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Matsuoka I, Kasai T, Onaga C, Ozaki A, Motomura H, Maemura Y, Tada Y, Mori H, Hara Y, Xiong Y, Sato K, Tamori S, Sasaki K, Ohno S, Akimoto K. Co‑expression of SLC20A1 and ALDH1A3 is associated with poor prognosis, and SLC20A1 is required for the survival of ALDH1‑positive pancreatic cancer stem cells. Oncol Lett 2024; 28:426. [PMID: 39021737 PMCID: PMC11253103 DOI: 10.3892/ol.2024.14558] [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: 07/23/2023] [Accepted: 02/23/2024] [Indexed: 07/20/2024] Open
Abstract
Solute carrier family 20 member 1 (SLC20A1) is a sodium/inorganic phosphate symporter, which has been identified as a prognostic marker in several types of cancer, including pancreatic cancer. However, to the best of our knowledge, the association between SLC20A1 expression and cancer stem cell (CSC) markers, such as aldehyde dehydrogenase 1 (ALDH1), in pancreatic ductal adenocarcinoma (PDAC), and the role of SLC20A1 in PDAC CSCs remains unclear. In the present study, a genomic dataset of primary pancreatic cancer (The Cancer Genome Atlas, Pan-Cancer Atlas) was downloaded and analyzed. Kaplan-Meier analysis and multivariate Cox regression analysis were performed to evaluate the overall survival, disease-specific survival (DSS), disease-free interval (DFI) and progression-free interval (PFI). Subsequently, SLC20A1 small interfering RNA (siRNA) knockdown (KD) was induced in the PANC-1 and MIA-PaCa-2 PDAC cell lines, and in sorted high ALDH1 activity (ALDH1high) cells, after which, cell viability, in vitro tumor sphere formation, cell death and caspase-3 activity were examined. The results revealed that patients with high expression of SLC20A1 (SLC20A1 high) at tumor stage I had a poor prognosis compared with patients with low expression of SLC20A1 (SLC20A1 low) in terms of DSS, DFI and PFI. In addition, patients with high expression of SLC20A1 and ALDH1A3 (SLC20A1 high ALDH1A3 high) exhibited poorer clinical outcomes than patients with high expression of SLC20A1 and low expression of ALDH1A3 (SLC20A1 high ALDH1A3 low), low expression of SLC20A1 and high expression of ALDH1A3 (SLC20A1 low ALDH1A3 high) and SLC20A1 low ALDH1A3 low. SLC20A1 siRNA KD in ALDH1high cells isolated from PANC-1 and MIA-PaCa-2 cell lines resulted in suppression of in vitro tumorsphere formation, and enhancement of cell death and caspase-3 activity. These results suggested that SLC20A1 was involved in cell survival via the suppression of caspase-3-dependent apoptosis, and contributed to cancer progression and poor clinical outcomes in PDAC. In conclusion, SLC20A1 may be used as a prognostic marker and novel therapeutic target of ALDH1-positive pancreatic CSCs.
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Affiliation(s)
- Izumi Matsuoka
- Department of Medicinal and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan
| | - Takahiro Kasai
- Department of Medicinal and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan
| | - Chotaro Onaga
- Department of Medicinal and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan
| | - Ayaka Ozaki
- Department of Medicinal and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan
| | - Hitomi Motomura
- Department of Medicinal and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan
| | - Yuki Maemura
- Department of Medicinal and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan
| | - Yuna Tada
- Department of Medicinal and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan
| | - Haruka Mori
- Department of Medicinal and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan
| | - Yasushi Hara
- Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan
| | - Yuyun Xiong
- Department of Medicinal and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan
| | - Keiko Sato
- Research Division of Medical Data Science, Research Institute for Science and Technology, Tokyo University of Science, Noda, Chiba 278-8510, Japan
- Department of Information Sciences, Faculty of Science and Technology, Tokyo University of Science, Noda, Chiba 278-8510, Japan
| | - Shoma Tamori
- Department of Medicinal and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan
- Research Division of Medical Data Science, Research Institute for Science and Technology, Tokyo University of Science, Noda, Chiba 278-8510, Japan
| | - Kazunori Sasaki
- Laboratory of Cancer Biology, Institute for Diseases of Old Age, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Shigeo Ohno
- Laboratory of Cancer Biology, Institute for Diseases of Old Age, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Kazunori Akimoto
- Department of Medicinal and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan
- Research Division of Medical Data Science, Research Institute for Science and Technology, Tokyo University of Science, Noda, Chiba 278-8510, Japan
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Zhang J, Wang Y, Wang L, You L, Zhang T. Pancreatic ductal adenocarcinoma chemoresistance: From metabolism reprogramming to novel treatment. Chin Med J (Engl) 2024; 137:408-420. [PMID: 37545027 PMCID: PMC10876258 DOI: 10.1097/cm9.0000000000002758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Indexed: 08/08/2023] Open
Abstract
ABSTRACT As pancreatic cancer (PC) is highly malignant, its patients tend to develop metastasis at an early stage and show a poor response to conventional chemotherapies. First-line chemotherapies for PC, according to current guidelines, include fluoropyrimidine- and gemcitabine-based regimens. Accumulating research on drug resistance has shown that biochemical metabolic aberrations in PC, especially those involving glycolysis and glutamine metabolism, are highly associated with chemoresistance. Additionally, lipid metabolism is a major factor in chemoresistance. However, emerging compounds that target these key metabolic pathways have the potential to overcome chemoresistance. This review summarizes how PC develops chemoresistance through aberrations in biochemical metabolism and discusses novel critical targets and pathways within cancer metabolism for new drug research.
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Affiliation(s)
- Jingcheng Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Yutong Wang
- Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Lejunzi Wang
- Department of Anaesthesia, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Taiping Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Clinical Immunology Centre, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
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Guo Y, Cui J, Liang X, Chen T, Lu C, Peng T. Pancreatic cancer stem cell-derived exosomal miR-210 mediates macrophage M2 polarization and promotes gemcitabine resistance by targeting FGFRL1. Int Immunopharmacol 2024; 127:111407. [PMID: 38134594 DOI: 10.1016/j.intimp.2023.111407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 11/28/2023] [Accepted: 12/14/2023] [Indexed: 12/24/2023]
Abstract
Pancreatic cancer (PC) is a serious threat to human health, with most patients diagnosed at the advanced stages of the disease. Treatment with gemcitabine (GEM) leads to PC GEM resistance. In addition, cancer stem cell (CSC)-derived exosomes play an important role in cancer progression. We aimed to investigate the role and mechanism of action of PC stem cell-derived exosomes in PC drug resistance and progression. CSC-derived exosomes increased the proportion of F4/80+/CD86 + cells and levels of M2 polarization factors. miR-210 is expressed in CSC-derived exosomes. Thus, following co-culture, miR-210 was taken up by macrophages. Transfection or the addition of miR-210 mimics increased the proportion of F4/80+/CD206 + cells and levels of M2 polarization factors. Further, the miR-210 targets inhibited the levels of FGFRL1. The FGFRL1 overexpression plasmid also inhibited miR-210-mediated M2 polarization. After co-culture of THP-M2 cells with PC cells and treatment with GEM, the survival rate, migration rate, and levels of MDR, YB-1, BCRP, p-PI3K, p-AKT, and p-mTOR in PC cells increased. And THP-M2 increased the tumor volume and MDR, YB-1, BCRP, p-PI3K, p-AKT, and p-mTOR levels. Overall, miR-210 from PC stem cell-derived exosome targets and inhibits FGFRL1 to promote macrophage M2 polarization, which activates the p-PI3K/p-AKT/p-mTOR pathway and increases GEM resistance.
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Affiliation(s)
- Yao Guo
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jing Cui
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xueyi Liang
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Taoyu Chen
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Chong Lu
- Department of thyroid and breast surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Tao Peng
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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Abd Kadir E, Uchegbu IF, Schätzlein AG. High-capacity glycol chitosan-based nanoemulsion for efficient delivery of disulfiram. Int J Pharm 2023; 640:123036. [PMID: 37169106 DOI: 10.1016/j.ijpharm.2023.123036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 04/14/2023] [Accepted: 05/05/2023] [Indexed: 05/13/2023]
Abstract
Disulfiram (DS) is an anti-alcoholism drug capable of acting against important and hard-to-treat cancers. The drug's relative instability and variable absorption/distribution have led to its variable pharmacokinetics and suboptimal exposure. Hence, it was hypothesised that a nano-enabled form of DS might be able to overcome such limitations. Encapsulation of the labile DS was achieved with quaternary ammonium palmitoyl glycol chitosan (GCPQ) to form a high-capacity, soybean oil-based DS-GCPQ nanoemulsion. DS-GCPQ showed capability of oil-loading up to 50% v/v for a stable entrapment of high drug content. With increasing oil content (10 to 50% v/v), the mean particle size and polydispersity index were also increased (166 to 351 nm and 0.14 to 0.22, respectively) for a given amount of GCPQ. Formulations showed a highly positive particle surface charge (50.9 ± 1.3 mV), contributing to the colloidal stability of the individual particles. DS-GCPQ showed marked cytotoxicity against pancreatic cancer cell lines with enhanced activity in the presence of copper. An intravenous pharmacokinetic study of DS-GCPQ in vivo showed improved plasma drug stability with a DS half-life of 17 min. Prolonged survival was seen in tumour-bearing animals treated with DS-GCPQ supplemented with copper. In conclusion, DS-GCPQ nanoemulsion has the potential to be developed further for cancer therapeutic purposes.
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Affiliation(s)
- Erazuliana Abd Kadir
- UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK; Department of Toxicology, Advanced Medical & Dental Institute, Universiti Sains Malaysia, 13200, Kepala Batas, Pulau Pinang, Malaysia.
| | - Ijeoma F Uchegbu
- UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK
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Yuan M, Wu Q, Zhang M, Lai M, Chen W, Yang J, Jiang L, Cao J. Disulfiram enhances the antitumor activity of cisplatin by inhibiting the Fanconi anemia repair pathway. J Zhejiang Univ Sci B 2023; 24:207-220. [PMID: 36915997 PMCID: PMC10014319 DOI: 10.1631/jzus.b2200405] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023]
Abstract
A series of chemotherapeutic drugs that induce DNA damage, such as cisplatin (DDP), are standard clinical treatments for ovarian cancer, testicular cancer, and other diseases that lack effective targeted drug therapy. Drug resistance is one of the main factors limiting their application. Sensitizers can overcome the drug resistance of tumor cells, thereby enhancing the antitumor activity of chemotherapeutic drugs. In this study, we aimed to identify marketable drugs that could be potential chemotherapy sensitizers and explore the underlying mechanisms. We found that the alcohol withdrawal drug disulfiram (DSF) could significantly enhance the antitumor activity of DDP. JC-1 staining, propidium iodide (PI) staining, and western blotting confirmed that the combination of DSF and DDP could enhance the apoptosis of tumor cells. Subsequent RNA sequencing combined with Gene Set Enrichment Analysis (GSEA) pathway enrichment analysis and cell biology studies such as immunofluorescence suggested an underlying mechanism: DSF makes cells more vulnerable to DNA damage by inhibiting the Fanconi anemia (FA) repair pathway, exerting a sensitizing effect to DNA damaging agents including platinum chemotherapy drugs. Thus, our study illustrated the potential mechanism of action of DSF in enhancing the antitumor effect of DDP. This might provide an effective and safe solution for combating DDP resistance in clinical treatment.
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Affiliation(s)
- Meng Yuan
- Laboratory of Fruit Quality Biology / the State Agriculture Ministry Laboratory of Horticultural Plant Growth, Development and Quality Improvement, Fruit Science Institute, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou 310058, China
| | - Qian Wu
- Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Mingyang Zhang
- Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Minshan Lai
- Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.,Polytechnic Institute, Zhejiang University, Hangzhou 310015, China
| | - Wenbo Chen
- Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.,Polytechnic Institute, Zhejiang University, Hangzhou 310015, China
| | - Jianfeng Yang
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.,Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou 310006, China
| | - Li Jiang
- The Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou 310018, China.
| | - Ji Cao
- Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. .,The Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou 310018, China. .,Cancer Center of Zhejiang University, Hangzhou 310058, China.
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Zhong S, Shengyu Liu, Xin Shi, Zhang X, Li K, Liu G, Li L, Tao S, Zheng B, Sheng W, Ye Z, Xing Q, Zhai Q, Ren L, Wu Y, Bao Y. Disulfiram in glioma: Literature review of drug repurposing. Front Pharmacol 2022; 13:933655. [PMID: 36091753 PMCID: PMC9448899 DOI: 10.3389/fphar.2022.933655] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 07/19/2022] [Indexed: 11/13/2022] Open
Abstract
Gliomas are the most common malignant brain tumors. High-grade gliomas, represented by glioblastoma multiforme (GBM), have a poor prognosis and are prone to recurrence. The standard treatment strategy is tumor removal combined with radiotherapy and chemotherapy, such as temozolomide (TMZ). However, even after conventional treatment, they still have a high recurrence rate, resulting in an increasing demand for effective anti-glioma drugs. Drug repurposing is a method of reusing drugs that have already been widely approved for new indication. It has the advantages of reduced research cost, safety, and increased efficiency. Disulfiram (DSF), originally approved for alcohol dependence, has been repurposed for adjuvant chemotherapy in glioma. This article reviews the drug repurposing method and the progress of research on disulfiram reuse for glioma treatment.
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Yin C, Alqahtani A, Noel MS. The Next Frontier in Pancreatic Cancer: Targeting the Tumor Immune Milieu and Molecular Pathways. Cancers (Basel) 2022; 14:2619. [PMID: 35681599 PMCID: PMC9179513 DOI: 10.3390/cancers14112619] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 05/13/2022] [Accepted: 05/19/2022] [Indexed: 12/11/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with abysmal prognosis. It is currently the third most common cause of cancer-related mortality, despite being the 11th most common cancer. Chemotherapy is standard of care in all stages of pancreatic cancer, yet survival, particularly in the advanced stages, often remains under one year. We are turning to immunotherapies and targeted therapies in PDAC in order to directly attack the core features that make PDAC notoriously resistant to chemotherapy. While the initial studies of these agents in PDAC have generally been disappointing, we find optimism in recent preclinical and early clinical research. We find that despite the immunosuppressive effects of the PDAC tumor microenvironment, new strategies, such as combining immune checkpoint inhibitors with vaccine therapy or chemokine receptor antagonists, help elicit strong immune responses. We also expand on principles of DNA homologous recombination repair and highlight opportunities to use agents, such as PARP inhibitors, that exploit deficiencies in DNA repair pathways. Lastly, we describe advances in direct targeting of driver mutations and metabolic pathways and highlight some technological achievements such as novel KRAS inhibitors.
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Affiliation(s)
| | | | - Marcus S. Noel
- Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, USA; (C.Y.); (A.A.)
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Zirjacks L, Stransky N, Klumpp L, Prause L, Eckert F, Zips D, Schleicher S, Handgretinger R, Huber SM, Ganser K. Repurposing Disulfiram for Targeting of Glioblastoma Stem Cells: An In Vitro Study. Biomolecules 2021; 11:1561. [PMID: 34827559 PMCID: PMC8615869 DOI: 10.3390/biom11111561] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 10/12/2021] [Accepted: 10/16/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal glioblastoma stem cells (GSCs), a subpopulation in glioblastoma that are responsible for therapy resistance and tumor spreading in the brain, reportedly upregulate aldehyde dehydrogenase isoform-1A3 (ALDH1A3) which can be inhibited by disulfiram (DSF), an FDA-approved drug formerly prescribed in alcohol use disorder. Reportedly, DSF in combination with Cu2+ ions exerts multiple tumoricidal, chemo- and radio-therapy-sensitizing effects in several tumor entities. The present study aimed to quantify these DSF effects in glioblastoma stem cells in vitro, regarding dependence on ALDH1A3 expression. To this end, two patient-derived GSC cultures with differing ALDH1A3 expression were pretreated (in the presence of CuSO4, 100 nM) with DSF (0 or 100 nM) and the DNA-alkylating agent temozolomide (0 or 30 µM) and then cells were irradiated with a single dose of 0-8 Gy. As read-outs, cell cycle distribution and clonogenic survival were determined by flow cytometry and limited dilution assay, respectively. As a result, DSF modulated cell cycle distribution in both GSC cultures and dramatically decreased clonogenic survival independently of ALDH1A3 expression. This effect was additive to the impairment of clonogenic survival by radiation, but not associated with radiosensitization. Of note, cotreatment with temozolomide blunted the DSF inhibition of clonogenic survival. In conclusion, DSF targets GSCs independent of ALDH1A3 expression, suggesting a therapeutic efficacy also in glioblastomas with low mesenchymal GSC populations. As temozolomide somehow antagonized the DSF effects, strategies for future combination of DSF with the adjuvant standard therapy (fractionated radiotherapy and concomitant temozolomide chemotherapy followed by temozolomide maintenance therapy) are not supported by the present study.
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Affiliation(s)
- Lisa Zirjacks
- Department of Radiation Oncology, Eberhard-Karls University, 72076 Tübingen, Germany; (L.Z.); (N.S.); (L.K.); (L.P.); (F.E.); (D.Z.); (K.G.)
| | - Nicolai Stransky
- Department of Radiation Oncology, Eberhard-Karls University, 72076 Tübingen, Germany; (L.Z.); (N.S.); (L.K.); (L.P.); (F.E.); (D.Z.); (K.G.)
| | - Lukas Klumpp
- Department of Radiation Oncology, Eberhard-Karls University, 72076 Tübingen, Germany; (L.Z.); (N.S.); (L.K.); (L.P.); (F.E.); (D.Z.); (K.G.)
| | - Lukas Prause
- Department of Radiation Oncology, Eberhard-Karls University, 72076 Tübingen, Germany; (L.Z.); (N.S.); (L.K.); (L.P.); (F.E.); (D.Z.); (K.G.)
| | - Franziska Eckert
- Department of Radiation Oncology, Eberhard-Karls University, 72076 Tübingen, Germany; (L.Z.); (N.S.); (L.K.); (L.P.); (F.E.); (D.Z.); (K.G.)
| | - Daniel Zips
- Department of Radiation Oncology, Eberhard-Karls University, 72076 Tübingen, Germany; (L.Z.); (N.S.); (L.K.); (L.P.); (F.E.); (D.Z.); (K.G.)
| | - Sabine Schleicher
- Department of Hematology and Oncology, University Hospital Tuebingen, Children’s Hospital, 72076 Tuebingen, Germany; (S.S.); (R.H.)
| | - Rupert Handgretinger
- Department of Hematology and Oncology, University Hospital Tuebingen, Children’s Hospital, 72076 Tuebingen, Germany; (S.S.); (R.H.)
| | - Stephan M. Huber
- Department of Radiation Oncology, Eberhard-Karls University, 72076 Tübingen, Germany; (L.Z.); (N.S.); (L.K.); (L.P.); (F.E.); (D.Z.); (K.G.)
| | - Katrin Ganser
- Department of Radiation Oncology, Eberhard-Karls University, 72076 Tübingen, Germany; (L.Z.); (N.S.); (L.K.); (L.P.); (F.E.); (D.Z.); (K.G.)
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Morphological Heterogeneity in Pancreatic Cancer Reflects Structural and Functional Divergence. Cancers (Basel) 2021; 13:cancers13040895. [PMID: 33672734 PMCID: PMC7924365 DOI: 10.3390/cancers13040895] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 02/12/2021] [Accepted: 02/16/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Pancreatic cancer has a poor prognosis, which is largely due to resistance to treatment. Tumor heterogeneity is a known cause for treatment failure and has been studied at the molecular level. Morphological heterogeneity is common but has not been investigated, despite the fact that pathology examination is an integral part of clinical diagnostics. This study assessed whether morphological heterogeneity reflects structural and functional diversity in key cancer biological processes. Using archival tissues from resected pancreatic cancer, we selected four common and distinct morphological phenotypes and demonstrated that these differed significantly for a panel of 26 structural and functional features of the cancer-cell and stromal compartments. The strong link between these features and morphological phenotypes allowed prediction of the latter based on the results for the panel of features. The findings of this study indicate that morphological heterogeneity reflects biological diversity and that its assessment may potentially provide clinically relevant information. Abstract Inter- and intratumor heterogeneity is an important cause of treatment failure. In human pancreatic cancer (PC), heterogeneity has been investigated almost exclusively at the genomic and transcriptional level. Morphological heterogeneity, though prominent and potentially easily assessable in clinical practice, remains unexplored. This proof-of-concept study aims at demonstrating that morphological heterogeneity reflects structural and functional divergence. From the wide morphological spectrum of conventional PC, four common and distinctive patterns were investigated in 233 foci from 39 surgical specimens. Twenty-six features involved in key biological processes in PC were analyzed (immuno-)histochemically and morphometrically: cancer cell proliferation (Ki67) and migration (collagen fiber alignment, MMP14), cancer stem cells (CD44, CD133, ALDH1), amount, composition and spatial arrangement of extracellular matrix (epithelial proximity, total collagen, collagen I and III, fibronectin, hyaluronan), cancer-associated fibroblasts (density, αSMA), and cancer-stroma interactions (integrins α2, α5, α1; caveolin-1). All features differed significantly between at least two of the patterns. Stromal and cancer-cell-related features co-varied with morphology and allowed prediction of the morphological pattern. In conclusion, morphological heterogeneity in the cancer-cell and stromal compartments of PC correlates with structural and functional diversity. As such, histopathology has the potential to inform on the operationality of key biological processes in individual tumors.
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Kaul L, Süss R, Zannettino A, Richter K. The revival of dithiocarbamates: from pesticides to innovative medical treatments. iScience 2021; 24:102092. [PMID: 33598645 PMCID: PMC7868997 DOI: 10.1016/j.isci.2021.102092] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Abstract
Dithiocarbamates (DTCs) have been used for various applications, including as hardening agents in rubber manufacturing, as fungicide in agriculture, and as medications to treat alcohol misuse disorder. The multi-faceted effects of DTCs rely mainly on metal binding abilities and a high reactivity with thiol groups. Therefore, the list of potential applications is still increasing, exemplified by the US Food and Drug Administration approval of disulfiram (Antabuse) and its metabolite diethyldithiocarbamate in clinical trials against cancer, human immunodeficiency virus, and Lyme disease, as well as new DTC-related compounds that have been synthesized to target diseases with unmet therapeutic needs. In this review, we will discuss the latest progress of DTCs as anti-cancer agents and provide a summary of the mechanisms of action. We will explain the expansion of DTCs' activity in the fields of microbiology, neurology, cardiology, and ophthalmology, thereby providing evidence for the important role and therapeutic potential of DTCs as innovative medical treatments.
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Affiliation(s)
- Laurine Kaul
- Richter Lab, Department of Surgery, Basil Hetzel Institute for Translational Health Research, University of Adelaide, Adelaide, SA 5011, Australia
- Department of Pharmaceutical Technology and Biopharmacy, Institute of Pharmaceutical Sciences, University of Freiburg, Freiburg 79104, Germany
- Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5005, Australia
| | - Regine Süss
- Department of Pharmaceutical Technology and Biopharmacy, Institute of Pharmaceutical Sciences, University of Freiburg, Freiburg 79104, Germany
| | - Andrew Zannettino
- Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5005, Australia
- Precision Medicine Theme, South Australian Health & Medical Research Institute, Adelaide, SA 5000, Australia
- Central Adelaide Local Health Network, Adelaide, SA 5011, Australia
| | - Katharina Richter
- Richter Lab, Department of Surgery, Basil Hetzel Institute for Translational Health Research, University of Adelaide, Adelaide, SA 5011, Australia
- Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5005, Australia
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11
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Li Z, Xie X, Tan G, Xie F, Liu N, Li W, Sun X. Disulfiram Synergizes with SRC Inhibitors to Suppress the Growth of Pancreatic Ductal Adenocarcinoma Cells in Vitro and in Vivo. Biol Pharm Bull 2021; 44:1323-1331. [PMID: 34471060 DOI: 10.1248/bpb.b21-00353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Disulfiram (DSF), an old anti-alcoholism drug, has emerged as a candidate for drug repurposing in oncology. In exploratory studies on its therapeutic effects, we unexpectedly discovered that DSF increased the phosphorylation of SRC, a proto-oncogene tyrosine-protein kinase elevated in 70% of pancreatic ductal adenocarcinoma (PDAC) cases. This serendipitous and novel finding led to our hypothesis for the current study which proposes DSF may synergize with SRC inhibitors in suppressing PDAC. Human PDAC PANC-1 and BXPC-3 cells were incubated with DSF chelated with copper (Cu2+), SRC inhibitors (PP2 and dasatinib), or transfected with lentiviral short hairpin RNA (shRNA), and their proliferation and apoptosis were analyzed. A xenograft model was employed to verify the in vitro results. The expression of key molecules was detected. DSF significantly inhibited cell proliferation and induced cell apoptosis by increasing the cleavage of poly ADP ribose polymerase (PARP), downregulating Bcl-2 and upregulating p27 in concentration- and time-dependent manners. DSF had little effect on signal transducer and activator of transcription 3 (STAT3) expression but inhibited its phosphorylation. DSF did not alter SRC expression but significantly increased its phosphorylation through upregulating actin filament associated protein 1 like 2 (AFAP1L2). DSF exhibited a synergistic effect, as analyzed by drug coefficient interactions, with either PP2, or dasatinib, or SRC depletion in suppressing PDAC cells in vitro and/or in vivo. The present results indicate DSF is a potential therapeutic drug, particularly when it is combined with SRC inhibitors, and warrant further studies on the pharmacological utility of DSF as a promising adjunct therapy for the treatment of PDAC.
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Affiliation(s)
- Ziyi Li
- Hepatosplenic Surgery Center, the First Affiliated Hospital of Harbin Medical University
| | - Xiangjun Xie
- Department of Gastroenterology, Qingdao Municipal Hospital Affiliated to Qingdao University
| | - Gang Tan
- Department of General Surgery, the Fourth Affiliated Hospital of Harbin Medical University
| | - Fangyu Xie
- Department of Cardiology, Qingdao Municipal Hospital Affiliated to Qingdao University
| | - Nianjiao Liu
- Department of Endocrinology, the First Hospital Affiliated of Harbin Medical University
| | - Weidong Li
- Hepatosplenic Surgery Center, the First Affiliated Hospital of Harbin Medical University
- Department of General Surgery, the Fourth Affiliated Hospital of Harbin Medical University
| | - Xueying Sun
- Hepatosplenic Surgery Center, the First Affiliated Hospital of Harbin Medical University
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12
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Nezhadi S, Saadat E, Handali S, Dorkoosh F. Nanomedicine and chemotherapeutics drug delivery: challenges and opportunities. J Drug Target 2020; 29:185-198. [PMID: 32772739 DOI: 10.1080/1061186x.2020.1808000] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cancer is considered as one of the biggest threats to humans worldwide. Researchers suggest that tumour is not just a single mass, it comprises cancerous cells surrounded by noncancerous cells such as immune cells, adipocytes and cancer stem cells (CSCs) in the extracellular matrix (ECM) containing distinct components such as proteins, glycoproteins and enzymes; thus tumour microenvironment (TME) is partially complex. Multiple interactions happen in the dynamic microenvironment (ME) lead to an acidic, hypoxic and stiff ME that is considered as one of the major contributors to cancer progression and metastasis. Furthermore, TME involves in drug resistance mechanisms and affects enhanced permeability and retention (EPR) in tumours. In such a scenario, the first step to accomplish satisfying results is the identification and recognition of this ME. Then designing proper drug delivery systems can perform selectively towards cancerous cells. In this way, several targeting and stimuli/enzyme responsive drug delivery systems have been designed. More importantly, it is necessary to design a drug delivery system that can penetrate deeper into the tumours, efficiently and selectively. Various drug delivery systems such as exosomes and size-switchable nanocarriers (NCs) could decrease side effects and increase tumour treatment results by selective accumulation in tumours. In this review, TME features, current drug delivery approaches, challenges and promising strategies towards cancer treatment are discussed.
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Affiliation(s)
- Sepideh Nezhadi
- Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Ir an
| | | | - Somayeh Handali
- Medical Biomaterial Research Center (MBRC), Tehran University of Medical Sciences, Tehran, Iran
| | - Farid Dorkoosh
- Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Ir an.,Medical Biomaterial Research Center (MBRC), Tehran University of Medical Sciences, Tehran, Iran
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13
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Yang Q, Yao Y, Li K, Jiao L, Zhu J, Ni C, Li M, Dou QP, Yang H. An Updated Review of Disulfiram: Molecular Targets and Strategies for Cancer Treatment. Curr Pharm Des 2020; 25:3248-3256. [PMID: 31419930 DOI: 10.2174/1381612825666190816233755] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 08/06/2019] [Indexed: 12/31/2022]
Abstract
Repurposing already approved drugs as new anticancer agents is a promising strategy considering the advantages such as low costs, low risks and less time-consumption. Disulfiram (DSF), as the first drug for antialcoholism, was approved by the U.S. Food and Drug Administration (FDA) over 60 years ago. Increasing evidence indicates that DSF has great potential for the treatment of various human cancers. Several mechanisms and targets of DSF related to cancer therapy have been proposed, including the inhibition of ubiquitin-proteasome system (UPS), cancer cell stemness and cancer metastasis, and alteration of the intracellular reactive oxygen species (ROS). This article provides a brief review about the history of the use of DSF in humans and its molecular mechanisms and targets of anticancer therapy, describes DSF delivery strategies for cancer treatment, summarizes completed and ongoing cancer clinical trials involving DSF, and offers strategies to better use DSF in cancer therapies.
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Affiliation(s)
- Qingzhu Yang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Yao Yao
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Kai Li
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Lin Jiao
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Jiazhen Zhu
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Cheng Ni
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Mengmeng Li
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Q Ping Dou
- Departments of Oncology, Pharmacology and Pathology, Barbara Ann Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, United States
| | - Huanjie Yang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
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14
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Wang W, Zheng S, He H, Ge H, Saeed BR. N,N-diethylaminobenzaldehyde targets aldehyde dehydrogenase to eradicate human pancreatic cancer cells. Exp Ther Med 2020; 20:662-670. [PMID: 32550888 DOI: 10.3892/etm.2020.8691] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 03/10/2020] [Indexed: 12/14/2022] Open
Abstract
Pancreatic cancer is a common cause of worldwide cancer-related mortality with a poor 5-year survival rate. Aldehyde dehydrogenase (ALDH) activity is a possible marker for malignant stem cells in solid organ systems, including the pancreas, and N,N-diethylaminobenzaldehyde (DEAB) is able to inhibit ALDH activity. In the present study, the role of DEAB in the treatment of pancreatic cancer cells and the potential underlying mechanisms were investigated. The ALDH activities of pancreatic cancer cell lines treated with or without DEAB were analyzed by an ALDEFLUOR™ assay. The Cell Counting Kit-8 and colony formation assays, and cell cycle analysis were used to evaluate the viability, colony-forming ability and cell quiescence of cell lines under DEAB treatment, respectively. DEAB and/or gemcitabine-induced cell apoptosis was assessed by flow cytometry. DEAB reduced ALDH activity and inhibited the proliferation, colony-forming ability and cell quiescence of pancreatic cancer cell lines. Compared with respective controls, DEAB alone and the combination of gemcitabine and DEAB significantly decreased cell viability and increased cell apoptosis. Moreover, reverse transcription-PCR and western blotting were used to measure the expressions of B cell lymphoma 2 (Bcl2) associated X protein (Bax) and Bcl2 mRNA and protein. The anti-cancer effect of DEAB was associated with upregulation of Bax expression. Therefore, targeting ALDH with DEAB may be a potential therapeutic choice for pancreatic cancer, demonstrating a synergic effect with gemcitabine.
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Affiliation(s)
- Wenwen Wang
- Department of Oncology, The Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, Jiangsu 214000, P.R. China
| | - Shiya Zheng
- Department of Oncology, Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Haiju He
- Department of Medicine V, University of Heidelberg, D-69120 Heidelberg, Germany
| | - Hao Ge
- Department of Oncology, Liyang People's Hospital, Liyang, Jiangsu 213300, P.R. China
| | - Borhan R Saeed
- Department of Medicine V, University of Heidelberg, D-69120 Heidelberg, Germany
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15
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Isayev O, Zhu Y, Gasimov E, Werner J, Bazhin AV. Effect of Chemotherapeutic Agents on the Expression of Retinoid Receptors and Markers of Cancer Stem Cells and Epithelial-Mesenchymal Transition. BIOCHEMISTRY (MOSCOW) 2019; 84:1424-1432. [PMID: 31760928 DOI: 10.1134/s0006297919110166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
A large body of evidence suggests that cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT), as well as expression and function of retinoid receptors, are pivotal features of tumor initiation, progression, and chemoresistance. This is also true for pancreatic ductal adenocarcinoma (PDAC), which represents a clinical challenge due to poor prognosis and increasing incidence. Understanding the above features of cancer cells could open new avenues for PDAC treatment strategies. The aim of this study was to investigate the relation between CSCs, EMT, and retinoid receptors in PDAC after treatment with the chemotherapeutic agents - gemcitabine and 5-fluorouracil. First, we demonstrated the difference in the expression levels of CSC and EMT markers and retinoid receptors in the untreated Mia PaCa-2 and Panc1 cells that also differed in the frequency of spontaneous apoptosis and distribution between the cell cycle phases. Chemotherapy reduced the number of cancer cells in the S phase. Gemcitabine and 5-fluorouracil modulated expression of CSC markers, E-cadherin, and RXRβ in Panc1 but not in Mia PaCa-2 cells. We suggest that these effects could be attributed to the difference in the basal levels of expression of the investigated genes. The obtained data could be interesting in the context of future preclinical research.
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Affiliation(s)
- O Isayev
- Department of Histology, Embryology and Cytology, Azerbaijan Medical University, Baku, AZ1022, Azerbaijan. .,Genetic Resources Institute, Azerbaijan National Academy of Sciences, Baku, AZ1106, Azerbaijan
| | - Y Zhu
- International Joint Laboratory for Cell Medical Engineering of Henan Province, Department of Oncology, Henan University Huaihe Hospital, Kaifeng, Henan, 475000, P. R. China.
| | - E Gasimov
- Department of Histology, Embryology and Cytology, Azerbaijan Medical University, Baku, AZ1022, Azerbaijan.
| | - J Werner
- Department of General, Visceral, and Transplantation Surgery, Ludwig-Maximilians-University Munich, Munich, 81377, Germany
| | - A V Bazhin
- Department of General, Visceral, and Transplantation Surgery, Ludwig-Maximilians-University Munich, Munich, 81377, Germany.
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16
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Recent advances in the delivery of disulfiram: a critical analysis of promising approaches to improve its pharmacokinetic profile and anticancer efficacy. ACTA ACUST UNITED AC 2019; 27:853-862. [PMID: 31758497 DOI: 10.1007/s40199-019-00308-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Accepted: 10/11/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND Disulfiram (DSF) has a long history of being used as a first-line promising therapy for treatment of alcoholism in human. Besides its prominence in the treatment of alcoholism, extensive investigations have been carried out to explore other biomedical and pharmacological effects of DSF. Amongst other biomedical implications, plenty researches have shown evidence of promising anticancer efficacy of this agent for treatment of wide range of cancers such as breast cancer, liver cancer and lung carcinoma. METHODS Electronic databases, including Google scholar, PubMed and Web of science were searched with the keywords disulfiram, nanoparticles, cancer, drug delivery systems. RESULT Despite its excellent anticancer efficacy, the pharmaceutical significance and clinical applicability of DSF are hampered due to poor stability, low solubility, short plasma half-life, rapid metabolism, and early clearance from systemic circulation. Various attempts have been made to eradicate these issues. Nanotechnology based interventions have gained remarkable recognition in improving pharmacokinetic and pharmacodynamic profile of DSF by improving its stability and avoiding its degradation. CONCLUSION The aim of the present review is to critically analyse all recent developments in designing various nanotechnology-based delivery systems, to ponder their relevance in improving stability, pharmacokinetic and pharmacodynamic profile, and achieving target-specific delivery of this agent to cancer cells to effectively eradicate cancer and abolish its metastasis. Nanotechnology is a novel approach for overcoming such obstacles faced presently, the results obtained so far using different novel drug delivery systems seem to be very promising to increase the stability and half-life of DSF. Graphical abstract Nanocrrier mediated drug delivery systems for disulfiram.
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17
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Peng X, Pan Q, Zhang B, Wan S, Li S, Luo K, Pu Y, He B. Highly Stable, Coordinated Polymeric Nanoparticles Loading Copper(II) Diethyldithiocarbamate for Combinational Chemo/Chemodynamic Therapy of Cancer. Biomacromolecules 2019; 20:2372-2383. [PMID: 31117352 DOI: 10.1021/acs.biomac.9b00367] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Affiliation(s)
- Xinyu Peng
- National Engineering
Research Center for Biomaterials, Sichuan University, Chengdu 610064, China
| | - Qingqing Pan
- National Engineering
Research Center for Biomaterials, Sichuan University, Chengdu 610064, China
| | - Boya Zhang
- National Engineering
Research Center for Biomaterials, Sichuan University, Chengdu 610064, China
| | - Shiyu Wan
- School of Chemical Engineering, Sichuan University, Chengdu 610065, China
| | - Sai Li
- School of Chemical Engineering, Sichuan University, Chengdu 610065, China
| | - Kui Luo
- Huaxi MR Research
Center (HMRRC), Department of Radiology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yuji Pu
- National Engineering
Research Center for Biomaterials, Sichuan University, Chengdu 610064, China
| | - Bin He
- National Engineering
Research Center for Biomaterials, Sichuan University, Chengdu 610064, China
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18
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Paramasivan P, Kankia IH, Langdon SP, Deeni YY. Emerging role of nuclear factor erythroid 2-related factor 2 in the mechanism of action and resistance to anticancer therapies. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2019; 2:490-515. [PMID: 35582567 PMCID: PMC8992506 DOI: 10.20517/cdr.2019.57] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 08/12/2019] [Accepted: 08/26/2019] [Indexed: 04/28/2023]
Abstract
Nuclear factor E2-related factor 2 (NRF2), a transcription factor, is a master regulator of an array of genes related to oxidative and electrophilic stress that promote and maintain redox homeostasis. NRF2 function is well studied in in vitro, animal and general physiology models. However, emerging data has uncovered novel functionality of this transcription factor in human diseases such as cancer, autism, anxiety disorders and diabetes. A key finding in these emerging roles has been its constitutive upregulation in multiple cancers promoting pro-survival phenotypes. The survivability pathways in these studies were mostly explained by classical NRF2 activation involving KEAP-1 relief and transcriptional induction of reactive oxygen species (ROS) neutralizing and cytoprotective drug-metabolizing enzymes (phase I, II, III and 0). Further, NRF2 status and activation is associated with lowered cancer therapeutic efficacy and the eventual emergence of therapeutic resistance. Interestingly, we and others have provided further evidence of direct NRF2 regulation of anticancer drug targets like receptor tyrosine kinases and DNA damage and repair proteins and kinases with implications for therapy outcome. This novel finding demonstrates a renewed role of NRF2 as a key modulatory factor informing anticancer therapeutic outcomes, which extends beyond its described classical role as a ROS regulator. This review will provide a knowledge base for these emerging roles of NRF2 in anticancer therapies involving feedback and feed forward models and will consolidate and present such findings in a systematic manner. This places NRF2 as a key determinant of action, effectiveness and resistance to anticancer therapy.
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Affiliation(s)
- Poornima Paramasivan
- Division of Science, School of Applied Sciences, Abertay University, Dundee DD1 1HG, United Kingdom
| | - Ibrahim H. Kankia
- Division of Science, School of Applied Sciences, Abertay University, Dundee DD1 1HG, United Kingdom
- Department of Biochemistry, Faculty of Natural and Applied Sciences, Umaru Musa Yar’adua University, Katsina PMB 2218, Nigeria
| | - Simon P. Langdon
- Cancer Research UK Edinburgh Centre and Edinburgh Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, United Kingdom
| | - Yusuf Y. Deeni
- Division of Science, School of Applied Sciences, Abertay University, Dundee DD1 1HG, United Kingdom
- Correspondence Address: Prof. Yusuf Y Deeni, Division of Science, School of Applied Sciences, Abertay University, Dundee DD1 1HG, United Kingdom. E-mail:
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19
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Toledo-Guzmán ME, Bigoni-Ordóñez GD, Ibáñez Hernández M, Ortiz-Sánchez E. Cancer stem cell impact on clinical oncology. World J Stem Cells 2018; 10:183-195. [PMID: 30613312 PMCID: PMC6306557 DOI: 10.4252/wjsc.v10.i12.183] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 10/15/2018] [Accepted: 11/15/2018] [Indexed: 02/06/2023] Open
Abstract
Cancer is a widespread worldwide chronic disease. In most cases, the high mortality rate from cancer correlates with a lack of clear symptoms, which results in late diagnosis for patients, and consequently, advanced tumor disease with poor probabilities for cure, since many patients will show chemo- and radio-resistance. Several mechanisms have been studied to explain chemo- and radio-resistance to anti-tumor therapies, including cell signaling pathways, anti-apoptotic mechanisms, stemness, metabolism, and cellular phenotypes. Interestingly, the presence of cancer stem cells (CSCs), which are a subset of cells within the tumors, has been related to therapy resistance. In this review, we focus on evaluating the presence of CSCs in different tumors such as breast cancer, gastric cancer, lung cancer, and hematological neoplasias, highlighting studies where CSCs were identified in patient samples. It is evident that there has been a great drive to identify the cell surface phenotypes of CSCs so that they can be used as a tool for anti-tumor therapy treatment design. We also review the potential effect of nanoparticles, drugs, natural compounds, aldehyde dehydrogenase inhibitors, cell signaling inhibitors, and antibodies to treat CSCs from specific tumors. Taken together, we present an overview of the role of CSCs in tumorigenesis and how research is advancing to target these highly tumorigenic cells to improve oncology patient outcomes.
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Affiliation(s)
- Mariel E Toledo-Guzmán
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Mexico City 14080, Mexico
| | | | - Miguel Ibáñez Hernández
- Departamento de Bioquímica, Laboratorio de Terapia Génica, Escuela Nacional de Ciencias Biológicas, Posgrado de Biomedicina y Biotecnología Molecular, Instituto Politécnico Nacional, Mexico City 11340, Mexico
| | - Elizabeth Ortiz-Sánchez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Mexico City 14080, Mexico.
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20
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Sanh N, Fadul H, Hussein N, Lyn-Cook BD, Hammons G, Ramos-Cardona XE, Mohamed K, Mohammed SI. Proteomics Profiling of Pancreatic Cancer and Pancreatitis for Biomarkers Discovery. ACTA ACUST UNITED AC 2018; 9. [PMID: 31032145 DOI: 10.4172/2157-7013.1000287] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Pancreatic cancer is one of the most aggressive malignancies with an increase in incidence predicted, particularly in African Americans. Pancreatic cancer is considered a silent disease with poor prognosis and a lack of early biomarkers for detection. Proteomics has been applied in many diseases for identifying or discovering biomarkers. It has long been suggested that chronic pancreatitis may be a risk factor for developing pancreatic cancer. This study identified proteins that are altered in expression in pancreatic cancer and pancreatitis compared to normal using proteomic technology. Proteins were extracted from laser captured micro-dissected tissues and separated in 2-DPAGE and imaged. The protein profiles of pancreatic cancer and pancreatitis are similar but differed with the protein profile of normal adjacent tissues. Representative proteins, overexpressed in tumor and pancreatitis but not normal tissues, were excised from gels, subjected to in-gel digestion, and analyzed by MALDI-TOF mass spectrometry. Proteins identified included transferrin, ER-60 protein, proapolipoprotein, tropomyosin 1, alpha 1 actin precursor, ACTB protein, and gamma 2 propeptide, aldehyde dehydrogenase 1A1, pancreatic lipase and annexin A1. Several proteins, which were shown in pancreatic cancer, were also observed in pancreatitis samples. Understanding the role of these specific proteins and their mechanistic action will give insights into their involvement in pancreatic cancers.
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Affiliation(s)
- N Sanh
- Department of Comparative Pathobiology and Purdue University Center for Cancer Research, Purdue University, West Lafayette, USA
| | - H Fadul
- Department of Comparative Pathobiology and Purdue University Center for Cancer Research, Purdue University, West Lafayette, USA
| | - N Hussein
- Franklin College, IUPUI- Indiana University Purdue University Indianapolis, Indianapolis, USA
| | - B D Lyn-Cook
- Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, USA
| | - G Hammons
- Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, USA
| | - X E Ramos-Cardona
- Department of Comparative Pathobiology and Purdue University Center for Cancer Research, Purdue University, West Lafayette, USA
| | - K Mohamed
- Radiation and Isotopes Center Khartoum (RICK), Sudan
| | - S I Mohammed
- Department of Comparative Pathobiology and Purdue University Center for Cancer Research, Purdue University, West Lafayette, USA
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21
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Di Carlo C, Brandi J, Cecconi D. Pancreatic cancer stem cells: Perspectives on potential therapeutic approaches of pancreatic ductal adenocarcinoma. World J Stem Cells 2018; 10:172-182. [PMID: 30631392 PMCID: PMC6325076 DOI: 10.4252/wjsc.v10.i11.172] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 09/10/2018] [Accepted: 10/17/2018] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma is one of the most aggressive solid tumours of the pancreas, characterised by a five-year survival rate less than 8%. Recent reports that pancreatic cancer stem cells (PCSCs) contribute to the tumorigenesis, progression, and chemoresistance of pancreatic cancer have prompted the investigation of new therapeutic approaches able to directly target PCSCs. In the present paper the non-cancer related drugs that have been proposed to target CSCs that could potentially combat pancreatic cancer are reviewed and evaluated. The role of some pathways and deregulated proteins in PCSCs as new therapeutic targets are also discussed with a focus on selected specific inhibitors. Finally, advances in the development of nanoparticles for targeting PCSCs and site-specific drug delivery are highlighted, and their limitations considered.
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Affiliation(s)
- Claudia Di Carlo
- Department of Biotechnology, Proteomics and Mass Spectrometry Laboratory, University of Verona, Verona 37134, Italy
| | - Jessica Brandi
- Department of Biotechnology, Proteomics and Mass Spectrometry Laboratory, University of Verona, Verona 37134, Italy.
| | - Daniela Cecconi
- Department of Biotechnology, Proteomics and Mass Spectrometry Laboratory, University of Verona, Verona 37134, Italy
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22
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Martins-Neves SR, Cleton-Jansen AM, Gomes CMF. Therapy-induced enrichment of cancer stem-like cells in solid human tumors: Where do we stand? Pharmacol Res 2018; 137:193-204. [PMID: 30316903 DOI: 10.1016/j.phrs.2018.10.011] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 10/05/2018] [Accepted: 10/09/2018] [Indexed: 12/11/2022]
Abstract
The development of local recurrence and metastatic disease, most probably attributable to the intrinsic or acquired resistance of tumor cells to standard therapy, still constitute the major clinical problem preventing the cure of cancer patients. Despite progress in the research of new therapeutic targets and compounds, resistant cells displaying stem-like properties seem to play a leading role in therapeutic failures and to be the culprit cells responsible for associated tumor recurrence. A whole new plethora of research studies suggest that drug-tolerant cancer stem cells may be induced by conventional cancer chemotherapeutics such as doxorubicin, cisplatinum and ionizing radiation. This phenotypic plasticity and transition from a differentiated to stem-like cell state associates with the activation of diverse stem cell self-renewal (e.g. Notch, Hedgehog, Wnt), drug efflux (e.g. ABC transporters) and survival-related pathways (e.g. TGF-β, ERK, AKT), which may confer resistance and treatment failures in solid tumors. Therefore, combined therapeutic strategies aiming to simultaneously target drug-sensitive tumor cells and their capacity of phenotypic switching may lead to survival benefits and meaningful disease remissions. This knowledge can be applicable to the clinic and contribute to better therapeutic outcomes and prevent tumor recurrence.
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Affiliation(s)
- Sara R Martins-Neves
- Institute of Pharmacology and Experimental Therapeutics, Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Azinhaga de Sta. Comba, Celas, 3000-354 Coimbra, Portugal; CNC.IBILI, University of Coimbra, Coimbra, Portugal; CIMAGO, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Department of Pathology, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
| | - Anne-Marie Cleton-Jansen
- Department of Pathology, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
| | - Célia M F Gomes
- Institute of Pharmacology and Experimental Therapeutics, Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Azinhaga de Sta. Comba, Celas, 3000-354 Coimbra, Portugal; CNC.IBILI, University of Coimbra, Coimbra, Portugal; CIMAGO, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
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23
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Chen W, Qin Y, Liu S. Cytokines, breast cancer stem cells (BCSCs) and chemoresistance. Clin Transl Med 2018; 7:27. [PMID: 30175384 PMCID: PMC6119679 DOI: 10.1186/s40169-018-0205-6] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Accepted: 07/20/2018] [Indexed: 02/06/2023] Open
Abstract
Chemotherapy resistance of breast cancer poses a great challenge to the survival of patients. During breast cancer treatment, the development of intrinsic and acquired drug resistance tends to further induce adverse prognosis, such as metastasis. In recent years, the progress of research on cytokine-modulated tumor microenvironment and breast cancer stem cells (BCSCs) has shed light on defining the mechanisms of drug resistance gradually. In this review, we have discussed cytokine regulation on breast cancer chemoresistance. Cytokines can affect tumor cell behavior or reprogram tumor niche through specific signaling pathways, thereby regulating the progress of drug resistance. In addition, we summarized the mutually regulatory networks between cytokines and BCSCs in mediating chemoresistance. Cytokines in the tumor microenvironment can regulate the self-renewal and survival of BCSCs in a variety of ways, sequentially promoting chemotherapeutic resistance. Therefore, the combinational treatment of BCSC targeting and cytokine blockade may have a positive effect on the clinical treatment of breast cancer.
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Affiliation(s)
- Weilong Chen
- School of Life Science, The CAS Key Laboratory of Innate Immunity and Chronic Disease, University of Science & Technology of China, Hefei, 230027, Anhui, China
| | - Yuanyuan Qin
- School of Life Science, The CAS Key Laboratory of Innate Immunity and Chronic Disease, University of Science & Technology of China, Hefei, 230027, Anhui, China
| | - Suling Liu
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; Key Laboratory of Medical Epigenetics and Metabolism; Innovation Center for Cell Signaling Network, Shanghai Medical College; Fudan University, Shanghai, 200032, China.
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24
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Oria VO, Bronsert P, Thomsen AR, Föll MC, Zamboglou C, Hannibal L, Behringer S, Biniossek ML, Schreiber C, Grosu AL, Bolm L, Rades D, Keck T, Werner M, Wellner UF, Schilling O. Proteome Profiling of Primary Pancreatic Ductal Adenocarcinomas Undergoing Additive Chemoradiation Link ALDH1A1 to Early Local Recurrence and Chemoradiation Resistance. Transl Oncol 2018; 11:1307-1322. [PMID: 30172883 PMCID: PMC6121830 DOI: 10.1016/j.tranon.2018.08.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 08/02/2018] [Accepted: 08/03/2018] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with frequent post-surgical local recurrence. The combination of adjuvant chemotherapy with radiotherapy is under consideration to achieve a prolonged progression-free survival (PFS). To date, few studies have determined the proteome profiles associated with response to adjuvant chemoradiation. We herein analyzed the proteomes of primary PDAC tumors subjected to additive chemoradiation after surgical resection and achieving short PFS (median 6 months) versus prolonged PFS (median 28 months). Proteomic analysis revealed the overexpression of Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1) and Monoamine Oxidase A (MAOA) in the short PFS cohort, which were corroborated by immunohistochemistry. In vitro, specific inhibition of ALDH1A1 by A37 in combination with gemcitabine, radiation, and chemoradiation lowered cell viability and augmented cell death in MiaPaCa-2 and Panc 05.04 cells. ALDH1A1 silencing in both cell lines dampened cell proliferation, cell metabolism, and colony formation. In MiaPaCa-2 cells, ALDH1A1 silencing sensitized cells towards treatment with gemcitabine, radiation or chemoradiation. In Panc 05.04, increased cell death was observed upon gemcitabine treatment only. These findings are in line with previous studies that have suggested a role of ALDH1A1 chemoradiation resistance, e.g., in esophageal cancer. In summary, we present one of the first proteome studies to investigate the responsiveness of PDAC to chemoradiation and provide further evidence for a role of ALDH1A1 in therapy resistance.
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Affiliation(s)
- V O Oria
- Institute of Molecular Medicine and Cell Research, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany; Spemann Graduate School of Biology and Medicine, Freiburg, Germany
| | - P Bronsert
- Institute of Surgical Pathology, University Medical Center, Freiburg, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Heidelberg, Germany; Tumorbank Comprehensive Cancer Center Freiburg, Medical Center- University of Freiburg, Germany; Faculty of Medicine, University of Freiburg, Germany
| | - A R Thomsen
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Heidelberg, Germany; Faculty of Medicine, University of Freiburg, Germany; Department of Radiation Oncology, Medical Center - University of Freiburg, Germany
| | - M C Föll
- Institute of Molecular Medicine and Cell Research, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - C Zamboglou
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Heidelberg, Germany; Faculty of Medicine, University of Freiburg, Germany; Department of Radiation Oncology, Medical Center - University of Freiburg, Germany
| | - Luciana Hannibal
- Laboratory of Clinical Biochemistry and Metabolism, Department for Pediatrics, Medical Center, University of Freiburg, Freiburg, Germany
| | - S Behringer
- Laboratory of Clinical Biochemistry and Metabolism, Department for Pediatrics, Medical Center, University of Freiburg, Freiburg, Germany
| | - M L Biniossek
- Institute of Molecular Medicine and Cell Research, Freiburg, Germany
| | - C Schreiber
- Institute of Pathology, UKSH Campus Lübeck, Lübeck, Germany
| | - A L Grosu
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Heidelberg, Germany; Faculty of Medicine, University of Freiburg, Germany; Department of Radiation Oncology, Medical Center - University of Freiburg, Germany
| | - L Bolm
- Clinic of Surgery, UKSH Campus Lübeck, Lübeck, Germany
| | - D Rades
- Department of Radiation Oncology, UKSH Campus Lübeck, Lübeck, Germany
| | - T Keck
- Clinic of Surgery, UKSH Campus Lübeck, Lübeck, Germany
| | - M Werner
- Institute of Surgical Pathology, University Medical Center, Freiburg, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Heidelberg, Germany; Tumorbank Comprehensive Cancer Center Freiburg, Medical Center- University of Freiburg, Germany; Faculty of Medicine, University of Freiburg, Germany
| | - U F Wellner
- Clinic of Surgery, UKSH Campus Lübeck, Lübeck, Germany
| | - O Schilling
- Institute of Molecular Medicine and Cell Research, Freiburg, Germany; Institute of Surgical Pathology, University Medical Center, Freiburg, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Heidelberg, Germany; BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany.
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25
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Viola-Rhenals M, Patel KR, Jaimes-Santamaria L, Wu G, Liu J, Dou QP. Recent Advances in Antabuse (Disulfiram): The Importance of its Metal-binding Ability to its Anticancer Activity. Curr Med Chem 2018; 25:506-524. [PMID: 29065820 PMCID: PMC6873226 DOI: 10.2174/0929867324666171023161121] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Revised: 12/05/2016] [Accepted: 12/13/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Considerable evidence demonstrates the importance of dithiocarbamates especially disulfiram as anticancer drugs. However there are no systematic reviews outlining how their metal-binding ability is related to their anticancer activity. This review aims to summarize chemical features and metal-binding activity of disulfiram and its metabolite DEDTC, and discuss different mechanisms of action of disulfiram and their contributions to the drug's anticancer activity. METHODS We undertook a disulfiram-related search on bibliographic databases of peerreviewed research literature, including many historic papers and in vitro, in vivo, preclinical and clinical studies. The selected papers were carefully reviewed and summarized. RESULTS More than five hundreds of papers were obtained in the initial search and one hundred eighteen (118) papers were included in the review, most of which deal with chemical and biological aspects of Disulfiram and the relationship of its chemical and biological properties. Eighty one (81) papers outline biological aspects of dithiocarbamates, and fifty seven (57) papers report biological activity of Disulfiram as an inhibitor of proteasomes or inhibitor of aldehyde dehydrogenase enzymes, interaction with other anticancer drugs, or mechanism of action related to reactive oxygen species. Other papers reviewed focus on chemical aspects of dithiocarbamates. CONCLUSION This review confirms the importance of chemical features of compounds such as Disulfiram to their biological activities, and supports repurposing DSF as a potential anticancer agent.
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Affiliation(s)
- Maricela Viola-Rhenals
- Biochemistry and Cell Biology of Cancer Group, Exacts and Natural Science Faculty, University of Cartagena, Cartagena, Colombia
| | - Kush R. Patel
- Barbara Ann Karmanos Cancer Institute, Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, United States
| | - Laura Jaimes-Santamaria
- Biochemistry and Cell Biology of Cancer Group, Exacts and Natural Science Faculty, University of Cartagena, Cartagena, Colombia
| | - Guojun Wu
- Barbara Ann Karmanos Cancer Institute, Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, United States
| | - Jinbao Liu
- Guangzhou Medical University, Protein Modification and Degradation Lab, Dongfeng Xi road 195#, Guangzhou, Guangdong 510182, China
| | - Q. Ping Dou
- Barbara Ann Karmanos Cancer Institute, Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, United States
- Guangzhou Medical University, Protein Modification and Degradation Lab, Dongfeng Xi road 195#, Guangzhou, Guangdong 510182, China
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26
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Lipid Metabolism and Lipid Droplets in Pancreatic Cancer and Stellate Cells. Cancers (Basel) 2017; 10:cancers10010003. [PMID: 29295482 PMCID: PMC5789353 DOI: 10.3390/cancers10010003] [Citation(s) in RCA: 106] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 12/19/2017] [Accepted: 12/20/2017] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second deadliest cancer by 2030, and the overall 5-year survival rate is currently less than 7%. Cancer cells frequently exhibit reprogramming of their metabolic activity. It is increasingly recognized that aberrant de novo lipid synthesis and reprogrammed lipid metabolism are both associated with the development and progression of various cancers, including pancreatic cancer. In this review, the current knowledge about lipid metabolism and lipid droplets in pancreatic cancer is discussed. In the first part, molecular mechanisms of lipid metabolism and roles of enzymes involved in lipid metabolism which are relevant for pancreatic cancer research are presented. Further, preclinical studies and clinical trials with drugs/inhibitors targeting cancer metabolic systems in cancer are summarized. An increase of our knowledge in lipid metabolism in pancreatic cancer cells and in tumor stroma is important for developing novel strategies of future individualized therapies of pancreatic cancer.
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27
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Murtaja A, Eyol E, Xiaoqi J, Berger MR, Adwan H. The ribosome inhibiting protein riproximin shows antineoplastic activity in experimental pancreatic cancer liver metastasis. Oncol Lett 2017; 15:1441-1448. [PMID: 29434835 PMCID: PMC5777105 DOI: 10.3892/ol.2017.7526] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Accepted: 08/04/2017] [Indexed: 12/18/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has one of the poorest prognoses of all malignancy types. To improve the survival of patients with PDAC, the development of novel anticancer agents is warranted. Riproximin (Rpx) is a newly identified plant lectin, which was isolated from Ximenia americana. The ribosome inactivating protein of type II exhibits potent anticancer activity as recently demonstrated. The rat PDAC cell line ASML was used for in vitro and in vivo studies. The antiproliferative effect of Rpx was assessed using an MTT assay. The modulation of proteins involved in apoptosis was evaluated using western blotting. Tumor-bearing nude rats were treated with Rpx, gemcitabine (GEM) or dinaline (DIN) as single agents, or a combination of Rpx with GEM, or DIN. Rpx was administered intraperitoneally at doses of 1.7–5.4 µg/kg, three times/week, GEM was administered intravenously (50 mg/kg/week) and DIN perorally (10 mg/kg, 5 times/week). Rpx inhibited ASML cell proliferation at IC50-values of 0.8–172 pM, caused apoptosis and reduced tumor growth significantly by 90% (P<0.05). The survival rate of rats was significantly increased (21.8 days for Rpx treated vs. 17.6 days for control rats; P=0.05). Higher doses of Rpx caused no further reduction in tumor size when compared with the low dose of Rpx or a combination of Rpx with GEM, or DIN. The standard drug GEM alone was less effective compared with Rpx. In addition, DIN was ineffective, and in combination, reduced the activity of Rpx. These results suggest that Rpx has an evident potential for use in pancreatic cancer treatment. Further experiments are required in order to elucidate its affinity for certain cancer cells and to optimize the combination therapy with other antineoplastic agents.
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Affiliation(s)
- Ahmed Murtaja
- German Cancer Research Center, Toxicology and Chemotherapy Unit, D-69120 Heidelberg, Germany.,Klinikum der Stadt Ludwigshafen, D-67063 Ludwigshafen, Germany
| | - Ergül Eyol
- German Cancer Research Center, Toxicology and Chemotherapy Unit, D-69120 Heidelberg, Germany.,Faculty of Pharmacy, University of Inonu, 44280 Malatya, Turkey
| | - Jiang Xiaoqi
- German Cancer Research Center, Division of Biostatistics, D-69120 Heidelberg, Germany
| | - Martin R Berger
- German Cancer Research Center, Toxicology and Chemotherapy Unit, D-69120 Heidelberg, Germany
| | - Hassan Adwan
- The German University in Cairo-GUC, New Cairo 11835, Egypt
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28
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Jiao Y, Hannafon BN, Zhang RR, Fung KM, Ding WQ. Docosahexaenoic acid and disulfiram act in concert to kill cancer cells: a mutual enhancement of their anticancer actions. Oncotarget 2017; 8:17908-17920. [PMID: 28107189 PMCID: PMC5392296 DOI: 10.18632/oncotarget.14702] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Accepted: 12/16/2016] [Indexed: 12/20/2022] Open
Abstract
We previously reported a synergistic anticancer action of clioquinol and docosahexaenoic acid (DHA) in human cancer cells. However, clioquinol has been banned from the clinic due to its neurotoxicity. This study identified disulfiram (DSF) as a substitute compound to clioquinol, acting in concert with DHA to more effectively kill cancer cells and suppress tumor growth. Treatment with DSF and DHA induced greater apoptotic cell death and suppression of tumor growth in vitro and in vivo, as compared to DSF and DHA used alone. Mechanistic studies demonstrated that DSF enhances DHA-induced cellular oxidative stress as evidenced by up-regulation of Nrf2-mediated heme oxygenase 1 (HO-1) gene transcription. On the other hand, DHA was found to enhance DSF-induced suppression of mammosphere formation and stem cell frequency in a selected cancer model system, indicating that alterations to cancer cell stemness are involved in the combinatory anticancer action of DSF and DHA. Thus, DHA and DSF, both clinically approved drugs, act in concert to more effectively kill cancer cells. This combinatory action involves an enhancement of cellular oxidative stress and suppression of cancer cell stemness.
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Affiliation(s)
- Yang Jiao
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.,School of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou 215123, P.R. China
| | - Bethany N Hannafon
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Roy R Zhang
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Kar-Ming Fung
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.,Peggy and Charles Stephenson Cancer Center, Oklahoma City, OK 73104, USA
| | - Wei-Qun Ding
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.,Peggy and Charles Stephenson Cancer Center, Oklahoma City, OK 73104, USA
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29
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Moriya C, Taniguchi H, Miyata K, Nishiyama N, Kataoka K, Imai K. Inhibition of PRDM14 expression in pancreatic cancer suppresses cancer stem-like properties and liver metastasis in mice. Carcinogenesis 2017; 38:638-648. [PMID: 28498896 DOI: 10.1093/carcin/bgx040] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Accepted: 05/04/2017] [Indexed: 01/04/2023] Open
Abstract
Pancreatic cancer is one of the most lethal types of cancer, with aggressive properties characterized by metastasis, recurrence and drug resistance. Cancer stem cells are considered to be responsible for these properties. PRDM14, a transcriptional regulator that maintains pluripotency in embryonic stem cells, is overexpressed in some cancers. Here, we assessed PRDM14 expression and the effects of PRDM14 knockdown on cancer stem-like phenotypes in pancreatic cancer. We observed that PRDM14 protein was overexpressed in pancreatic cancer tissues compared with normal pancreatic tissues. Using lentiviral shRNA-transduced pancreatic cancer cells, we found that PRDM14 knockdown decreased sphere formation, number of side population and cell surface marker-positive cells and subcutaneous xenograft tumors and liver metastasis in mice. This was accompanied by upregulation of some microRNAs (miRNAs), including miR-125a-3p. miR-125a-3p, a tumor suppressor that is down-regulated in pancreatic cancer, has been suggested to regulate the expression of the Src-family kinase, Fyn. In PRDM14-knockdown cells, Fyn was expressed at lower levels and downstream proteins were less activated. These changes were considered to cause suppression of the above cancer phenotypes. In addition, we used small interfering RNA (siRNA)-based therapy targeting PRDM14 in a mouse model of liver metastasis induced using MIA-PaCa2 cells, and this treatment significantly decreased metastasis and in vitro migration. Taken together, these results suggest that targeting the overexpression of PRDM14 suppresses cancer stem-like phenotypes, including liver metastasis, via miRNA regulation and siRNA-based therapy targeting it shows promise as a treatment for patients with pancreatic cancer.
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Affiliation(s)
| | | | - Kanjiro Miyata
- Center for Antibody and Vaccine Therapy, Research Hospital, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan, Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, Tokyo 113-8656, Japan
| | - Nobuhiro Nishiyama
- Polymer Chemistry Division, Chemical Resources Laboratory, Tokyo Institute of Technology, Yokohama 226-8503, Japan and
| | - Kazunori Kataoka
- Center for Antibody and Vaccine Therapy, Research Hospital, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan, Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, Tokyo 113-8656, Japan
| | - Kohzoh Imai
- Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
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30
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Tesson M, Anselmi G, Bell C, Mairs R. Cell cycle specific radiosensitisation by the disulfiram and copper complex. Oncotarget 2017; 8:65900-65916. [PMID: 29029481 PMCID: PMC5630381 DOI: 10.18632/oncotarget.19539] [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: 11/09/2016] [Accepted: 06/29/2017] [Indexed: 12/14/2022] Open
Abstract
The disulfiram and copper complex (DSF:Cu) has emerged as a potent radiosensitising anti-cancer agent. The ability of copper to stabilise DSF in a planar conformation and to inhibit DNA replication enzymes stimulated our investigation of the effect of DSF:Cu on cell cycle regulation. Flow cytometry and immunoblotting were used to assess the effect of DSF:Cu on cell cycle progression of the neuroblastoma cell line SK-N-BE(2c) and the glioma cell line UVW. Treatment with 0.1 and 0.3 μM DSF:Cu inhibited DNA synthesis in SK-N-BE(2c) and UVW cells, respectively. The increased potency of ionising radiation treatment induced by DSF:Cu and/or gemcitabine was determined by clonogenic assay. Treatment with 0.3 μM DSF:Cu resulted in greater radiation kill, exemplified by dose enhancement factor values of 2.64 and 2.84 in SK-N-BE(2c) and UVW cells, respectively. Although DSF:Cu failed to sensitise S phase cells to irradiation, we observed that DSF:Cu radiosensitisation was potentiated by the S phase-specific cytotoxic drug gemcitabine. The efficacy of the combination treatment consisting of DSF:Cu, gemcitabine and ionising radiation was schedule-dependent. Together, these results describe cell cycle specific radiosensitisation by DSF:Cu. The well-established toxicity profiles of DSF and gemcitabine should facilitate their evaluation as a combination treatment in patients undergoing radiotherapy.
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Affiliation(s)
- Mathias Tesson
- Radiation Oncology, Institute of Cancer Sciences, Wolfson Wohl Translational Cancer Research Center, University of Glasgow, Bearsden, Glasgow, UK
| | - Giorgio Anselmi
- Centre for Molecular and Cellular Biology of Inflammation, Peter Gorer Department of Immunobiology, Division of Immunology, Infection and Inflammatory Diseases, King's College London, London, UK
| | - Caitlin Bell
- Cancer Research UK Beatson Institute, Bearsden, Glasgow, UK
| | - Robert Mairs
- Radiation Oncology, Institute of Cancer Sciences, Wolfson Wohl Translational Cancer Research Center, University of Glasgow, Bearsden, Glasgow, UK
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31
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Repurposing Established Compounds to Target Pancreatic Cancer Stem Cells (CSCs). Med Sci (Basel) 2017; 5:medsci5020014. [PMID: 29099030 PMCID: PMC5635789 DOI: 10.3390/medsci5020014] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Revised: 06/11/2017] [Accepted: 06/11/2017] [Indexed: 02/08/2023] Open
Abstract
The diagnosis of pancreatic ductal adenocarcinoma (PDAC) carries a dismal prognosis, in particular, when patients present with unresectable disease. While significant progress has been made in understanding the biology of PDAC, this knowledge has not translated into a clear clinical benefit and current chemotherapeutic strategies only offer a modest improvement in overall survival. Accordingly, novel approaches are desperately needed. One hypothesis that could—at least in part—explain the desolate response of PDAC to chemotherapy is the so-called cancer stem cell (CSC) concept, which attributes specific traits, such as chemoresistance, metastatic potential and a distinct metabolism to a small cellular subpopulation of the whole tumor. At the same time, however, some of these attributes could make CSCs more permissive for novel therapeutic strategies with compounds that are already in clinical use. Most recently, several publications have tried to enlighten the field with the idea of repurposing established drugs for antineoplastic use. As such, recycling drugs could present an intriguing and fast-track method with new therapeutic paradigms in anti-cancer and anti-CSC treatments. Here, we aim to summarize important aspects and novel findings of this emerging field.
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32
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Li Y, Atkinson K, Zhang T. Combination of chemotherapy and cancer stem cell targeting agents: Preclinical and clinical studies. Cancer Lett 2017; 396:103-109. [PMID: 28300634 DOI: 10.1016/j.canlet.2017.03.008] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Revised: 03/03/2017] [Accepted: 03/06/2017] [Indexed: 12/12/2022]
Abstract
The cancer stem cell model claims that the initiation, maintenance, and growth of a tumor are driven by a small population of cancer cells termed cancer stem cells. Cancer stem cells possess a variety of phenotypes associated with therapeutic resistance and often cause recurrence of the diseases. Several strategies have been investigated to target cancer stem cells in a variety of cancers, such as blocking one or more self-renewal signaling pathways, reducing the expression of drug efflux and ATP-binding cassette efflux transporters, modulating epigenetic aberrations, and promoting cancer stem cell differentiation. A number of cell and animal studies strongly support the potential benefits of combining chemotherapeutic drugs with cancer stem cell targeting agents. Clinical trials are still underway to address the pharmacokinetics, safety, and efficacy of combination treatment. This mini-review provides an updated discussion of these preclinical and clinical studies.
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Affiliation(s)
- Yanyan Li
- College of Science and Humanities, Husson University, 1 College Circle, Bangor, ME, 04401, USA.
| | - Katharine Atkinson
- College of Science and Humanities, Husson University, 1 College Circle, Bangor, ME, 04401, USA
| | - Tao Zhang
- School of Pharmacy, Husson University, 1 College Circle, Bangor, ME, 04401, USA
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33
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Moreb JS, Ucar-Bilyeu DA, Khan A. Use of retinoic acid/aldehyde dehydrogenase pathway as potential targeted therapy against cancer stem cells. Cancer Chemother Pharmacol 2016; 79:295-301. [PMID: 27942929 DOI: 10.1007/s00280-016-3213-5] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 11/29/2016] [Indexed: 12/28/2022]
Abstract
A large number of studies have investigated possible drug resistance mechanisms of cancer cells and suggested strategies to overcome it. In this review, we outline the role and function of aldehyde dehydrogenase (ALDH) activity in multiple cellular functions and in cancer stem cells (CSCs) and focus on the role of retinoic acid (RA), one of the products of ALDH isozymes. We discuss our observation that ATRA and other RAs can suppress ALDH activity and decrease different ALDH isozyme proteins and result in detrimental effects on cell proliferation, invasion and chemotherapy sensitivity. We review the known uses of different RAs in the treatment of cancers. We review the use of RAs in combination with chemo-/radiotherapy and the major signaling pathways affected in different tumor types. We provide follow-up on studies that may have used our prior observation with the aim of targeting the CSCs. We conclude with summary of the findings and potential impact of published studies on future use of RAs in the targeting of CSCs and drug resistance.
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Affiliation(s)
- Jan S Moreb
- Hematology/Oncology Division, Department of Medicine, University of Florida, 1600 SW Archer Rd, PO Box 100277, Gainesville, FL, 32610, USA.
| | | | - Abdullah Khan
- Hematology/Oncology Division, Department of Medicine, University of Florida, 1600 SW Archer Rd, PO Box 100277, Gainesville, FL, 32610, USA
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34
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Affiliation(s)
- Ashish R Kadia
- Department of Pharmacology and Clinical Pharmacy, K.B. Institute of Pharmaceutical Education and Research, Gandhinagar, Gujarat, India
| | - Gaurang B Shah
- Department of Pharmacology and Clinical Pharmacy, K.B. Institute of Pharmaceutical Education and Research, Gandhinagar, Gujarat, India
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35
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Bai X, Chen Y, Hou X, Huang M, Jin J. Emerging role of NRF2 in chemoresistance by regulating drug-metabolizing enzymes and efflux transporters. Drug Metab Rev 2016; 48:541-567. [PMID: 27320238 DOI: 10.1080/03602532.2016.1197239] [Citation(s) in RCA: 129] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Chemoresistance is a disturbing barrier in cancer therapy, which always results in limited therapeutic options and unfavorable prognosis. Nuclear factor E2-related factor 2 (NRF2) controls the expression of genes encoding cytoprotective enzymes and transporters that protect against oxidative stress and electrophilic injury to maintain intrinsic redox homeostasis. However, recent studies have demonstrated that aberrant activation of NRF2 due to genetic and/or epigenetic mutations in tumor contributes to the high expression of phase I and phase II drug-metabolizing enzymes, phase III transporters, and other cytoprotective proteins, which leads to the decreased therapeutic efficacy of anticancer drugs through biotransformation or extrusion during chemotherapy. Therefore, a better understanding of the role of NRF2 in regulation of these enzymes and transporters in tumors is necessary to find new strategies that improve chemotherapeutic efficacy. In this review, we summarized the recent findings about the chemoresistance-promoting role of NRF2, NRF2-regulated phase I and phase II drug-metabolizing enzymes, phase III drug efflux transporters, and other cytoprotective genes. Most importantly, the potential of NRF2 was proposed to counteract drug resistance in cancer treatment.
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Affiliation(s)
- Xupeng Bai
- a School of Pharmaceutical Sciences , Sun Yat-Sen University , Guangzhou , China
| | - Yibei Chen
- a School of Pharmaceutical Sciences , Sun Yat-Sen University , Guangzhou , China
| | - Xiangyu Hou
- a School of Pharmaceutical Sciences , Sun Yat-Sen University , Guangzhou , China
| | - Min Huang
- a School of Pharmaceutical Sciences , Sun Yat-Sen University , Guangzhou , China
| | - Jing Jin
- a School of Pharmaceutical Sciences , Sun Yat-Sen University , Guangzhou , China
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36
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Huang J, Campian JL, Gujar AD, Tran DD, Lockhart AC, DeWees TA, Tsien CI, Kim AH. A phase I study to repurpose disulfiram in combination with temozolomide to treat newly diagnosed glioblastoma after chemoradiotherapy. J Neurooncol 2016; 128:259-66. [DOI: 10.1007/s11060-016-2104-2] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2015] [Accepted: 03/05/2016] [Indexed: 12/31/2022]
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Rodriguez-Torres M, Allan AL. Aldehyde dehydrogenase as a marker and functional mediator of metastasis in solid tumors. Clin Exp Metastasis 2015; 33:97-113. [PMID: 26445849 PMCID: PMC4740561 DOI: 10.1007/s10585-015-9755-9] [Citation(s) in RCA: 96] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2015] [Accepted: 10/01/2015] [Indexed: 12/16/2022]
Abstract
There is accumulating evidence indicating that aldehyde dehydrogenase (ALDH) activity selects for cancer cells with increased aggressiveness, capacity for sustained proliferation, and plasticity in primary tumors. However, emerging data also suggests an important mechanistic role for the ALDH family of isoenzymes in the metastatic activity of tumor cells. Recent studies indicate that ALDH correlates with either increased or decreased metastatic capacity in a cellular context-dependent manner. Importantly, it appears that different ALDH isoforms support increased metastatic capacity in different tumor types. This review assesses the potential of ALDH as biological marker and mechanistic mediator of metastasis in solid tumors. In many malignancies, most notably in breast cancer, ALDH activity and expression appears to be a promising marker and potential therapeutic target for treating metastasis in the clinical setting.
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Affiliation(s)
- Mauricio Rodriguez-Torres
- London Regional Cancer Program, London Health Sciences Centre, London, ON, Canada.,Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Alison L Allan
- London Regional Cancer Program, London Health Sciences Centre, London, ON, Canada. .,Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada. .,Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada. .,Lawson Health Research Institute, London, ON, Canada. .,London Regional Cancer Program, Room A4-132, 790 Commissioners Road East, London, ON, N6A 4L6, Canada.
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Kast RE, Karpel-Massler G, Halatsch ME. CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide. Oncotarget 2015; 5:8052-82. [PMID: 25211298 PMCID: PMC4226667 DOI: 10.18632/oncotarget.2408] [Citation(s) in RCA: 93] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
CUSP9 treatment protocol for recurrent glioblastoma was published one year ago. We now present a slight modification, designated CUSP9*. CUSP9* drugs--aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, sertraline, ritonavir, are all widely approved by regulatory authorities, marketed for non-cancer indications. Each drug inhibits one or more important growth-enhancing pathways used by glioblastoma. By blocking survival paths, the aim is to render temozolomide, the current standard cytotoxic drug used in primary glioblastoma treatment, more effective. Although esthetically unpleasing to use so many drugs at once, the closely similar drugs of the original CUSP9 used together have been well-tolerated when given on a compassionate-use basis in the cases that have come to our attention so far. We expect similarly good tolerability for CUSP9*. The combined action of this suite of drugs blocks signaling at, or the activity of, AKT phosphorylation, aldehyde dehydrogenase, angiotensin converting enzyme, carbonic anhydrase -2,- 9, -12, cyclooxygenase-1 and -2, cathepsin B, Hedgehog, interleukin-6, 5-lipoxygenase, matrix metalloproteinase -2 and -9, mammalian target of rapamycin, neurokinin-1, p-gp efflux pump, thioredoxin reductase, tissue factor, 20 kDa translationally controlled tumor protein, and vascular endothelial growth factor. We believe that given the current prognosis after a glioblastoma has recurred, a trial of CUSP9* is warranted.
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Affiliation(s)
| | - Georg Karpel-Massler
- University of Ulm, Department of Neurosurgery, Albert-Einstein-Allee 23, Ulm, Germany
| | - Marc-Eric Halatsch
- University of Ulm, Department of Neurosurgery, Albert-Einstein-Allee 23, Ulm, Germany
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Abstract
OBJECTIVES Survivin, an antiapoptotic gene inhibited by p53, is overexpressed in human cancers and correlates with chemotherapy resistance. Here, we investigated the mutual regulatory mechanism between MGMT (O-methylguanine DNA methyltransferase) and survivin. METHODS This study used standard techniques for protein and messenger RNA levels, promoter activity, protein-DNA interaction, cell viability, and correlative animal model. RESULTS O-benzylguanine (BG), a potent inhibitor of MGMT (a DNA repair protein), curtails the expression of survivin in pancreatic cancer. Silencing MGMT by small interfering RNA down-regulates survivin transcription. p53 inhibition enhances MGMT and survivin expressions. When p53 was silenced, BG-induced MGMT inhibition was not associated with the down-regulation of survivin, underscoring the regulatory role of p53 in the MGMT-survivin axis. O-benzylguanine inhibits survivin and PCNA (proliferating cell nuclear antigen) at messenger RNA and protein levels in PANC-1 and L3.6pl cells and decreases survivin promoter activity via increased p53 recruitment to the survivin promoter. In orthotopic pancreatic xenografts established in nude mice, BG ± gemcitabine (GEM) decrease survivin expression in tumor tissue; protein levels and immunohistochemistry show significant decrease in survivin and PCNA levels, which correlate with increased sensitivity to GEM. CONCLUSIONS MGMT inhibition is associated with decrease in survivin expression and increase in sensitivity to GEM in pancreatic cancer.
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Cojoc M, Mäbert K, Muders MH, Dubrovska A. A role for cancer stem cells in therapy resistance: Cellular and molecular mechanisms. Semin Cancer Biol 2015; 31:16-27. [DOI: 10.1016/j.semcancer.2014.06.004] [Citation(s) in RCA: 289] [Impact Index Per Article: 28.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Revised: 06/04/2014] [Accepted: 06/11/2014] [Indexed: 12/11/2022]
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Singh S, Arcaroli J, Thompson DC, Messersmith W, Vasiliou V. Acetaldehyde and retinaldehyde-metabolizing enzymes in colon and pancreatic cancers. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2015; 815:281-94. [PMID: 25427913 DOI: 10.1007/978-3-319-09614-8_16] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Colorectal cancer (CRC) and pancreatic cancer are two very significant contributors to cancer-related deaths. Chronic alcohol consumption is an important risk factor for these cancers. Ethanol is oxidized primarily by alcohol dehydrogenases to acetaldehyde, an agent capable of initiating tumors by forming adducts with proteins and DNA. Acetaldehyde is metabolized by ALDH2, ALDH1B1, and ALDH1A1 to acetate. Retinoic acid (RA) is required for cellular differentiation and is known to arrest tumor development. RA is synthesized from retinaldehyde by the retinaldehyde dehydrogenases, specifically ALDH1A1, ALDH1A2, ALDH1A3, and ALDH8A1. By eliminating acetaldehyde and generating RA, ALDHs can play a crucial regulatory role in the initiation and progression of cancers. ALDH1 catalytic activity has been used as a biomarker to identify and isolate normal and cancer stem cells; its presence in a tumor is associated with poor prognosis in colon and pancreatic cancer. In summary, these ALDHs are not only biomarkers for CRC and pancreatic cancer but also play important mechanistic role in cancer initiation, progression, and eventual prognosis.
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Affiliation(s)
- S Singh
- Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Mail Stop C238-P20, 12850 E Montview Blvd, Aurora, CO, 80045, USA
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Hoshino Y, Nishida J, Katsuno Y, Koinuma D, Aoki T, Kokudo N, Miyazono K, Ehata S. Smad4 Decreases the Population of Pancreatic Cancer-Initiating Cells through Transcriptional Repression of ALDH1A1. THE AMERICAN JOURNAL OF PATHOLOGY 2015; 185:1457-70. [PMID: 25769430 DOI: 10.1016/j.ajpath.2015.01.011] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/12/2014] [Revised: 12/16/2014] [Accepted: 01/06/2015] [Indexed: 12/16/2022]
Abstract
Cancer progression involves a rare population of undifferentiated cancer-initiating cells that have stem cell-like properties for self-renewal capacity and high tumorigenicity. We investigated how maintenance of pancreatic cancer-initiating cells is influenced by Smad4, which is frequently deleted or mutated in pancreatic cancers cells. Smad4 silencing up-regulated the expression of aldehyde dehydrogenase 1A1 (ALDH1A1) mRNA, whereas forced expression of Smad4 in pancreatic cancer cells down-regulated it. Smad4 and ALDH1 expression inversely correlated in some human clinical pancreatic adenocarcinoma tissues, suggesting that ALDH1 in pancreatic cancer cells was associated with decreased Smad4 expression. We then examined whether ALDH1 served as a marker of pancreatic cancer-initiating cells. Pancreatic cancer cells contained ALDH1(hi) cells in 3% to 10% of total cells, with high tumorigenic potential. Because Smad4 is a major mediator of transforming growth factor (TGF)-β family signaling, we investigated the regulatory mechanism of ALDH activity by TGF-β and bone morphogenetic proteins. Treatment with TGF-β attenuated ALDH1(hi) cells in several pancreatic cancer cells, whereas bone morphogenetic protein-4 was not as potent. Biochemical experiments revealed that TGF-β regulated ALDH1A1 mRNA transcription through binding of Smad4 to its regulatory sequence. It appears that TGF-β negatively regulates ALDH1 expression in pancreatic cancer cells in a Smad-dependent manner and in turn impairs the activity of pancreatic cancer-initiating cells.
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Affiliation(s)
- Yukari Hoshino
- Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Jun Nishida
- Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yoko Katsuno
- Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Daizo Koinuma
- Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Taku Aoki
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Norihiro Kokudo
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kohei Miyazono
- Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Shogo Ehata
- Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Adwan H, Murtaja A, Kadhim Al-Taee K, Pervaiz A, Hielscher T, Berger MR. Riproximin's activity depends on gene expression and sensitizes PDAC cells to TRAIL. Cancer Biol Ther 2014; 15:1185-97. [PMID: 24918923 PMCID: PMC4128861 DOI: 10.4161/cbt.29503] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Accepted: 06/05/2014] [Indexed: 01/05/2023] Open
Abstract
Riproximin (Rpx) is a type II ribosome inactivating protein, which was investigated for its activity in pancreatic ductal adenocarcinoma (PDAC) in a panel of 17 human and rat PDAC cell lines and in rat pancreatic cancer liver metastasis. Cytotoxicity in response to Rpx was determined by MTT assay, apoptosis by flow cytometry and qRT-PCR for apoptosis related genes, and the modulation of the transcriptome was monitored by micro array analysis. The combination effect of Rpx and TRAIL was assessed by MTT assay. Rpx showed high but varying cytotoxicity in PDAC cells. Based on overall gene expression, the sensitivity of these cells was linked to genes involved in apoptosis. Furthermore, based on the affinity of Rpx for CEA, the expression of carcinoembryonic antigen-related cell adhesion molecule (CEACAM) genes was significantly related to Rpx's cytotoxicity in cells with CEACAM gene expression. Exposure of Suit2-007 cells to Rpx induced the mRNA expression of members of signaling pathways initiating from most death receptors, and down modulation of TRAIL. Apoptosis was increased as shown by FACS analysis. Combination of Rpx with TRAIL resulted in a synergistic cytotoxic effect in human Suit2-007 and rat ASML cells, as evidenced by a 6-fold lower tumor cell survival than expected from an additive combination effect. Treatment of BDX rats bearing intra-portally implanted Suit2-007 cells showed a highly significant anticancer effect and indicated an application of Rpx against pancreatic cancer metastasis to the liver. These data favor further evaluation of Rpx as anticancer agent in PDAC.
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Affiliation(s)
- Hassan Adwan
- Toxicology and Chemotherapy Unit; German Cancer Research Center (DKFZ); Heidelberg, Germany
| | - Ahmed Murtaja
- Toxicology and Chemotherapy Unit; German Cancer Research Center (DKFZ); Heidelberg, Germany
| | - Khamael Kadhim Al-Taee
- Toxicology and Chemotherapy Unit; German Cancer Research Center (DKFZ); Heidelberg, Germany
| | - Asim Pervaiz
- Toxicology and Chemotherapy Unit; German Cancer Research Center (DKFZ); Heidelberg, Germany
| | - Thomas Hielscher
- Division of Biostatistics; Statistics for Translational Oncology; DKFZ; Heidelberg, Germany
| | - Martin R Berger
- Toxicology and Chemotherapy Unit; German Cancer Research Center (DKFZ); Heidelberg, Germany
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Löhr JM, Haas SL, Kröger JC, Friess HM, Höft R, Goretzki PE, Peschel C, Schweigert M, Salmons B, Gunzburg WH. Encapsulated cells expressing a chemotherapeutic activating enzyme allow the targeting of subtoxic chemotherapy and are safe and efficacious: data from two clinical trials in pancreatic cancer. Pharmaceutics 2014; 6:447-466. [PMID: 25116885 PMCID: PMC4190529 DOI: 10.3390/pharmaceutics6030447] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2014] [Revised: 07/02/2014] [Accepted: 07/30/2014] [Indexed: 02/07/2023] Open
Abstract
Despite progress in the treatment of pancreatic cancer, there is still a need for improved therapies. In this manuscript, we report clinical experience with a new therapy for the treatment of pancreatic cancer involving the implantation of encapsulated cells over-expressing a cytochrome P450 enzyme followed by subsequent low-dose ifosfamide administrations as a means to target activated ifosfamide to the tumor. The safety and efficacy of the angiographic instillation of encapsulated allogeneic cells overexpressing cytochrome P450 in combination with low-dose systemic ifosfamide administration has now been evaluated in 27 patients in total. These patients were successfully treated in four centers by three different interventional radiologists, arguing strongly that the treatment can be successfully used in different centers. The safety of the intra-arterial delivery of the capsules and the lack of evidence that the patients developed an inflammatory or immune response to the encapsulated cells or encapsulation material was shown in all 27 patients. The ifosfamide dose of 1 g/m2/day used in the first trial was well tolerated by all patients. In contrast, the ifosfamide dose of 2 g/m2/day used in the second trial was poorly tolerated in most patients. Since the median survival in the first trial was 40 weeks and only 33 weeks in the second trial, this strongly suggests that there is no survival benefit to increasing the dose of ifosfamide, and indeed, a lower dose is beneficial for quality of life and the lack of side effects. This is supported by the one-year survival rate in the first trial being 38%, whilst that in the second trial was only 23%. However, taking the data from both trials together, a total of nine of the 27 patients were alive after one year, and two of these nine patients were alive for two years or more.
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Affiliation(s)
- J Matthias Löhr
- Gastrocentrum, Karolinska University Hospital, Hälsovägen 1, SE-141 86 Stockholm, Sweden.
| | - Stephan L Haas
- Gastrocentrum, Karolinska University Hospital, Hälsovägen 1, SE-141 86 Stockholm, Sweden.
| | - Jens C Kröger
- Institute of Diagnostic und Interventional Radiology, University Medicine Rostock, Ernst-Heydemann-Strasse 6, D-18057 Rostock, Germany.
| | - Helmut M Friess
- Department of Surgery, Klinikum rechts der Isar der Technischen Universität München, Ismaninger Strasse 22, D-81675 Munich, Germany.
| | - Raimund Höft
- Abteilung für Gastroenterologie, Klinik und Poliklinik für Innere Medizin, Universität Rostock, Ernst-Heydemann-Strasse 6, D-18057 Rostock, Germany.
| | - Peter E Goretzki
- Chirurgische Klinik und Poliklinik, Medizinische Einrichtungen der Heinrich Heine Universität, Moorenstrasse 5, D-40225 Düsseldorf, Germany.
| | - Christian Peschel
- Medizinische Klinik und Poliklinik, Klinikum Rechts der Isar der Technischen Universität München III, Ismaninger Strasse 22, D-81675 Munich, Germany.
| | - Markus Schweigert
- Medizinische Klinik (Onkologie/Hämatologie) Campus Mitte, Universitätsklinikum Charité II, Schumannstrasse 21/22, D-10098 Berlin, Germany.
| | - Brian Salmons
- Austrianova Singapore Pte Ltd, Centros, Biopolis, Singapore.
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Affiliation(s)
- Ansgar Brüning
- University Hospital Munich; Department of OB/GYB; Molecular Biology Laboratory; Munich, Germany
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Herreros-Villanueva M, Bujanda L, Billadeau DD, Zhang JS. Embryonic stem cell factors and pancreatic cancer. World J Gastroenterol 2014; 20:2247-2254. [PMID: 24605024 PMCID: PMC3942830 DOI: 10.3748/wjg.v20.i9.2247] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 12/15/2013] [Accepted: 01/14/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic tumor, is a highly aggressive human cancer with the lowest five-year survival rate of any human maligancy primarily due to its early- metastasis and lack of response to chemotherapy and radiation. Recent research suggests that PDAC cells comprise a hierarchy of tumor cells that develop around a population of cancer stem cells (CSCs), a small and distinct population of cancer cells that mediates tumoregenesis, metastasis and resistance to standard treatments. Thus, CSCs could be a target for more effective treatment options. Interestingly, pancreatic CSCs are subject to regulation by some of key embryonic stem cell (ESC) transctiption factors abberently expressed in PDAC, such as SOX2, OCT4 and NANOG. ESC transcription factors are important DNA-binding proteins present in both embryonic and adult somatic cells. The critical role of these factors in reprogramming processes makes them essential not only for embryonic development but also tumorigenesis. Here we provide an overview of stem cell transcription factors, particularly SOX2, OCT4, and NANOG, on their expression and function in pancreatic cancer. In contrast to embryonic stem cells, in which OCT4 and SOX2 are tightly regulated and physically interact to regulate a wide spectrum of target genes, de novo SOX2 expression alone in pancreatic cancer cells is sufficient to promote self-renewal, de-differentiation and imparting stemness characteristics via impacting specific cell cycle regulatory genes and epithelial-mesnechymal transtion driver genes. Thus, targeting ESC factors, particularly SOX2, could be a worthy strategy for pancreatic cancer therapy.
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