radiology, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Akbar Aliasgharzedeh
- Department of Medical Physics and Radiology, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Mehran Mohseni
- Department of Medical Physics and Radiology, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran
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11
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Gaillard B, Seguin C, Remy JS, Pons F, Lebeau L. Erufosine (ErPC3) Cationic Prodrugs as Dual Gene Delivery Reagents for Combined Antitumor Therapy. Chemistry 2019; 25:15662-15679. [PMID: 31549752 DOI: 10.1002/chem.201903976] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 09/23/2019] [Indexed: 12/14/2022]
Abstract
Sixteen cationic prodrugs of the antitumor alkylphospholipid (APL) erufosine were rationally synthesized to provide original gene delivery reagents with improved cytotoxicity profile. The DNA complexation properties of these cationic lipids were determined and associated transfection rates were measured. Furthermore, the self-assembly properties of the pro-erufosine compounds were investigated and their critical aggregation concentration was determined. Their hydrolytic stability under pH conditions mimicking the extracellular environment and the late endosome milieu was measured. Hemolytic activity and cytotoxicity of the compounds were investigated. The results obtained in various cell lines demonstrate that the prodrugs of erufosine display antineoplastic activity similar to that of the parent antitumor drug but are not associated with hemolytic toxicity, which is a dose-limiting side effect of APLs and a major obstacle to their use in anticancer therapeutic regimen. Furthermore, by using lipoplexes prepared from a prodrug of erufosine and a plasmid DNA encoding a pro-apoptotic protein (TRAIL), evidence was provided for selective cytotoxicity towards tumor cells while nontumor cells were resistant. This study demonstrates that the combination approach involving well tolerated erufosine cationic prodrugs and cancer gene therapy holds significant promise in tumor therapy.
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Affiliation(s)
- Boris Gaillard
- Laboratoire de Conception et Application de Molécules Bioactives, UMR 7199 CNRS-Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin-BP 60024, 67401, Illkirch, France
| | - Cendrine Seguin
- Laboratoire de Conception et Application de Molécules Bioactives, UMR 7199 CNRS-Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin-BP 60024, 67401, Illkirch, France
| | - Jean-Serge Remy
- Laboratoire de Conception et Application de Molécules Bioactives, UMR 7199 CNRS-Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin-BP 60024, 67401, Illkirch, France
| | - Françoise Pons
- Laboratoire de Conception et Application de Molécules Bioactives, UMR 7199 CNRS-Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin-BP 60024, 67401, Illkirch, France
| | - Luc Lebeau
- Laboratoire de Conception et Application de Molécules Bioactives, UMR 7199 CNRS-Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin-BP 60024, 67401, Illkirch, France
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12
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Malyarenko OS, Malyarenko TV, Kicha AA, Ivanchina NV, Ermakova SP. Effects of Polar Steroids from the Starfish Patiria (=Asterina) pectinifera in Combination with X-Ray Radiation on Colony Formation and Apoptosis Induction of Human Colorectal Carcinoma Cells. Molecules 2019; 24:molecules24173154. [PMID: 31470638 PMCID: PMC6749381 DOI: 10.3390/molecules24173154] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 08/14/2019] [Accepted: 08/27/2019] [Indexed: 12/24/2022] Open
Abstract
Despite significant advances in the understanding, prevention, and treatment of cancer, the disease continues to affect millions of people worldwide. Chemoradiation therapy is a rational approach that has already proven beneficial for several malignancies. However, the existence of toxicity to normal tissue is a serious limitation of this treatment modality. The aim of the present study is to investigate the ability of polar steroids from starfish Patiria (=Asterina) pectinifera to enhance the efficacy of radiation therapy in colorectal carcinoma cells. The cytotoxic activity of polar steroids and X-ray radiation against DLD-1, HCT 116, and HT-29 cells was determined by an MTS assay. The effect of compounds, X-ray, and their combination on colony formation was studied using the soft agar method. The molecular mechanism of the radiosensitizing activity of asterosaponin P1 was elucidated by western blotting and the DNA comet assay. Polar steroids inhibited colony formation in the tested cells, and to a greater extent in HT-29 cells. Asterosaponin P1 enhanced the efficacy of radiation and, as a result, reduced the number and size of the colonies of colorectal cancer cells. The radiosensitizing activity of asterosaponin P1 was realized by apoptosis induction through the regulation of anti- and pro-apoptotic protein expression followed by caspase activation and DNA degradation.
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Affiliation(s)
- Olesya S Malyarenko
- G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, 159 100-let Vladivostok Ave., 690022 Vladivostok, Russia.
| | - Timofey V Malyarenko
- G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, 159 100-let Vladivostok Ave., 690022 Vladivostok, Russia
- Department of Bioorganic chemistry and Biotechnology, School of Natural Sciences, Far Eastern Federal University, Sukhanova str. 8, 690000 Vladivostok, Russia
| | - Alla A Kicha
- G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, 159 100-let Vladivostok Ave., 690022 Vladivostok, Russia
| | - Natalia V Ivanchina
- G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, 159 100-let Vladivostok Ave., 690022 Vladivostok, Russia
| | - Svetlana P Ermakova
- G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, 159 100-let Vladivostok Ave., 690022 Vladivostok, Russia
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13
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Malyarenko OS, Zdobnova EV, Silchenko AS, Kusaykin MI, Ermakova SP. Radiosensitizing effect of the fucoidan from brown alga Fucus evanescens and its derivative in human cancer cells. Carbohydr Polym 2019; 205:465-471. [PMID: 30446129 DOI: 10.1016/j.carbpol.2018.10.083] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Revised: 10/24/2018] [Accepted: 10/24/2018] [Indexed: 01/05/2023]
Abstract
Fucoidan from brown alga Fucus evanescens and its product of enzymatic hydrolysis have precisely established structure and possess significant biological activities. The aim of present study was to determine radiosensitizing activity of fucoidan from brown alga F. evanescens and its derivative in human melanoma, breast adenocarcinoma, and colorectal carcinoma cell lines and elucidate mechanism of their action. The fucoidan from F. evanescens and its derivative had a comparable radiosensitizing activity and increased the inhibiting effect of X-ray radiation on proliferation and colony formation of human cancer cells, with significant inhibition of melanoma cells. The molecular mechanism of this action was associated with the induction of apoptosis by activating the initiator and effector caspases, suppressing the expression of the anti-apoptotic protein, and enhancing the fragmentation of DNA. The obtained data confirm the prospects of using fucoidan's derivative in combination with radiation therapy for the improvement of the schemes of cancer therapy.
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Affiliation(s)
- O S Malyarenko
- Laboratory of Enzyme Chemistry, G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-Eastern Branch, Russian Academy of Sciences, Vladivostok, Russian Federation.
| | - E V Zdobnova
- Laboratory of Enzyme Chemistry, G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-Eastern Branch, Russian Academy of Sciences, Vladivostok, Russian Federation.
| | - A S Silchenko
- Laboratory of Enzyme Chemistry, G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-Eastern Branch, Russian Academy of Sciences, Vladivostok, Russian Federation.
| | - M I Kusaykin
- Laboratory of Enzyme Chemistry, G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-Eastern Branch, Russian Academy of Sciences, Vladivostok, Russian Federation.
| | - S P Ermakova
- Laboratory of Enzyme Chemistry, G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-Eastern Branch, Russian Academy of Sciences, Vladivostok, Russian Federation.
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14
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Yashavarddhan MH, Shukla SK, Chaudhary P, Srivastava NN, Joshi J, Suar M, Gupta ML. Targeting DNA Repair through Podophyllotoxin and Rutin Formulation in Hematopoietic Radioprotection: An in Silico, in Vitro, and in Vivo Study. Front Pharmacol 2017; 8:750. [PMID: 29163150 PMCID: PMC5671582 DOI: 10.3389/fphar.2017.00750] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 10/03/2017] [Indexed: 11/13/2022] Open
Abstract
Drug discovery field has tremendously progressed during last few decades, however, an effective radiation countermeasure agent for the safe administration to the victims of radiation exposure is still unavailable. This multi-model study is aimed at elucidating the mechanistic aspects of a novel podophyllotoxin and rutin combination (henceforth referred as G-003M) in the hematopoietic radioprotection and its involvement in the DNA damage and repair signaling pathways. Using in silico study, we identified the binding sites and structural components of G-003M and validated in vitro. We further studied various in vivo endpoints related to the DNA repair and cell death pathways in mice pre-administered with G-003M, irradiated and subsequently euthanized to collect blood and bone marrow cells. In silico study showed the binding of podophyllotoxin to β-tubulin and presence of a functional hydroxyl group in the rutin, suggested their involvement in G2/M arrest and the free radical scavenging respectively. This experimentation was further validated through in vitro studies. In vivo mice studies confirmed that G-003M pre-administration attenuated DNA damage and enhanced repair after whole body exposure. We further noticed a decrease in the levels of γH2AX, p53BP1, and ATM kinase and an increase in the levels of DNA pk, Ku 80, Ligase IV, Mre 11, Rad 50 and NBS 1 in the blood and bone marrow cells of the G-003M pre-administered and irradiated mice. We noticed an overall increase in the pro-survival factors in the G-003M pre-treated and irradiated groups establishing the radioprotective efficacy of this formulation. The lead obtained from this study will certainly help in developing this formulation as a safe and effective radioprotector which could be used for humans against any planned or emergency exposure of radiation.
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Affiliation(s)
- M H Yashavarddhan
- Division of Radioprotective Drug Development Research, Institute of Nuclear Medicine and Allied Sciences, Defence Research and Development Organization, Timarpur, India.,KIIT School of Biotechnology, KIIT University, Bhubaneswar, India
| | - Sandeep K Shukla
- Division of Radioprotective Drug Development Research, Institute of Nuclear Medicine and Allied Sciences, Defence Research and Development Organization, Timarpur, India
| | - Pankaj Chaudhary
- Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom
| | - Nitya N Srivastava
- Department of Pharmacology, University of Illinois at Chicago, Chicago, IL, United States
| | - Jayadev Joshi
- Division of Radioprotective Drug Development Research, Institute of Nuclear Medicine and Allied Sciences, Defence Research and Development Organization, Timarpur, India
| | - Mrutyunjay Suar
- KIIT School of Biotechnology, KIIT University, Bhubaneswar, India
| | - Manju L Gupta
- Division of Radioprotective Drug Development Research, Institute of Nuclear Medicine and Allied Sciences, Defence Research and Development Organization, Timarpur, India
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15
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Naseri S, Moghahi SMHN, Mokhtari T, Roghani M, Shirazi AR, Malek F, Rastegar T. Radio-Protective Effects of Melatonin on Subventricular Zone in Irradiated Rat: Decrease in Apoptosis and Upregulation of Nestin. J Mol Neurosci 2017; 63:198-205. [DOI: 10.1007/s12031-017-0970-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2017] [Accepted: 08/24/2017] [Indexed: 12/12/2022]
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16
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Tsoutsou P, Annibaldi A, Viertl D, Ollivier J, Buchegger F, Vozenin MC, Bourhis J, Widmann C, Matzinger O. TAT-RasGAP 317-326 Enhances Radiosensitivity of Human Carcinoma Cell Lines In Vitro and In Vivo through Promotion of Delayed Mitotic Cell Death. Radiat Res 2017; 187:562-569. [PMID: 28323576 DOI: 10.1667/rr14509.1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
The synthetic peptide TAT-RasGAP317-326 has been shown to potentiate the efficacy of anti-cancer drugs. In this study, we explored the action of TAT-RasGAP317-326 when combined with radiation by investigating its radiosensitizing activity in vitro and in vivo. To investigate the modulation of intrinsic radiosensitivity induced by TAT-RasGAP317-326, clonogenic assays were performed using four human cancer cell lines, HCT116 p53+/+ (ATCC: CCL-247), HCT116 p53-/-, PANC-1 (ATCC: CRL-1469) and HeLa (ATCC: CCL-2), as well as one nontumor cell line, HaCaT (CLS: 300493). Next, to investigate tumor growth delay after irradiation, HCT116 cell lines were selected and xenografted onto nude mice that were then treated with TAT-RasGAP317-326 alone or in combination with radiation or cisplatin. Afterwards, cell cycle and death modulation were investigated by quantification of micronuclei and apoptosis-related protein array. TAT-RasGAP317-326 radiosensitized all four human carcinoma cell lines tested but displayed no effect on normal cells. It also displayed no effect when administered as monotherapy. This radiosensitizing effect was confirmed in vivo in both p53-positive and p53-negative HCT116 xenografts. TAT-RasGAP317-326 combined with radiation enhanced the number of cells in S phase and subsequently delayed cell death, but had almost no effect on major apoptosis-related proteins. TAT-RasGAP317-326 is a radiosensitizing agent that acts on carcinoma cells and its radiosensitizing effect might be mediated, at least in part, by the enhancement of mitotic cell death.
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Affiliation(s)
- Pelagia Tsoutsou
- Department of a Radiation Oncology, Lausanne University Hospital, Lausanne, Switzerland.,c Laboratoire de Radio-Oncologie, CHUV, Lausanne, Switzerland.,e Department of Radiation Oncology, Hôpital Neuchâtelois, La Chaux-de-Fonds, Switzerland
| | | | - David Viertl
- Department of a Radiation Oncology, Lausanne University Hospital, Lausanne, Switzerland.,b Department of Nuclear Medicine, Lausanne University Hospital, Lausanne, Switzerland.,c Laboratoire de Radio-Oncologie, CHUV, Lausanne, Switzerland
| | | | - Franz Buchegger
- b Department of Nuclear Medicine, Lausanne University Hospital, Lausanne, Switzerland
| | | | - Jean Bourhis
- Department of a Radiation Oncology, Lausanne University Hospital, Lausanne, Switzerland
| | - Christian Widmann
- d Department of Physiology, University of Lausanne, Lausanne, Switzerland
| | - Oscar Matzinger
- Department of a Radiation Oncology, Lausanne University Hospital, Lausanne, Switzerland
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17
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Singh A, Yashavarddhan MH, Kalita B, Ranjan R, Bajaj S, Prakash H, Gupta ML. Podophyllotoxin and Rutin Modulates Ionizing Radiation-Induced Oxidative Stress and Apoptotic Cell Death in Mice Bone Marrow and Spleen. Front Immunol 2017; 8:183. [PMID: 28289414 PMCID: PMC5326804 DOI: 10.3389/fimmu.2017.00183] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Accepted: 02/08/2017] [Indexed: 12/11/2022] Open
Abstract
The present study is aimed to investigate the radioprotective efficacy of G-003M (combination of podophyllotoxin and rutin) against gamma radiation-induced oxidative stress and subsequent cell death in mice bone marrow and spleen. Prophylactic administration of G-003M (−1 h) rendered more than 85% survival in mice exposed to 9 Gy (lethal dose) with dose reduction factor of 1.26. G-003M pretreated mice demonstrated significantly reduced level of reactive oxygen species, membrane lipid peroxidation, and retained glutathione level. In the same group, we obtained increased expression of master redox regulator, nuclear factor erythroid-derived like-2 factor (Nrf-2), and its downstream targets (heme oxygenase-1, Nqo-1, glutathione S-transferase, and thioredoxin reductase-1). In addition, G-003M preadministration has also shown a significant reduction in Keap-1 level (Nrf-2 inhibitor). Radiation-induced lethality was significantly amended in combination-treated (G-003M) mice as demonstrated by reduced 8-OHdG, annexin V FITC+ cells, and restored mitochondrial membrane potential. Expression of antiapoptotic protein Bcl-2 and Bcl-xL was restored in G-003M pretreated group. However, proapoptotic proteins (Puma, Bax, Bak, Caspase-3, and Caspase-7) were significantly declined in this group. Further analysis of immune cells revealed G-003M-mediated restoration of CD3 and CD19 receptor, which was found decreased to significant level following irradiation. Similarly, Gr-1, a marker of granulocytes, was also retained by G-003M administration prior to radiation. Modulatory potential of this formulation (G-003M) can be exploited as a safe and effective countermeasure against radiation-induced lymphohemopoietic injury.
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Affiliation(s)
- Abhinav Singh
- Division of Radioprotective Drug Development and Research, Institute of Nuclear Medicine and Allied Sciences, Defense Research and Development Organization , Delhi , India
| | - M H Yashavarddhan
- Division of Radioprotective Drug Development and Research, Institute of Nuclear Medicine and Allied Sciences, Defense Research and Development Organization , Delhi , India
| | - Bhargab Kalita
- Division of Radioprotective Drug Development and Research, Institute of Nuclear Medicine and Allied Sciences, Defense Research and Development Organization , Delhi , India
| | - Rajiv Ranjan
- Division of Radioprotective Drug Development and Research, Institute of Nuclear Medicine and Allied Sciences, Defense Research and Development Organization , Delhi , India
| | - Sania Bajaj
- Division of Radioprotective Drug Development and Research, Institute of Nuclear Medicine and Allied Sciences, Defense Research and Development Organization , Delhi , India
| | - Hridayesh Prakash
- Translational Medicine Laboratory, School of Life Sciences, University of Hyderabad , Hyderabad , India
| | - Manju Lata Gupta
- Division of Radioprotective Drug Development and Research, Institute of Nuclear Medicine and Allied Sciences, Defense Research and Development Organization , Delhi , India
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18
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Avan A, Narayan R, Giovannetti E, Peters GJ. Role of Akt signaling in resistance to DNA-targeted therapy. World J Clin Oncol 2016; 7:352-369. [PMID: 27777878 PMCID: PMC5056327 DOI: 10.5306/wjco.v7.i5.352] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Revised: 06/25/2016] [Accepted: 07/29/2016] [Indexed: 02/06/2023] Open
Abstract
The Akt signal transduction pathway controls most hallmarks of cancer. Activation of the Akt cascade promotes a malignant phenotype and is also widely implicated in drug resistance. Therefore, the modulation of Akt activity is regarded as an attractive strategy to enhance the efficacy of cancer therapy and irradiation. This pathway consists of phosphatidylinositol 3 kinase (PI3K), mammalian target of rapamycin, and the transforming serine-threonine kinase Akt protein isoforms, also known as protein kinase B. DNA-targeted agents, such as platinum agents, taxanes, and antimetabolites, as well as radiation have had a significant impact on cancer treatment by affecting DNA replication, which is aberrantly activated in malignancies. However, the caveat is that they may also trigger the activation of repairing mechanisms, such as upstream and downstream cascade of Akt survival pathway. Thus, each target can theoretically be inhibited in view of improving the potency of conventional treatment. Akt inhibitors, e.g., MK-2206 and perifosine, or PI3K modulators, e.g., LY294002 and Wortmannin, have shown some promising results in favor of sensitizing the cancer cells to the therapy in vitro and in vivo, which have provided the rationale for incorporation of these novel agents into multimodality treatment of different malignancies. Nevertheless, despite the acceptable safety profile of some of these agents in the clinical studies, with regard to the efficacy, the results are still too preliminary. Hence, we need to wait for the upcoming data from the ongoing trials before utilizing them into the standard care of cancer patients.
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19
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Targeted radiotherapy potentiates the cytotoxicity of a novel anti-human DR5 monoclonal antibody and the adenovirus encoding soluble TRAIL in prostate cancer. J Egypt Natl Canc Inst 2015; 27:205-15. [DOI: 10.1016/j.jnci.2015.08.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2015] [Revised: 08/26/2015] [Accepted: 08/27/2015] [Indexed: 11/23/2022] Open
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20
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Nambiar DK, Rajamani P, Deep G, Jain AK, Agarwal R, Singh RP. Silibinin Preferentially Radiosensitizes Prostate Cancer by Inhibiting DNA Repair Signaling. Mol Cancer Ther 2015; 14:2722-34. [PMID: 26516160 DOI: 10.1158/1535-7163.mct-15-0348] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Accepted: 09/23/2015] [Indexed: 12/21/2022]
Abstract
Radiotherapy, a frequent mode of cancer treatment, is often restricted by dose-related toxicity and development of therapeutic resistance. To develop a novel and selective radiosensitizer, we studied the radiosensitizing effects and associated mechanisms of silibinin in prostate cancer. The radiosensitizing effect of silibinin with ionizing radiation (IR) was assessed on radioresistant prostate cancer cell lines by clonogenic, cell cycle, cell death, and DNA repair assays. Tumor xenograft growth, immunohistochemical (IHC) analysis of tumor tissues, and toxicity-related parameters were measured in vivo. Silibinin (25 μmol/L) enhanced IR (2.5-10 Gy)-caused inhibition (up to 96%, P < 0.001) of colony formation selectively in prostate cancer cells, and prolonged and enhanced IR-caused G2-M arrest, apoptosis, and ROS production. Mechanistically, silibinin inhibited IR-induced DNA repair (ATM and Chk1/2) and EGFR signaling and attenuated the levels of antiapoptotic proteins. Specifically, silibinin suppressed IR-induced nuclear translocation of EGFR and DNA-PK, an important mediator of DSB repair, leading to an increased number of γ-H2AX (ser139) foci suggesting lesser DNA repair. In vivo, silibinin strongly radiosensitized DU145 tumor xenograft inhibition (84%, P < 0.01) with higher apoptotic response (10-fold, P < 0.01) and reduced repair of DNA damage, and rescued the mice from IR-induced toxicity and hematopoietic injury. Overall, silibinin enhanced the radiotherapeutic response via suppressing IR-induced prosurvival signaling and DSB repair by inhibiting nuclear translocation of EGFR and DNA-PK. Because silibinin is already in phase II clinical trial for prostate cancer patients, the present finding has translational relevance for radioresistant prostate cancer.
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Affiliation(s)
- Dhanya K Nambiar
- Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India. School of Environmental Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Paulraj Rajamani
- School of Environmental Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Gagan Deep
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado
| | - Anil K Jain
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado
| | - Rajesh Agarwal
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado
| | - Rana P Singh
- Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India. School of Life Sciences, Central University of Gujarat, Gandhinagar, India.
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21
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Kostadinova A, Topouzova-Hristova T, Momchilova A, Tzoneva R, Berger MR. Antitumor Lipids--Structure, Functions, and Medical Applications. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2015; 101:27-66. [PMID: 26572975 DOI: 10.1016/bs.apcsb.2015.08.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Cell proliferation and metastasis are considered hallmarks of tumor progression. Therefore, efforts have been made to develop novel anticancer drugs that inhibit both the proliferation and the motility of tumor cells. Synthetic antitumor lipids (ATLs), which are chemically divided into two main classes, comprise (i) alkylphospholipids (APLs) and (ii) alkylphosphocholines (APCs). They represent a new entity of drugs with distinct antiproliferative properties in tumor cells. These compounds do not interfere with the DNA or mitotic spindle apparatus of the cell, instead, they incorporate into cell membranes, where they accumulate and interfere with lipid metabolism and lipid-dependent signaling pathways. Recently, it has been shown that the most commonly studied APLs inhibit proliferation by inducing apoptosis in malignant cells while leaving normal cells unaffected and are potent sensitizers of conventional chemo- and radiotherapy, as well as of electrical field therapy. APLs resist catabolic degradation to a large extent, therefore accumulate in the cell and interfere with lipid-dependent survival signaling pathways, notably PI3K-Akt and Raf-Erk1/2, and de novo phospholipid biosynthesis. They are internalized in the cell membrane via raft domains and cause downstream reactions as inhibition of cell growth and migration, cell cycle arrest, actin stress fibers collapse, and apoptosis. This review summarizes the in vitro, in vivo, and clinical trials of most common ATLs and their mode of action at molecular and biochemical levels.
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Affiliation(s)
- Aneliya Kostadinova
- Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Sofia, Bulgaria.
| | | | - Albena Momchilova
- Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Sofia, Bulgaria
| | - Rumiana Tzoneva
- Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Sofia, Bulgaria.
| | - Martin R Berger
- German Cancer Research Center, Toxicology and Chemotherapy Unit, Heidelberg, Germany
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22
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Wang G, Wang JJ, To TSS, Zhao HF, Wang J. Role of SIRT1-mediated mitochondrial and Akt pathways in glioblastoma cell death induced by Cotinus coggygria flavonoid nanoliposomes. Int J Nanomedicine 2015; 10:5005-23. [PMID: 26345416 PMCID: PMC4531020 DOI: 10.2147/ijn.s82282] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Flavonoids, the major polyphenol components in Cotinus coggygria (CC), have been found to show an anticancer effect in our previous study; however, the exact mechanisms of inducing human glioblastoma (GBM) cell death remain to be resolved. In this study, a novel polyvinylpyrrolidone K-30/sodium dodecyl sulfate and polyethyleneglycol-coated liposome loaded with CC flavonoids (CCFs) was developed to enhance solubility and the antibrain tumor effect, and the molecular mechanism regarding how CCF nanoliposomes (CCF-NLs) induce apoptotic cell death in vitro was investigated. DBTRG-05MG GBM cell lines treated with CCF-NLs showed potential antiproliferative effects. Regarding the underlying mechanisms of inducing apoptosis in DBTRG-05MG GBM cells, CCF-NLs were shown to downregulate the expression of antiapoptotic B-cell lymphoma/leukemia 2 (Bcl-2), an apoptosis-related protein family member, but the expression of proapoptotic Bcl-2-associated X protein was enhanced compared with that in controls. CCF-NLs also inhibited the activity of caspase-3 and -9, which is the initiator caspase of the extrinsic and intrinsic apoptotic pathways. Blockade of caspase activation consistently induced apoptosis and inhibited growth in CCF-NL-treated DBTRG-05MG cells. This study further investigated the role of the Akt pathway in the apoptotic cell death by CCF-NLs, showing that CCF-NLs deactivated Akt. Specifically, CCF-NLs downregulated the expression of p-Akt and SIRT1 as well as the level of phosphorylated p53. Together, these results indicated SIRT1/p53-mediated cell death was induced by CCF-NLs, but not by extracellular signal-regulated kinase, in DBTRG-05MG cells. Overall, this study suggested caspase-dependent activation of both the intrinsic and extrinsic signaling pathways, probably through blockade of the SIRT1/p53-mediated mitochondrial and Akt pathways to exert the proapoptotic effect of CCF-NLs in DBTRG-05MG GBM cells.
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Affiliation(s)
- Gang Wang
- Department of Pharmaceutics, Shanghai Eighth People's Hospital, Shanghai, People's Republic of China ; College of Pharmacy, Hubei University of Medicine, Shiyan, Hubei Province, People's Republic of China
| | - Jun Jie Wang
- Department of Pharmaceutics, Shanghai Eighth People's Hospital, Shanghai, People's Republic of China ; College of Pharmacy, Hubei University of Medicine, Shiyan, Hubei Province, People's Republic of China
| | - Tony S S To
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, People's Republic of China
| | - Hua Fu Zhao
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, People's Republic of China
| | - Jing Wang
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, People's Republic of China
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Chang L, Graham PH, Ni J, Hao J, Bucci J, Cozzi PJ, Li Y. Targeting PI3K/Akt/mTOR signaling pathway in the treatment of prostate cancer radioresistance. Crit Rev Oncol Hematol 2015; 96:507-17. [PMID: 26253360 DOI: 10.1016/j.critrevonc.2015.07.005] [Citation(s) in RCA: 147] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Revised: 05/20/2015] [Accepted: 07/08/2015] [Indexed: 12/19/2022] Open
Abstract
The phosphatidylinositol-3-kinase/Akt and the mammalian target of rapamycin (PI3K/Akt/mTOR) pathway is one of the most frequently activated signaling pathways in prostate cancer (CaP) and other cancers, and responsible for the survival, metastasis and therapeutic resistance. Recent advances in radiation therapy indicate that activation of this pathway is closely associated with cancer radioresistance, which is a major challenge for the current CaP radiation treatment. Therefore, targeting this pathway by inhibitors to enhance radiosensitivity has great potential for clinical benefits of CaP patients. In this review, we summarize the recent findings in the PI3K/Akt/mTOR pathway in CaP radiotherapy research and discuss the potential use of the PI3K/Akt/mTOR pathway inhibitors as radiosensitizers in the treatment of CaP radioresistance in preclinical studies to explore novel approaches for future clinical trials.
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Affiliation(s)
- Lei Chang
- Cancer Care Centre and Prostate Cancer Institute, St. George Hospital, Sydney, NSW, Australia; St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Kensington, NSW, Australia
| | - Peter H Graham
- Cancer Care Centre and Prostate Cancer Institute, St. George Hospital, Sydney, NSW, Australia; St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Kensington, NSW, Australia
| | - Jie Ni
- Cancer Care Centre and Prostate Cancer Institute, St. George Hospital, Sydney, NSW, Australia; St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Kensington, NSW, Australia
| | - Jingli Hao
- Cancer Care Centre and Prostate Cancer Institute, St. George Hospital, Sydney, NSW, Australia; St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Kensington, NSW, Australia
| | - Joseph Bucci
- Cancer Care Centre and Prostate Cancer Institute, St. George Hospital, Sydney, NSW, Australia; St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Kensington, NSW, Australia
| | - Paul J Cozzi
- St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Kensington, NSW, Australia; Department of Surgery, St. George Hospital, Sydney, NSW, Australia
| | - Yong Li
- Cancer Care Centre and Prostate Cancer Institute, St. George Hospital, Sydney, NSW, Australia; St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Kensington, NSW, Australia.
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Nambiar DK, Rajamani P, Singh RP. Silibinin attenuates ionizing radiation-induced pro-angiogenic response and EMT in prostate cancer cells. Biochem Biophys Res Commun 2014; 456:262-8. [PMID: 25446081 DOI: 10.1016/j.bbrc.2014.11.069] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Accepted: 11/18/2014] [Indexed: 01/31/2023]
Abstract
Radiotherapy of is well established and frequently utilized in prostate cancer (PCa) patients. However, recurrence following therapy and distant metastases are commonly encountered problems. Previous studies underline that, in addition to its therapeutic effects, ionizing radiation (IR) increases the vascularity and invasiveness of surviving radioresistant cancer cells. This invasive phenotype of radioresistant cells is an upshot of IR-induced pro-survival and mitogenic signaling in cancer as well as endothelial cells. Here, we demonstrate that a plant flavonoid, silibinin can radiosensitize endothelial cells by inhibiting expression of pro-angiogenic factors. Combining silibinin with IR not only strongly down-regulated endothelial cell proliferation, clonogenicity and tube formation ability rather it strongly (p<0.001) reduced migratory and invasive properties of PCa cells which were otherwise marginally affected by IR treatment alone. Most of the pro-angiogenic (VEGF, iNOS), migratory (MMP-2) and EMT promoting proteins (uPA, vimentin, N-cadherin) were up-regulated by IR in PCa cells. Interestingly, all of these invasive and EMT promoting actions of IR were markedly decreased by silibinin. Further, we found that potentiated effect was an end result of attenuation of IR-activated mitogenic and pro-survival signaling, including Akt, Erk1/2 and STAT-3, by silibinin.
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Affiliation(s)
- Dhanya K Nambiar
- Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India; School of Environmental Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Paulraj Rajamani
- School of Environmental Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Rana P Singh
- Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India; School of Life Sciences, Central University of Gujarat, Gandhinagar, India.
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25
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Su CL, Wang YT, Chang MH, Fang K, Chen K. The novel heterocyclic trioxirane [(1,3,5-tris oxiran-2-yl)methyl)-1,3,5-triazinane-2,4,6-trione (TATT)] exhibits a better anticancer effect than platinum-based chemotherapy by induction of apoptosis and curcumin further enhances its chemosensitivity. Cell Biochem Biophys 2014; 68:597-609. [PMID: 24078402 DOI: 10.1007/s12013-013-9752-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The heterocyclic trioxirane compound [1,3,5-tris((oxiran-2-yl)methyl)-1,3,5-triazinane-2,4,6-trione (TATT)] is a synthetic compound which has been used as an experimental anticancer agent in human clinical trials. Curcumin, an active natural compound in turmeric and curry, is an ingredient commonly used in the traditional diet of many Asian countries. In the present study, we observed that TATT exhibited a better anticancer effect on chemoresistant human colorectal cancer HT-29 cells and displayed less cytotoxicity on normal human umbilical vein endothelial cells, compared with FDA-approved anticancer drugs (cisplatin, carboplatin, or oxaliplatin) using MTT assay. TATT also induced a stronger apoptotic effect than that seen with the three studied anticancer drugs, as characterized by externalization of phosphatidylserine using flow cytometry. Administration of caspase 8-specific inhibitor (z-IETD-fmk) and mitochondrial permeability transition pore inhibitor (cyclosporin A) demonstrated that TATT-induced apoptosis proceeded via both extrinsic and intrinsic signaling pathways. It is noteworthy that coadministration of curcumin further significantly increased TATT-induced cytotoxicity, externalization of phosphatidylserine (representing early apoptosis), and the percentages of cells at the sub-G1 phase (representing late apoptosis), producing an additivity and/or synergistic effect, and vice versa. Suppression of nuclear NF-κB was involved in curcumin-enhanced chemosensitivity of TATT. Overall, our data indicate that TATT exerts a chemotherapeutic effect on colorectal cancer cells and coadministration of curcumin enhances the treatment effect of TATT.
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Affiliation(s)
- Chun-Li Su
- Department of Human Development and Family Studies, National Taiwan Normal University, No. 162, Sec. 1, He-ping East Road, Taipei, 106, Taiwan,
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26
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Pintea B, Kinfe TM, Baumert BG, Boström J. Earlier and sustained response with incidental use of cardiovascular drugs among patients with low- to medium-grade meningiomas treated with radiosurgery (SRS) or stereotactic radiotherapy (SRT). Radiother Oncol 2014; 111:446-50. [PMID: 24998705 DOI: 10.1016/j.radonc.2014.05.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2014] [Revised: 05/05/2014] [Accepted: 05/13/2014] [Indexed: 12/26/2022]
Abstract
BACKGROUND AND PURPOSE Beneficial outcome for cancer treated with radiotherapy (RT) and β-blockers has been reported. We hypothesize a potential combined impact of stereotactic RT with incidental use of cardiovascular drugs also in meningiomas. MATERIALS AND METHODS In 64 patients with 70 intracranial meningiomas (male/female=17/53; median follow-up=2 years) from a prospective database with sustained RT/cardiovascular drug therapy tumor response (progression, stable disease, regression) was evaluated at predefined follow-up intervals of 3, 12 and 24 months based on MR-imaging. For this retrospective cohort analysis stepwise univariate and multivariate analyses for group comparison were performed. Between groups analysis and stepwise uni- and multivariate analysis was performed. RESULTS At one year follow-up there was a significant better tumor response for patients with antihypertensives use (p=0.008) and radiosurgery (SRS) (p=0.054), the difference between patients with and without antihypertensive medication remains significant in multivariate analysis. Two years after RT, only patients with β-blocker use had a significant better response to RT (p=0.032). Additionally, for the use of β-blockers a trend toward significance for early tumor response at 3 months compared to the control group was observed (p(one tailed)=0.059). CONCLUSIONS Our data suggest that concomitant antihypertensive medication (especially β-blockers) may lead to an earlier and sustained response in stereotactic irradiated low- to medium-grade intracranial meningiomas by affecting the β-adrenergic pathways.
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Affiliation(s)
- Bogdan Pintea
- Department of Neurosurgery, University of Bonn Medical Center, Germany
| | - Thomas M Kinfe
- Department of Neurosurgery, University of Bonn Medical Center, Germany
| | - Brigitta G Baumert
- Department of Radiosurgery and Stereotactic Radiotherapy, MediClin Robert Janker Clinic, Bonn, Germany; Clinical Cooperation Unit Neurooncology, MediClin Robert Janker Clinic & University of Bonn Medical Center, Germany
| | - Jan Boström
- Department of Neurosurgery, University of Bonn Medical Center, Germany; Department of Radiosurgery and Stereotactic Radiotherapy, MediClin Robert Janker Clinic, Bonn, Germany; Clinical Cooperation Unit Neurooncology, MediClin Robert Janker Clinic & University of Bonn Medical Center, Germany.
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27
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Hong CE, Park AK, Lyu SY. Synergistic anticancer effects of lectin and doxorubicin in breast cancer cells. Mol Cell Biochem 2014; 394:225-35. [PMID: 24878989 DOI: 10.1007/s11010-014-2099-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Accepted: 05/15/2014] [Indexed: 01/02/2023]
Abstract
We studied the effects, either combined or alone, of lectin from Korean mistletoe (Viscum album var. coloratum agglutinin, VCA) and doxorubicin (DOX) in MCF-7 (estrogen receptor-positive) and MDA-MB231 (estrogen receptor-negative) human breast cancer cells. When VCA and DOX were combined, a strong synergistic effect was shown in cell growth inhibition, compared to VCA or DOX treatment alone. In quantitative apoptosis studies analyzed by flow cytometry, a combination of two agents showed an increase in apoptosis in both cells, compared to agents alone. Also, pro-apoptotic proteins including Bax, Bik, and Puma were increased in both cells, and the survival factor Bcl-2 was inhibited in MCF-7 cells when drugs were combined. Furthermore, VCA combined with DOX mediated S phase arrest, accompanied with a decrease of cell number at G0/G1 phase. This suggests that VCA and DOX combination may possibly lead to a novel strategy for the treatment of breast cancer.
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Affiliation(s)
- Chang-Eui Hong
- Department of Biology, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju, 500-757, Korea
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28
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Claro S, Oshiro MEM, Mortara RA, Paredes-Gamero EJ, Pereira GJS, Smaili SS, Ferreira AT. γ-Rays-generated ROS induce apoptosis via mitochondrial and cell cycle alteration in smooth muscle cells. Int J Radiat Biol 2014; 90:914-27. [DOI: 10.3109/09553002.2014.911988] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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29
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Wang G, Wang JJ, Chen XL, Du SM, Li DS, Pei ZJ, Lan H, Wu LB. The JAK2/STAT3 and mitochondrial pathways are essential for quercetin nanoliposome-induced C6 glioma cell death. Cell Death Dis 2013; 4:e746. [PMID: 23907460 PMCID: PMC3763427 DOI: 10.1038/cddis.2013.242] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2013] [Revised: 06/02/2013] [Accepted: 06/03/2013] [Indexed: 01/12/2023]
Abstract
The formulation of quercetin nanoliposomes (QUE-NLs) has been shown to enhance QUE antitumor activity in C6 glioma cells. At high concentrations, QUE-NLs induce necrotic cell death. In this study, we probed the molecular mechanisms of QUE-NL-induced C6 glioma cell death and examined whether QUE-NL-induced programmed cell death involved Bcl-2 family and mitochondrial pathway through STAT3 signal transduction pathway. Downregulation of Bcl-2 and the overexpression of Bax by QUE-NL supported the involvement of Bcl-2 family proteins upstream of C6 glioma cell death. In addition, the activation of JAK2 and STAT3 were altered following exposure to QUE-NLs in C6 glioma cells, suggesting that QUE-NLs downregulated Bcl-2 mRNAs expression and enhanced the expression of mitochondrial mRNAs through STAT3-mediated signaling pathways either via direct or indirect mechanisms. There are several components such as ROS, mitochondrial, and Bcl-2 family shared by the necrotic and apoptotic pathways. Our studies indicate that the signaling cross point of the mitochondrial pathway and the JAK2/STAT3 signaling pathway in C6 glioma cell death is modulated by QUE-NLs. In conclusion, regulation of JAK2/STAT3 and ROS-mediated mitochondrial pathway agonists alone or in combination with treatment by QUE-NLs could be a more effective method of treating chemical-resistant glioma.
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Affiliation(s)
- G Wang
- Department of Pharmacy, Taihe Hospital, Hubei University of Medicine, Shiyan City, Hubei Province, People's Republic of China
| | - J J Wang
- Department of Pharmacy, Taihe Hospital, Hubei University of Medicine, Shiyan City, Hubei Province, People's Republic of China
| | - X L Chen
- Hubei Provincial Key Laboratory of Embryo Stem Cells, Shiyan City, Hubei Province, People's Republic of China
| | - S M Du
- Department of Pharmacy, Taihe Hospital, Hubei University of Medicine, Shiyan City, Hubei Province, People's Republic of China
| | - D S Li
- Hubei Provincial Key Laboratory of Embryo Stem Cells, Shiyan City, Hubei Province, People's Republic of China
| | - Z J Pei
- Hubei Provincial Key Laboratory of Embryo Stem Cells, Shiyan City, Hubei Province, People's Republic of China
| | - H Lan
- Department of Pharmacy, Taihe Hospital, Hubei University of Medicine, Shiyan City, Hubei Province, People's Republic of China
| | - L B Wu
- Hubei Provincial Key Laboratory of Embryo Stem Cells, Shiyan City, Hubei Province, People's Republic of China
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30
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Xuejiao S, Yong X, Ningyu W, Lidan Z, Xuanhong S, Youzhi X, Tinghong Y, Yaojie S, Yongxia Z, Luoting Y. A novel benzothiazole derivative YLT322 induces apoptosis via the mitochondrial apoptosis pathway in vitro with anti-tumor activity in solid malignancies. PLoS One 2013; 8:e63900. [PMID: 23737957 PMCID: PMC3667852 DOI: 10.1371/journal.pone.0063900] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2012] [Accepted: 04/08/2013] [Indexed: 02/05/2023] Open
Abstract
Benzothiazole derivatives are known for various biological activities, and their potency in cancer therapy has received considerable attention in recent years. YLT322, a novel synthesized benzothiazole derivative, exhibits potent anti-tumor activity via inducing apoptosis both in vitro and in vivo. In this study, we found that YLT322 showed growth inhibition against a broad spectrum of human cancer cells and induced apoptosis of HepG2 cells in a dose- and time-dependent manner. The occurrence of its apoptosis was associated with activation of caspases-3 and -9, but not caspase-8. YLT322 increased the expression of Bax, decreased the expression of Bcl-2, and induced the release of cytochrome c which activates the mitochondrial apoptotic pathway. The down-regulation of phosphorylated p42/44 MAPK and phosphorylated Akt was also observed. Moreover, YLT322 suppressed the growth of established tumors in xenograft models in mice without obvious side effects. Histological and immunohistochemical analyses revealed an increase in TUNEL and caspase-3-positive cells and a decrease in Ki67-positive cells upon YLT322. These results suggest that YLT322 may be a potential candidate for cancer therapy.
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Affiliation(s)
- Song Xuejiao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Xia Yong
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Wang Ningyu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Zhang Lidan
- Department of Pharmaceutical and Bioengineering, School of Chemical Engineering, Sichuan University, Chengdu, China
| | - Shi Xuanhong
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Xu Youzhi
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Ye Tinghong
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Shi Yaojie
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Zhu Yongxia
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Yu Luoting
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
- * E-mail:
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Schedule-dependent interactions between perifosine and radiotherapy in prostate cancer. ACTA ACUST UNITED AC 2013. [DOI: 10.1007/s13566-013-0101-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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32
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Estrogen inhibits renal cell carcinoma cell progression through estrogen receptor-β activation. PLoS One 2013; 8:e56667. [PMID: 23460808 PMCID: PMC3584057 DOI: 10.1371/journal.pone.0056667] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2012] [Accepted: 01/12/2013] [Indexed: 01/22/2023] Open
Abstract
Renal cell carcinoma (RCC) originates in the lining of the proximal convoluted tubule and accounts for approximately 3% of adult malignancies. The RCC incidence rate increases annually and is twofold higher in males than in females. Female hormones such as estrogen may play important roles during RCC carcinogenesis and result in significantly different incidence rates between males and females. In this study, we found that estrogen receptor β (ERβ) was more highly expressed in RCC cell lines (A498, RCC-1, 786-O, ACHN, and Caki-1) than in breast cancer cell lines (MCF-7 and HBL-100); however, no androgen receptor (AR) or estrogen receptor α (ERα) could be detected by western blot. In addition, proliferation of RCC cell lines was significantly decreased after estrogen (17-β-estradiol, E2) treatment. Since ERβ had been documented to be a potential tumor suppressor gene, we hypothesized that estrogen activates ERβ tumor suppressive function, which leads to different RCC incidence rates between males and females. We found that estrogen treatment inhibited cell proliferation, migration, invasion, and increased apoptosis of 786-O (high endogenous ERβ), and ERβ siRNA-induced silencing attenuated the estrogen-induced effects. Otherwise, ectopic ERβ expression in A498 (low endogenous ERβ) increased estrogen sensitivity and thus inhibited cell proliferation, migration, invasion, and increased apoptosis. Analysis of the molecular mechanisms revealed that estrogen-activated ERβ not only remarkably reduced growth hormone downstream signaling activation of the AKT, ERK, and JAK signaling pathways but also increased apoptotic cascade activation. In conclusion, this study found that estrogen-activated ERβ acts as a tumor suppressor. It may explain the different RCC incidence rates between males and females. Furthermore, it implies that ERβ may be a useful prognostic marker for RCC progression and a novel developmental direction for RCC treatment improvement.
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Anticancer mechanisms and clinical application of alkylphospholipids. Biochim Biophys Acta Mol Cell Biol Lipids 2012; 1831:663-74. [PMID: 23137567 DOI: 10.1016/j.bbalip.2012.10.008] [Citation(s) in RCA: 114] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2012] [Revised: 10/28/2012] [Accepted: 10/29/2012] [Indexed: 11/20/2022]
Abstract
Synthetic alkylphospholipids (ALPs), such as edelfosine, miltefosine, perifosine, erucylphosphocholine and erufosine, represent a relatively new class of structurally related antitumor agents that act on cell membranes rather than on DNA. They selectively target proliferating (tumor) cells, inducing growth arrest and apoptosis, and are potent sensitizers of conventional chemo- and radiotherapy. ALPs easily insert in the outer leaflet of the plasma membrane and cross the membrane via an ATP-dependent CDC50a-containing 'flippase' complex (in carcinoma cells), or are internalized by lipid raft-dependent endocytosis (in lymphoma/leukemic cells). ALPs resist catabolic degradation, therefore accumulate in the cell and interfere with lipid-dependent survival signaling pathways, notably PI3K-Akt and Raf-Erk1/2, and de novo phospholipid biosynthesis. At the same time, stress pathways (e.g. stress-activated protein kinase/JNK) are activated to promote apoptosis. In many preclinical and clinical studies, perifosine was the most effective ALP, mainly because it inhibits Akt activity potently and consistently, also in vivo. This property is successfully exploited clinically in highly malignant tumors, such as multiple myeloma and neuroblastoma, in which a tyrosine kinase receptor/Akt pathway is amplified. In such cases, perifosine therapy is most effective in combination with conventional anticancer regimens or with rapamycin-type mTOR inhibitors, and may overcome resistance to these agents. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.
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Mohseni M, Mihandoost E, Shirazi A, Sepehrizadeh Z, Bazzaz JT, Ghazi-khansari M. Melatonin may play a role in modulation of bax and bcl-2 expression levels to protect rat peripheral blood lymphocytes from gamma irradiation-induced apoptosis. Mutat Res 2012; 738-739:19-27. [PMID: 22982225 DOI: 10.1016/j.mrfmmm.2012.08.006] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2012] [Revised: 08/07/2012] [Accepted: 08/30/2012] [Indexed: 12/16/2022]
Abstract
The close relationship between free radicals effects and apoptosis process has been proved. Melatonin has been reported as a direct free radical scavenger. We investigated the capability of melatonin in the modification of radiation-induced apoptosis and apoptosis-associated upstream regulators expression in rat peripheral blood lymphocytes. Rats were irradiated with a single whole body Cobalt 60-gamma radiation dose of 8Gy at a dose rate of 101cGy/min with or without melatonin pretreatments at different concentrations of 10 and 100mg/kg body weight. The rats were divided into eight groups of control, irradiation-only, vehicle-only, vehicle plus irradiation, 10mg/kg melatonin alone, 10mg/kg melatonin plus irradiation, 100mg/kg melatonin alone and 100mg/kg melatonin plus irradiation. Rats were given an intraperitoneal (IP) injection of melatonin or the same volume of vehicle alone 1h prior to irradiation. Blood samples were taken 4, 24, 48 and 72h after irradiation for evaluation of flow cytometric analysis of apoptotic lymphocytes using Annexin V/PI assay and measurement of bax and bcl-2 expression using quantitative real-time PCR (RT(2)qPCR). Irradiation-only and vehicle plus irradiation showed an increase in the percentage of apoptotic lymphocytes significantly different from control group (P<0.01), while melatonin pretreatments in a dose-dependent manner reduced it as compared with the irradiation-only and vehicle plus irradiation groups (P<0.01) in all time points. This reduced apoptosis by melatonin was related to the downregulation of bax, upregulation of bcl-2, and therefore reduction of bax/bcl-2 ratio. Our results suggest that melatonin in these doses may provide modulation of bax and bcl-2 expression as well as bax/bcl-2 ratio to protect rat peripheral blood lymphocytes from gamma irradiation-induced apoptosis.
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Affiliation(s)
- Mehran Mohseni
- Department of Radiology and Medical Physics, Kashan University of Medical Sciences, Kashan, Iran.
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Effect of all-trans retinoic acid on the growth of two nasopharyngeal cancer cell lines and its treatment potential in combination with cisplatin. Eur Arch Otorhinolaryngol 2012; 270:695-704. [DOI: 10.1007/s00405-012-2068-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2011] [Accepted: 05/24/2012] [Indexed: 10/27/2022]
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Abstract
Conventional external-beam radiation therapy is dedicated to the treatment of localized disease, whereas radioimmunotherapy represents an innovative tool for the treatment of local or diffuse tumors. Radioimmunotherapy involves the administration of radiolabeled monoclonal antibodies that are directed specifically against tumor-associated antigens or against the tumor microenvironment. Although many tumor-associated antigens have been identified as possible targets for radioimmunotherapy of patients with hematological or solid tumors, clinical success has so far been achieved mostly with radiolabeled antibodies against CD20 ((131)I-tositumomab and (90)Y-ibritumomab tiuxetan) for the treatment of lymphoma. In this Review, we provide an update on the current challenges aimed to improve the efficacy of radioimmunotherapy and discuss the main radiobiological issues associated with clinical radioimmunotherapy.
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Li Y, Zeng Y, Mooney SM, Yin B, Mizokami A, Namiki M, Getzenberg RH. Resistance to paclitaxel increases the sensitivity to other microenvironmental stresses in prostate cancer cells. J Cell Biochem 2011; 112:2125-37. [PMID: 21465536 DOI: 10.1002/jcb.23134] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The microenvironment is central to many aspects of cancer pathobiology and has been proposed to play a role in the development of cancer cell resistance to therapy. To examine the response to microenvironmental conditions, two paclitaxel resistant prostate cancer (PCa) cell lines (stable and reversible) and one reversible heat resistant cell line were studied. In comparison to their parental cell lines, both paclitaxel resistant cell lines (stable and reversible) were more sensitive to microenvironmental heat, potentially yielding a synergistic therapeutic opportunity. In the two phenotypic cells repopulated after acute heat or paclitaxel treatments, there was an inverse correlation between paclitaxel and heat resistance: resistance to paclitaxel imparted sensitivity to heat; resistance to heat imparted sensitivity to paclitaxel. These studies indicate that as cancer cells evolve resistance to single microenvironmental stress they may be more sensitive to others, perhaps allowing us to design new approaches for PCa therapy.
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Affiliation(s)
- Youqiang Li
- Department of Urology, James Buchanan Brady Urological Institute, The Johns Hopkins School of Medicine, Baltimore, Maryland 21287, USA
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Shimura T. Acquired radioresistance of cancer and the AKT/GSK3β/cyclin D1 overexpression cycle. JOURNAL OF RADIATION RESEARCH 2011; 52:539-544. [PMID: 21881296 DOI: 10.1269/jrr.11098] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
Fractionated radiotherapy (RT) is widely used in cancer therapy for its advantages in the preservation of normal tissues. However, repopulation of surviving tumor cells during fractionated RT limits the efficacy of RT. In fact, repopulating tumors often acquire radioresistance and this is the major cause of failure of RT. We have recently demonstrated that human tumor cells acquire radioresistance when exposed to fractionated radiation (FR) of X-rays every 12 hours for 1 month. The acquired radioresistance was associated with overexpression of cyclin D1, a result of a series of molecular changes; constitutive activation of DNA-PK and AKT with concomitant down-regulation of glycogen synthase kinase-3β (GSK3β) which results in suppression of cyclin D1 proteolysis. Aberrant cyclin D1 overexpression in S-phase induced DNA double strand breaks which activated DNA-PK and established the vicious cycle of cycling D1 overexpression. This overexpression of cyclin D1 is responsible for the radioresistance phenotype of long-term FR cells, since this phenotype was completely abrogated by treatment of FR cells by the API-2, an AKT inhibitor or by a Cdk4 inhibitor. Thus, targeting the AKT/GSK3β/cyclin D1/Cdk4 pathway can be an efficient modality to suppress acquired radioresistance of tumor cells. In this article, I overview the newly discovered molecular mechanisms underlying acquired radioresistance of tumor cells induced by FR, and propose a strategy for eradication of tumors using fractionated RT by overcoming tumor radioresistance.
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Affiliation(s)
- Tsutomu Shimura
- Department of Pathology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
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Wang T, Languino LR, Lian J, Stein G, Blute M, Fitzgerald TJ. Molecular targets for radiation oncology in prostate cancer. Front Oncol 2011; 1:17. [PMID: 22645712 PMCID: PMC3355820 DOI: 10.3389/fonc.2011.00017] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2011] [Accepted: 06/27/2011] [Indexed: 12/31/2022] Open
Abstract
Recent selected developments of the molecular science of prostate cancer (PrCa) biology and radiation oncology are reviewed. We present potential targets for molecular integration treatment strategies with radiation therapy (RT), and highlight potential strategies for molecular treatment in combination with RT for patient care. We provide a synopsis of the information to date regarding molecular biology of PrCa, and potential integrated research strategy for improved treatment of PrCa. Many patients with early-stage disease at presentation can be treated effectively with androgen ablation treatment, surgery, or RT. However, a significant portion of men are diagnosed with advanced stage/high-risk disease and these patients progress despite curative therapeutic intervention. Unfortunately, management options for these patients are limited and are not always successful including treatment for hormone refractory disease. In this review, we focus on molecules of extracellular matrix component, apoptosis, androgen receptor, RUNX, and DNA methylation. Expanding our knowledge of the molecular biology of PrCa will permit the development of novel treatment strategies integrated with RT to improve patient outcome.
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Affiliation(s)
- Tao Wang
- Department of Radiation Oncology, University of Massachusetts Medical School Worcester, MA, USA
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Shimura T, Kakuda S, Ochiai Y, Kuwahara Y, Takai Y, Fukumoto M. Targeting the AKT/GSK3β/Cyclin D1/Cdk4 Survival Signaling Pathway for Eradication of Tumor Radioresistance Acquired by Fractionated Radiotherapy. Int J Radiat Oncol Biol Phys 2011; 80:540-8. [DOI: 10.1016/j.ijrobp.2010.12.065] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2010] [Revised: 12/18/2010] [Accepted: 12/20/2010] [Indexed: 11/30/2022]
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Wang H, Song X, Zhang H, Zhang J, Shen X, Zhou Y, Fan X, Dai L, Qian G, Hoffman AR, Hu JF, Ge S. Potentiation of tumor radiotherapy by a radiation-inducible oncolytic and oncoapoptotic adenovirus in cervical cancer xenografts. Int J Cancer 2011; 130:443-53. [PMID: 21351100 DOI: 10.1002/ijc.26013] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2010] [Accepted: 01/31/2011] [Indexed: 11/08/2022]
Abstract
The p53 tumor suppressor pathway is impaired in more than 90% of cervical cancers and cancer-derived cell lines as a result of infection by human papillomavirus (HPV). The HPV E6 oncoprotein forms complexes with p53 and promotes its degradation via ubiquitin-dependent mechanism. In our study, we attempted to improve the clinical outcomes of this combined therapy by modifying the p53-targeted adenovirus to become radiation-responsive. The antitumor adenovirus was constructed by inserting a radiation-responsive expression cassette composed of the promoter of early growth response-1 (Egr-1) and the proapoptotic protein TRAIL. We showed that the addition of adenovirus containing Egr-1/TRAIL significantly increased cell death and apoptosis caused by radiotherapy. In mice bearing xenograft tumors, intratumoral administration of the Egr-1/TRAIL adenovirus followed by radiation significantly reduced tumor growth and enhanced tumor survival. Our Egr-1/TRAIL adenoviral gene product may offer a novel "one-two punch" tumor therapy for cervical cancers not only by potentiating radiation treatment but also by preserving p53 defect-specific tumor killing of the oncolytic adenovirus.
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Affiliation(s)
- Haibo Wang
- Department of Biochemistry and Molecular Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, Peoples Republic of China
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Gao Y, Ishiyama H, Sun M, Brinkman KL, Wang X, Zhu J, Mai W, Huang Y, Floryk D, Ittmann M, Thompson TC, Butler EB, Xu B, Teh BS. The alkylphospholipid, perifosine, radiosensitizes prostate cancer cells both in vitro and in vivo. Radiat Oncol 2011; 6:39. [PMID: 21496273 PMCID: PMC3096921 DOI: 10.1186/1748-717x-6-39] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2010] [Accepted: 04/15/2011] [Indexed: 01/13/2023] Open
Abstract
Background Perifosine is a membrane-targeted alkylphospholipid developed to inhibit the PI3K/Akt pathway and has been suggested as a favorable candidate for combined use with radiotherapy. In this study, we investigated the effect of the combined treatment of perifosine and radiation (CTPR) on prostate cancer cells in vitro and on prostate cancer xenografts in vivo. Methods Human prostate cancer cell line, CWR22RV1, was treated with perifosine, radiation, or CTPR. Clonogenic survival assays, sulforhodamine B cytotoxity assays and cell density assays were used to assess the effectiveness of each therapy in vitro. Measurements of apoptosis, cell cycle analysis by flow cytometry and Western blots were used to evaluate mechanisms of action in vitro. Tumor growth delay assays were used to evaluate radiation induced tumor responses in vivo. Results In vitro, CTPR had greater inhibitory effects on prostate cancer cell viability and clonogenic survival than either perifosine or radiation treatment alone. A marked increase in prostate cancer cell apoptosis was noted in CTPR. Phosphorylation of AKT-T308 AKT and S473 were decreased when using perifosine treatment or CTPR. Cleaved caspase 3 was significantly increased in the CTPR group. In vivo, CTPR had greater inhibitory effects on the growth of xenografts when compared with perifosine or radiation treatment alone groups. Conclusions Perifosine enhances prostate cancer radiosensitivity in vitro and in vivo. These data provide strong support for further development of this combination therapy in clinical studies.
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Affiliation(s)
- Yuanhong Gao
- Department of Radiation Oncology, The Methodist Hospital Research Institute, Weill Cornell Medical College, Houston, TX 77030, USA
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Jendrossek V. Targeting apoptosis pathways by Celecoxib in cancer. Cancer Lett 2011; 332:313-24. [PMID: 21345578 DOI: 10.1016/j.canlet.2011.01.012] [Citation(s) in RCA: 136] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2010] [Revised: 12/23/2010] [Accepted: 01/01/2011] [Indexed: 12/19/2022]
Abstract
Celecoxib is a paradigmatic selective inhibitor of cyclooxygenase-2 (COX-2). This anti-inflammatory drug has potent anti-tumor activity in a wide variety of human epithelial tumor types, such as colorectal, breast, non-small cell lung, and prostate cancers. Up to now, the drug found application in cancer prevention in patients with familial adenomatous polyposis. Moreover, the use of Celecoxib is currently tested in the prevention and treatment of pancreatic, breast, ovarian, non-small cell lung cancer and other advanced human epithelial cancers. Induction of apoptosis contributes to the anti-neoplastic activity of Celecoxib. In most cellular systems Celecoxib induces apoptosis independently from its COX-2 inhibitory action via a mitochondrial apoptosis pathway which is however, not inhibited by overexpression of Bcl-2. In addition, Celecoxib exerts antagonistic effects on the anti-apoptotic proteins Mcl-1 and survivin. Consequently, the use of Celecoxib may be of specific value for the treatment of apoptosis-resistant tumors with overexpression of Bcl-2, Mcl-1, or survivin as single drug or in combination with radiotherapy, chemotherapy, or targeted pro-apoptotic drugs that are inhibited by survivin, Bcl-2 or Mcl-1. As COX-2 inhibition has been associated with cardiovascular toxicity, the value of drug derivatives without COX-2 inhibitory action should be validated for prevention and treatment of human epithelial tumors to reduce the risk for heart attack or stroke. However, its additional COX-2 inhibitory action may qualify Celecoxib for a cautious use in COX-2-dependent epithelial tumors, where the drug could additionally suppress COX-2-mediated growth and survival promoting signals from the tumor and the stromal cells.
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Affiliation(s)
- Verena Jendrossek
- Institute for Cell Biology (Cancer Research), Department of Molecular Cell Biology, University of Duisburg-Essen Medical School, Virchowstrasse 173, 45122 Essen, Germany.
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Peng Z, Xu ZW, Wen WS, Wang RS. Tea polyphenols protect against irradiation-induced injury in submandibular glands' cells: a preliminary study. Arch Oral Biol 2011; 56:738-43. [PMID: 21292239 DOI: 10.1016/j.archoralbio.2010.12.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2010] [Revised: 12/13/2010] [Accepted: 12/14/2010] [Indexed: 02/01/2023]
Abstract
AIM To study the protective effect of tea polyphenols (TPs) on submandibular glands affected by radiation injury. METHODS Sixty rats were randomly divided into radiation group (R-group, N = 30) and TP-pre-treated-radiation group (TPR-group, N = 30). The rats were intragastrically administered with TP or normal sodium from 14 days before radiation, continuously daily, until the experiment. All the rats in both groups were irradiated with a single exposure dose of 15 Gy gamma rays that were delivered to the head and neck areas. Ten rats of each group were anatomised on the 3rd, 6th and 30th day after irradiation, respectively. The submandibular glands of the rats were removed for the study. The morphologic changes of the submandibular glands were observed by transmission electron microscopy (TEM). The terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP)-biotin nick-end labelling (TUNEL) method was used to detect apoptosis of the submandibular glands' cells. RESULTS Electron microscope observation of the submandibular glands showed that the lesions of the TPR-group were mild. Change in apoptosis of the cells was not obvious compared with the R-group. The cell apotosis was typical after irradiation in the R-group. Apoptosis index that was detected in the cells of submandibular glands of the TPR-group was statistically significantly decreased compared with the R-group (P < 0.01) on the 3rd, 6th and 30th day after irradiation. CONCLUSION TP could protect submandibular glands from radiation injuries, and the protection mechanism may be realised by anti-apoptosis.
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Affiliation(s)
- Zhe Peng
- Department of Otolaryngology and Head and Neck Surgery, The First Affiliated Hospital, Guangxi Medical University, Shuangyong Road, Nanning 530021, Guangxi, China
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MEK-ERK-dependent multiple caspase activation by mitochondrial proapoptotic Bcl-2 family proteins is essential for heavy ion irradiation-induced glioma cell death. Cell Death Dis 2010; 1:e60. [PMID: 21364665 PMCID: PMC3039836 DOI: 10.1038/cddis.2010.37] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Recently developed heavy ion irradiation therapy using a carbon beam (CB) against systemic malignancy has numerous advantages. However, the clinical results of CB therapy against glioblastoma still have room for improvement. Therefore, we tried to clarify the molecular mechanism of CB-induced glioma cell death. T98G and U251 human glioblastoma cell lines were irradiated by CB, and caspase-dependent apoptosis was induced in both cell lines in a dose-dependent manner. Knockdown of Bax (BCL-2-associated X protein) and Bak (BCL-2-associated killer) and overexpression of Bcl-2 or Bcl-xl (B-cell lymphoma-extra large) showed the involvement of Bcl-2 family proteins upstream of caspase activation, including caspase-8, in CB-induced glioma cell death. We also detected the activation of extracellular signal-regulated kinase (ERK) and the knockdown of ERK regulator mitogen-activated protein kinase kinase (MEK)1/2 or overexpression of a dominant-negative (DN) ERK inhibited CB-induced glioma cell death upstream of the mitochondria. In addition, application of MEK-specific inhibitors for defined periods showed that the recovery of activation of ERK between 2 and 36 h after irradiation is essential for CB-induced glioma cell death. Furthermore, MEK inhibitors or overexpression of a DN ERK failed to significantly inhibit X-ray-induced T98G and U251 cell death. These results suggested that the MEK–ERK cascade has a crucial role in CB-induced glioma cell death, which is known to have a limited contribution to X-ray-induced glioma cell death.
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Jiang H, Cannon MJ, Banach M, Pinchuk AN, Ton GN, Scheuerell C, Longino MA, Weichert JP, Tollefson R, Clarke WR, Ji QC, Jiang X. Quantification of CLR1401, a novel alkylphosphocholine anticancer agent, in rat plasma by hydrophilic interaction liquid chromatography–tandem mass spectrometric detection. J Chromatogr B Analyt Technol Biomed Life Sci 2010; 878:1513-8. [DOI: 10.1016/j.jchromb.2010.04.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2009] [Revised: 03/20/2010] [Accepted: 04/03/2010] [Indexed: 10/19/2022]
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Kargiotis O, Geka A, Rao JS, Kyritsis AP. Effects of irradiation on tumor cell survival, invasion and angiogenesis. J Neurooncol 2010; 100:323-38. [PMID: 20449629 DOI: 10.1007/s11060-010-0199-4] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2010] [Accepted: 04/13/2010] [Indexed: 12/19/2022]
Abstract
Ionizing irradiation is a widely applied therapeutic method for the majority of solid malignant neoplasms, including brain tumors where, depending on localization, this might often be the only feasible primary intervention.Without doubt, it has been proved to be a fundamental tool available in the battlefield against cancer, offering a clear survival benefit in most cases. However, numerous studies have associated tumor irradiation with enhanced aggressive phenotype of the remaining cancer cells. A cell population manages to survive after the exposure, either because it receives sublethal doses and/or because it successfully utilizes the repair mechanisms. The biology of irradiated cells is altered leading to up-regulation of genes that favor cell survival, invasion and angiogenesis. In addition, hypoxia within the tumor mass limits the cytotoxicity of irradiation, whereas irradiation itself may worsen hypoxic conditions, which also contribute to the generation of resistant cells. Activation of cell surface receptors, such as the epidermal growth factor receptor, utilization of signaling pathways, and over-expression of cytokines, proteases and growth factors, for example the matrix metalloproteinases and vascular endothelial growth factor, protect tumor and non-tumor cells from apoptosis, increase their ability to invade to adjacent or distant areas, and trigger angiogenesis. This review will try to unfold the various molecular events and interactions that control tumor cell survival, invasion and angiogenesis and which are elicited or influenced by irradiation of the tumor mass, and to emphasize the importance of combining irradiation therapy with molecular targeting.
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Affiliation(s)
- Odysseas Kargiotis
- Neurosurgical Research Institute, University of Ioannina, Ioannina, Greece.
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Betulinic Acid a Radiosensitizer in Head and Neck Squamous Cell Carcinoma Cell Lines. Strahlenther Onkol 2010; 186:143-8. [DOI: 10.1007/s00066-010-2069-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2009] [Accepted: 12/22/2009] [Indexed: 10/19/2022]
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Verheij M, Vens C, van Triest B. Novel therapeutics in combination with radiotherapy to improve cancer treatment: Rationale, mechanisms of action and clinical perspective. Drug Resist Updat 2010; 13:29-43. [DOI: 10.1016/j.drup.2010.01.002] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2009] [Revised: 01/21/2010] [Accepted: 01/22/2010] [Indexed: 12/27/2022]
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Schoop RAL, Verdegaal EME, de Jong RJB, Noteborn MHM. Apoptin Enhances Radiation-Induced Cell Death in Poorly Responding Head and Neck Squamous Cell Carcinoma Cells. Basic Clin Pharmacol Toxicol 2010; 106:130-4. [PMID: 19874285 DOI: 10.1111/j.1742-7843.2009.00482.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
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