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Zhong R, Qiu C, Chan S, Wang Y, Liu K, Xia Y, Zhang H, Zou B. TDH-11 inhibits the proliferation and colonization of colorectal cancer by reducing the activity of HDAC. Cell Signal 2025; 132:111817. [PMID: 40250693 DOI: 10.1016/j.cellsig.2025.111817] [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: 12/17/2024] [Revised: 03/28/2025] [Accepted: 04/14/2025] [Indexed: 04/20/2025]
Abstract
Histone deacetylase inhibitors (HDACIs) have demonstrated significant efficacy and minimal toxic side effects in certain hematological tumors. Nevertheless, their utilization in the therapy of solid tumors, including colorectal cancer (CRC), is constrained by the occurrence of adverse effects such as myelosuppression and cardiotoxicity. Therefore, the development of more efficient and safer HDACIs is crucial for managing CRC. Here, the effects of TDH-11 (a novel HDAC inhibitor) and the underlying molecular mechanisms that inhibits the deveolpment and progression of CRC cells were investigated using in vitro and in vivo experiments. The results indicated that TDH-11 inhibited CRC tumorigenic behavior while also promoted apoptosis and cell cycle arrest. In vivo, TDH-11 markedly inhibited tumor progression and reduces tumor colonization without causing substantial damage to key organs, such as the kidneys, heart, lungs, spleen, and liver. Results of RNA sequencing and western blot suggested that TDH-11 exerted its antitumor effects through modulation of the p53 signaling pathway and its downstream pathways involved in apoptosis and cell cycle regulation. In summary, TDH-11 exhibited significant potential in suppressing the growth and colonization of CRC, as determined in both cellular and animal models. These results provided novel insights into CRC-associated pathways and suggest promising prospects for managing advanced and metastatic CRC.
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Affiliation(s)
- Rulei Zhong
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China; Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei, China; Anhui Medical University, Hefei, 230032, Anhui, China
| | - Chenyang Qiu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China; Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei, China; Anhui Medical University, Hefei, 230032, Anhui, China
| | - Shixin Chan
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China; Anhui Medical University, Hefei, 230032, Anhui, China
| | - Yiming Wang
- Department of Biochemistry and Molecular Biology, Metabolic Disease Research Center, School of Basic Medicine, Anhui Medical University, Hefei 230032, Anhui, China; Anhui Medical University, Hefei, 230032, Anhui, China
| | - Kaige Liu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China; Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei, China; Anhui Medical University, Hefei, 230032, Anhui, China
| | - Yihui Xia
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China; Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei, China; Anhui Medical University, Hefei, 230032, Anhui, China
| | - Huabing Zhang
- Department of Biochemistry and Molecular Biology, Metabolic Disease Research Center, School of Basic Medicine, Anhui Medical University, Hefei 230032, Anhui, China; Anhui Medical University, Hefei, 230032, Anhui, China.
| | - Bingbing Zou
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China; Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei, China; Anhui Medical University, Hefei, 230032, Anhui, China.
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Tahghighi A, Seyedhashemi E, Mohammadi J, Moradi A, Esmaeili A, Pornour M, Jafarifar K, Ganji SM. Epigenetic marvels: exploring the landscape of colorectal cancer treatment through cutting-edge epigenetic-based drug strategies. Clin Epigenetics 2025; 17:34. [PMID: 39987205 PMCID: PMC11847397 DOI: 10.1186/s13148-025-01844-w] [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: 09/01/2024] [Accepted: 02/14/2025] [Indexed: 02/24/2025] Open
Abstract
Epigenetics is currently considered the investigation of inheritable changes in gene expression that do not rely on DNA sequence alteration. Significant epigenetic procedures are involved, such as DNA methylations, histone modifications, and non-coding RNA actions. It is confirmed through several investigations that epigenetic changes are associated with the formation, development, and metastasis of various cancers, such as colorectal cancer (CRC). The difference between epigenetic changes and genetic mutations is that the former could be reversed or prevented; therefore, cancer treatment and prevention could be achieved by restoring abnormal epigenetic events within the neoplastic cells. These treatments, consequently, cause the anti-tumour effects augmentation, drug resistance reduction, and host immune response stimulation. In this article, we begin our survey by exploring basic epigenetic mechanisms to understand epigenetic tools and strategies for treating colorectal cancer in monotherapy and combination with chemotherapy or immunotherapy.
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Affiliation(s)
- Azar Tahghighi
- Medicinal Chemistry Laboratory, Clinical Research Department, Pasteur Institute of Iran, Tehran, Iran
| | - Effat Seyedhashemi
- Department of Molecular Medicine, Department of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Shahrak-E Pajoohesh, Km 15, P.O. Box 14965/161, Tehran, Iran
| | - Javad Mohammadi
- Department of Molecular Medicine, Department of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Shahrak-E Pajoohesh, Km 15, P.O. Box 14965/161, Tehran, Iran
- Department of Life Science Engineering, Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran
| | - Arash Moradi
- Department of Molecular Medicine, Department of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Shahrak-E Pajoohesh, Km 15, P.O. Box 14965/161, Tehran, Iran
| | - Aria Esmaeili
- Department of Molecular Medicine, Department of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Shahrak-E Pajoohesh, Km 15, P.O. Box 14965/161, Tehran, Iran
| | - Majid Pornour
- Department of Biochemistry and Molecular Biology, University of Maryland, Baltimore, MD, USA
| | - Kimia Jafarifar
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Shahla Mohammad Ganji
- Department of Molecular Medicine, Department of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Shahrak-E Pajoohesh, Km 15, P.O. Box 14965/161, Tehran, Iran.
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Tian S, Chen M. The mechanisms and drug therapies of colorectal cancer and epigenetics: bibliometrics and visualized analysis. Front Pharmacol 2024; 15:1466156. [PMID: 39268463 PMCID: PMC11391208 DOI: 10.3389/fphar.2024.1466156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 08/19/2024] [Indexed: 09/15/2024] Open
Abstract
BACKGROUND Numerous studies have demonstrated a link between epigenetics and CRC. However, there has been no systematic analysis or visualization of relevant publications using bibliometrics. METHODS 839 publications obtained from the Web of Science Core (WoSCC) were systematically analyzed using CiteSpace and VOSviewer software. RESULTS The results show that the countries, institutions, and authors with the most published articles are the United States, Harvard University, and Ogino and Shuji, respectively. SEPT9 is a blood test for the early detection of colorectal cancer. Vitamin D and gut microbiota mediate colorectal cancer and epigenetics, and probiotics may reduce colorectal cancer-related symptoms. We summarize the specific epigenetic mechanisms of CRC and the current existence and potential epigenetic drugs associated with these mechanisms. It is closely integrated with clinical practice, and the possible research directions and challenges in the future are proposed. CONCLUSION This study reviews the current research trends and hotspots in CRC and epigenetics, which can promote the development of this field and provide references for researchers in this field.
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Affiliation(s)
- Siyu Tian
- School of Clinical Medicine, Chengdu University of TCM, Chengdu, China
| | - Min Chen
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Lopes N, Salta S, Flores BT, Miranda-Gonçalves V, Correia MP, Gigliano D, Guimarães R, Henrique R, Jerónimo C. Anti-tumour activity of Panobinostat in oesophageal adenocarcinoma and squamous cell carcinoma cell lines. Clin Epigenetics 2024; 16:102. [PMID: 39097736 PMCID: PMC11297794 DOI: 10.1186/s13148-024-01700-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 06/21/2024] [Indexed: 08/05/2024] Open
Abstract
BACKGROUND Oesophageal cancer remains a challenging disease with high mortality rates and few therapeutic options. In view of these difficulties, epigenetic drugs have emerged as potential alternatives for patient care. The goal of this study was to evaluate the effect and biological consequences of Panobinostat treatment, an HDAC (histone deacetylase) inhibitor already approved for treatment of patients with multiple myeloma, in oesophageal cell lines of normal and malignant origin, with the latter being representative of the two main histological subtypes: adenocarcinoma and squamous cell carcinoma. RESULTS Panobinostat treatment inhibited growth and hindered proliferation, colony formation and invasion of oesophageal cancer cells. Considering HDAC tissue expression, HDAC1 was significantly upregulated in normal oesophageal epithelium in comparison with tumour tissue, whereas HDAC3 was overexpressed in oesophageal cancer compared to non-malignant mucosa. No differences between normal and tumour tissue were observed for HDAC2 and HDAC8 expression. CONCLUSIONS Panobinostat exposure effectively impaired malignant features of oesophageal cancer cells. Because HDAC3 was shown to be overexpressed in oesophageal tumour samples, this epigenetic drug may represent an alternative therapeutic option for oesophageal cancer patients.
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Affiliation(s)
- Nair Lopes
- Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP) - CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC), Research Center-LAB 3, F Bdg, 1st Floor, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Sofia Salta
- Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP) - CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC), Research Center-LAB 3, F Bdg, 1st Floor, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
- Doctoral Program in Pathology and Molecular Genetics, ICBAS - School of Medicine and Biomedical Sciences - University of Porto (ICBAS-UP), Rua de Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal
| | - Bianca Troncarelli Flores
- Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP) - CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC), Research Center-LAB 3, F Bdg, 1st Floor, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Vera Miranda-Gonçalves
- Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP) - CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC), Research Center-LAB 3, F Bdg, 1st Floor, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
- Department of Pathology and Molecular Immunology, ICBAS-School of Medicine and Biomedical Sciences, University of Porto (ICBAS-UP), Rua de Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal
| | - Margareta P Correia
- Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP) - CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC), Research Center-LAB 3, F Bdg, 1st Floor, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
- Department of Pathology and Molecular Immunology, ICBAS-School of Medicine and Biomedical Sciences, University of Porto (ICBAS-UP), Rua de Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal
| | - Davide Gigliano
- Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Rita Guimarães
- Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Rui Henrique
- Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP) - CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC), Research Center-LAB 3, F Bdg, 1st Floor, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
- Department of Pathology and Molecular Immunology, ICBAS-School of Medicine and Biomedical Sciences, University of Porto (ICBAS-UP), Rua de Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal
- Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Carmen Jerónimo
- Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP) - CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC), Research Center-LAB 3, F Bdg, 1st Floor, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.
- Department of Pathology and Molecular Immunology, ICBAS-School of Medicine and Biomedical Sciences, University of Porto (ICBAS-UP), Rua de Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal.
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Martino E, Thakur S, Kumar A, Yadav AK, Boschi D, Kumar D, Lolli M. Insight in Quinazoline-based HDAC Inhibitors as Anti-cancer Agents. Mini Rev Med Chem 2024; 24:1983-2007. [PMID: 38859778 DOI: 10.2174/0113895575303614240527093106] [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: 02/22/2024] [Revised: 03/20/2024] [Accepted: 03/28/2024] [Indexed: 06/12/2024]
Abstract
Cancer remains a primary cause of death globally, and effective treatments are still limited. While chemotherapy has notably enhanced survival rates, it brings about numerous side effects. Consequently, the ongoing challenge persists in developing potent anti-cancer agents with minimal toxicity. The versatile nature of the quinazoline moiety has positioned it as a pivotal component in the development of various antitumor agents, showcasing its promising role in innovative cancer therapeutics. This concise review aims to reveal the potential of quinazolines in creating anticancer medications that target histone deacetylases (HDACs).
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Affiliation(s)
- Elena Martino
- Department of Science and Drug Technology, University of Turin, via Pietro Giuria 9, Turin, 10125, Italy
| | - Shruti Thakur
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Shoolini University, Himachal Pradesh, Solan-173229, India
| | - Arun Kumar
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Shoolini University, Himachal Pradesh, Solan-173229, India
| | - Ashok Kumar Yadav
- University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India
| | - Donatella Boschi
- Department of Science and Drug Technology, University of Turin, via Pietro Giuria 9, Turin, 10125, Italy
| | - Deepak Kumar
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Shoolini University, Himachal Pradesh, Solan-173229, India
| | - Marco Lolli
- Department of Science and Drug Technology, University of Turin, via Pietro Giuria 9, Turin, 10125, Italy
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Wang C, Zhang Y, Zhang T, Xu J, Yan S, Liang B, Xing D. Epidermal growth factor receptor dual-target inhibitors as a novel therapy for cancer: A review. Int J Biol Macromol 2023; 253:127440. [PMID: 37839594 DOI: 10.1016/j.ijbiomac.2023.127440] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 10/10/2023] [Accepted: 10/12/2023] [Indexed: 10/17/2023]
Abstract
Overexpression of the epidermal growth factor receptor (EGFR) has been linked to several human cancers, including esophageal cancer, pancreatic cancer, anal cancer, breast cancer, and lung cancer, particularly non-small cell lung cancer (NSCLC). Therefore, EGFR has emerged as a critical target for treating solid tumors. Many 1st-, 2nd-, 3rd-, and 4th-generation EGFR single-target inhibitors with clinical efficacy have been designed and synthesized in recent years. Drug resistance caused by EGFR mutations has posed a significant challenge to the large-scale clinical application of EGFR single-target inhibitors and the discovery of novel EGFR inhibitors. Therapeutic methods for overcoming multipoint EGFR mutations are still needed in medicine. EGFR dual-target inhibitors are more promising than single-target inhibitors as they have a lower risk of drug resistance, higher efficacy, lower dosage, and fewer adverse events. EGFR dual-target inhibitors have been developed sequentially to date, providing new options for remission in patients with previously untreatable malignancies and laying the groundwork for a future generation of compounds. This paper introduces the EGFR family proteins and their synergistic effects with other anticancer targets, and provides a comprehensive review of the development of EGFR dual-target inhibitors in cancer, as well as the opportunities and challenges associated with those fields.
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Affiliation(s)
- Chao Wang
- The Affiliated Hospital of Qingdao University, Cancer Institute, Qingdao University, Qingdao 266071, Shandong, China; Qingdao Cancer Institute, Qingdao University, Qingdao 266071, Shandong, China
| | - Yujing Zhang
- The Affiliated Cardiovascular Hospital of Qingdao University, Qingdao University, Qingdao 266071, Shandong, China.
| | - Tingting Zhang
- The Affiliated Hospital of Qingdao University, Cancer Institute, Qingdao University, Qingdao 266071, Shandong, China; Qingdao Cancer Institute, Qingdao University, Qingdao 266071, Shandong, China
| | - Jiazhen Xu
- The Affiliated Hospital of Qingdao University, Cancer Institute, Qingdao University, Qingdao 266071, Shandong, China; Qingdao Cancer Institute, Qingdao University, Qingdao 266071, Shandong, China
| | - Saisai Yan
- The Affiliated Hospital of Qingdao University, Cancer Institute, Qingdao University, Qingdao 266071, Shandong, China; Qingdao Cancer Institute, Qingdao University, Qingdao 266071, Shandong, China.
| | - Bing Liang
- The Affiliated Hospital of Qingdao University, Cancer Institute, Qingdao University, Qingdao 266071, Shandong, China; Qingdao Cancer Institute, Qingdao University, Qingdao 266071, Shandong, China.
| | - Dongming Xing
- The Affiliated Hospital of Qingdao University, Cancer Institute, Qingdao University, Qingdao 266071, Shandong, China; Qingdao Cancer Institute, Qingdao University, Qingdao 266071, Shandong, China; School of Life Sciences, Tsinghua University, Beijing 100084, China
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7
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Mckertish CM, Kayser V. A Novel Dual-Payload ADC for the Treatment of HER2+ Breast and Colon Cancer. Pharmaceutics 2023; 15:2020. [PMID: 37631234 PMCID: PMC10459570 DOI: 10.3390/pharmaceutics15082020] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 07/14/2023] [Accepted: 07/24/2023] [Indexed: 08/27/2023] Open
Abstract
Antibody-drug conjugates (ADCs) have demonstrated a great therapeutic potential against cancer due to their target specificity and cytotoxicity. To exert a maximum therapeutic effect on cancerous cells, we have conjugated two different payloads to different amino acids, cysteines (cys) and lysines (lys), on trastuzumab, which is a humanised anti-HER2 monoclonal antibody. First, trastuzumab was conjugated with monomethyl auristatin E (MMAE), an antimitotic agent, through a cleavable linker (Val-Cit) to prepare ADC (Tmab-VcMMAE). Then, the ADC (Tmab-VcMMAE) was conjugated with a second antimitotic agent, Mertansine (DM1), via a non-cleavable linker Succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) to form a dual conjugate (Tmab-VcMMAE-SMCC-DM1). Our results indicated that the dual-payload conjugate, Tmab-VcMMAE-SMCC-DM1, had a synergistic and superior cytotoxic effect compared to trastuzumab alone. Ultimately employing a dual conjugation approach has the potential to overcome treatment-resistance and tumour recurrences and could pave the way to employ other payloads to construct dual (or multiple) payload complexes.
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Affiliation(s)
| | - Veysel Kayser
- Sydney School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia
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Tan L, Zhang J, Wang Y, Wang X, Wang Y, Zhang Z, Shuai W, Wang G, Chen J, Wang C, Ouyang L, Li W. Development of Dual Inhibitors Targeting Epidermal Growth Factor Receptor in Cancer Therapy. J Med Chem 2022; 65:5149-5183. [PMID: 35311289 DOI: 10.1021/acs.jmedchem.1c01714] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Epidermal growth factor receptor (EGFR) is of great significance in mediating cell signaling transduction and tumor behaviors. Currently, third-generation inhibitors of EGFR, especially osimertinib, are at the clinical frontier for the treatment of EGFR-mutant non-small-cell lung cancer (NSCLC). Regrettably, the rapidly developing drug resistance caused by EGFR mutations and the compensatory mechanism have largely limited their clinical efficacy. Given the synergistic effect between EGFR and other compensatory targets during tumorigenesis and tumor development, EGFR dual-target inhibitors are promising for their reduced risk of drug resistance, higher efficacy, lower dosage, and fewer adverse events than those of single-target inhibitors. Hence, we present the synergistic mechanism underlying the role of EGFR dual-target inhibitors against drug resistance, their structure-activity relationships, and their therapeutic potential. Most importantly, we emphasize the optimal target combinations and design strategies for EGFR dual-target inhibitors and provide some perspectives on new challenges and future directions in this field.
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Affiliation(s)
- Lun Tan
- Department of Respiratory and Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China.,Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China.,Precision Medicine Key Laboratory of Sichuan Province and Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China
| | - Jifa Zhang
- Department of Respiratory and Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China.,Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China.,Precision Medicine Key Laboratory of Sichuan Province and Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China
| | - Yuxi Wang
- Department of Respiratory and Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China.,Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China.,Precision Medicine Key Laboratory of Sichuan Province and Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China
| | - Xiye Wang
- Department of Respiratory and Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China
| | - Yanyan Wang
- Department of Respiratory and Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China
| | - Zhixiong Zhang
- Department of Respiratory and Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China
| | - Wen Shuai
- Department of Respiratory and Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China.,Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China.,Precision Medicine Key Laboratory of Sichuan Province and Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China
| | - Guan Wang
- Department of Respiratory and Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China
| | - Juncheng Chen
- Department of Respiratory and Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China.,Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China.,Precision Medicine Key Laboratory of Sichuan Province and Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China
| | - Chengdi Wang
- Department of Respiratory and Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China.,Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China
| | - Liang Ouyang
- Department of Respiratory and Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China.,Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China.,Precision Medicine Key Laboratory of Sichuan Province and Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China
| | - Weimin Li
- Department of Respiratory and Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China.,Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China.,Precision Medicine Key Laboratory of Sichuan Province and Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China
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Liu Q, Hao B, Zhang M, Liu Z, Huang Y, Zhao X, Hu H, Tan M, Xu JY. An Integrative Proteome-Based Pharmacologic Characterization and Therapeutic Strategy Exploration of SAHA in Solid Malignancies. J Proteome Res 2022; 21:953-964. [PMID: 35172096 DOI: 10.1021/acs.jproteome.1c00791] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Targeting histone epigenetic modification is an important strategy for anticancer therapy. Histone deacetylase inhibitors (HDACis) have been clinically approved in the treatment of diverse hematological cancers, but mechanisms of drug resistance and poor therapeutic efficacy in solid malignancies remain largely unknown. In this study, we applied a mass spectrometry-based quantitative proteomic strategy to investigate the molecular differences in HDACi vorinostat (SAHA) sensitive and resistant cell lines. The proteomic results revealed that the glycolysis pathway was highly enriched after vorinostat treatment in the resistant cell line, leading to the prediction of a new drug combination, SAHA and hexokinase inhibitor (2-deoxyglucose). The efficacy of this combination was further verified in several solid tumor cell lines. Quantitative proteomics revealed that alterations in the transcription process and protein homeostasis could play roles in the synergetic utilization of these two compounds. Our study showed the application of proteomics in elucidating the drug mechanism and predicting drug combination and the potential of expanding the utilization of HDACi.
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Affiliation(s)
- Quan Liu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Bingbing Hao
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Mingya Zhang
- School of Chinese Materia Medical, Nanjing University of Chinese Medicine, Nanjing, 210023 Jiangsu, China
| | - Zhiwei Liu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yuqi Huang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xiaoxiao Zhao
- School of Chinese Materia Medical, Nanjing University of Chinese Medicine, Nanjing, 210023 Jiangsu, China
| | - Hao Hu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Minjia Tan
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.,University of Chinese Academy of Sciences, Beijing 100049, China.,School of Chinese Materia Medical, Nanjing University of Chinese Medicine, Nanjing, 210023 Jiangsu, China
| | - Jun-Yu Xu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.,University of Chinese Academy of Sciences, Beijing 100049, China
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10
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Role of Gut Microbiota and Probiotics in Colorectal Cancer: Onset and Progression. Microorganisms 2021; 9:microorganisms9051021. [PMID: 34068653 PMCID: PMC8151957 DOI: 10.3390/microorganisms9051021] [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] [Received: 04/18/2021] [Revised: 05/03/2021] [Accepted: 05/07/2021] [Indexed: 12/11/2022] Open
Abstract
The gut microbiota plays an important role in maintaining homeostasis in the human body, and the disruption of these communities can lead to compromised host health and the onset of disease. Current research on probiotics is quite promising and, in particular, these microorganisms have demonstrated their potential for use as adjuvants for the treatment of colorectal cancer. This review addresses the possible applications of probiotics, postbiotics, synbiotics, and next-generation probiotics in colorectal cancer research.
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11
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Zhao L, Fan T, Shi Z, Ding C, Zhang C, Yuan Z, Sun Q, Tan C, Chu B, Jiang Y. Design, synthesis and evaluation of novel ErbB/HDAC multitargeted inhibitors with selectivity in EGFR T790M mutant cell lines. Eur J Med Chem 2021; 213:113173. [PMID: 33493830 DOI: 10.1016/j.ejmech.2021.113173] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 12/23/2020] [Accepted: 01/06/2021] [Indexed: 12/20/2022]
Abstract
Acquired resistance leads to the failure of EGFR TKIs in NSCLC treatment. A novel series of hydroxamic acid-containing 4-aminoquinazoline derivatives as irreversible ErbB/HDAC multitargeted inhibitors for NSCLC therapy had been designed and synthesized, which displayed weak anti-proliferative activity in several EGFR wild-type cancer cell lines (NCI-H838, SK-BR-3, A549, A431) yet retained moderate activity to EGFRT790M resistance mutation harboring NCI-H1975 cells. The mechanistic studies revealed that the representative compound 11e was able to inhibit the phosphorylation of EGFR, up-regulate hyperacetylation of histone H3 and even reduce the expression of EGFR and Akt in NCI-H1975 cells. In further assays, compound 11e also showed moderate anti-proliferative activity in other EGFRT790M harboring tumor cell lines (NCI-H820, Ba/F3_EGFR_Del19-T790M-C797S) and low toxicities in normal cell lines (HL-7702, FHC). This selectivity of designed multitargeted compounds could serve as a potential strategy to circumvent multiple mechanisms of acquired resistance to EGFR-targeted therapy without severe toxicities and side effects resulting from broad inhibition.
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Affiliation(s)
- Lei Zhao
- Department of Chemistry, Tsinghua University, Beijing, 100084, PR China; State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, PR China
| | - Tingting Fan
- State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, PR China; Department of Chemistry Southern University of Science and Technology, Shenzhen, 518055, PR China
| | - Zhichao Shi
- Department of Chemistry, Tsinghua University, Beijing, 100084, PR China; State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, PR China
| | - Chao Ding
- State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, PR China
| | - Cunlong Zhang
- State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, PR China
| | - Zigao Yuan
- State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, PR China
| | - Qinsheng Sun
- State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, PR China
| | - Chunyan Tan
- State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, PR China
| | - Bizhu Chu
- Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, PR China.
| | - Yuyang Jiang
- Department of Chemistry, Tsinghua University, Beijing, 100084, PR China; State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, PR China; Department of Chemistry Southern University of Science and Technology, Shenzhen, 518055, PR China; Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing, 100084, PR China; Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, PR China.
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12
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Hashimoto-Hill S, Kelly D, Alenghat T. Epigenomics of intestinal disease. MEDICAL EPIGENETICS 2021:213-230. [DOI: 10.1016/b978-0-12-823928-5.00018-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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13
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Chang Y, Lee YB, Cho EJ, Lee JH, Yu SJ, Kim YJ, Yoon JH. CKD-5, a novel pan-histone deacetylase inhibitor, synergistically enhances the efficacy of sorafenib for hepatocellular carcinoma. BMC Cancer 2020; 20:1001. [PMID: 33059615 PMCID: PMC7559883 DOI: 10.1186/s12885-020-07471-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 09/29/2020] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Histone deacetylase inhibitors (HDACIs) have distinctive epigenetic targets involved in hepatocarcinogenesis and chemoresistance. A recent phase I/II study reported the possibility of HDACI as a chemosensitizer in sorafenib-resistant patients. In this study, we evaluated whether CKD-5, a novel pan-HDACI, can potentiate the efficacy of sorafenib. METHODS The anticancer effect of CKD-5 with and without sorafenib was evaluated in vitro using an MTS assay with human HCC cells (SNU-3058 and SNU-761) under both normoxic and hypoxic conditions. Microarray analysis was performed to investigate the mechanism of cell death, which was also evaluated by small interfering RNA (siRNA) transfection and subsequent immunoblot assays. In vivo experiments were conducted using two different murine HCC models. C3H mice implanted with MH134 cells and C57BL/6 mice implanted with RIL-175 cells were treated with weekly CKD-5 with and without sorafenib for 2 weeks. RESULTS CKD-5 treatment significantly suppressed human HCC cell growth in both normoxic and hypoxic conditions. Microarray analysis and real-time PCR showed that CKD-5 treatment significantly increased peripherin expression in HCC cells and that downregulation of peripherin by siRNA decreased CKD-5-induced apoptosis. The combination of CKD-5 and sorafenib decreased cell viability more effectively than sorafenib or CKD-5 monotherapy in human and murine HCC cells. The effectiveness of the combination therapy was consistently demonstrated in the animal models. Histological and biochemical analyses demonstrated good tolerance of CKD-5 plus sorafenib in vivo. CONCLUSION CKD-5 may enhance sorafenib efficacy through epigenetic regulation. The combination of CKD-5 and sorafenib might be a novel therapeutic option for the treatment of HCC.
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Affiliation(s)
- Young Chang
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.,Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Yun Bin Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Eun Ju Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Su Jong Yu
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Jung-Hwan Yoon
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
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14
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Kim YA, Sarto Basso R, Wojtowicz D, Liu AS, Hochbaum DS, Vandin F, Przytycka TM. Identifying Drug Sensitivity Subnetworks with NETPHIX. iScience 2020; 23:101619. [PMID: 33089107 PMCID: PMC7566085 DOI: 10.1016/j.isci.2020.101619] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 09/08/2020] [Accepted: 09/24/2020] [Indexed: 12/29/2022] Open
Abstract
Phenotypic heterogeneity in cancer is often caused by different patterns of genetic alterations. Understanding such phenotype-genotype relationships is fundamental for the advance of personalized medicine. We develop a computational method, named NETPHIX (NETwork-to-PHenotype association with eXclusivity) to identify subnetworks of genes whose genetic alterations are associated with drug response or other continuous cancer phenotypes. Leveraging interaction information among genes and properties of cancer mutations such as mutual exclusivity, we formulate the problem as an integer linear program and solve it optimally to obtain a subnetwork of associated genes. Applied to a large-scale drug screening dataset, NETPHIX uncovered gene modules significantly associated with drug responses. Utilizing interaction information, NETPHIX modules are functionally coherent and can thus provide important insights into drug action. In addition, we show that modules identified by NETPHIX together with their association patterns can be leveraged to suggest drug combinations.
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Affiliation(s)
- Yoo-Ah Kim
- National Center of Biotechnology Information, National Library of Medicine, NIH, Bethesda, MD 20894, USA
| | - Rebecca Sarto Basso
- Department of Industrial Engineering and Operations Research, University of California at Berkeley, Berkeley, CA 94709, USA
| | - Damian Wojtowicz
- National Center of Biotechnology Information, National Library of Medicine, NIH, Bethesda, MD 20894, USA
| | - Amanda S Liu
- Montgomery Blair High School, Silver Spring, MD 20901, USA
| | - Dorit S Hochbaum
- Department of Industrial Engineering and Operations Research, University of California at Berkeley, Berkeley, CA 94709, USA
| | - Fabio Vandin
- Department of Information Engineering, University of Padova, Padova 35131, Italy
| | - Teresa M Przytycka
- National Center of Biotechnology Information, National Library of Medicine, NIH, Bethesda, MD 20894, USA
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15
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Development of a simple, sensitive and selective colorimetric aptasensor for the detection of cancer-derived exosomes. Biosens Bioelectron 2020; 169:112576. [PMID: 32919211 DOI: 10.1016/j.bios.2020.112576] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 07/04/2020] [Accepted: 08/28/2020] [Indexed: 01/05/2023]
Abstract
There is a growing need for cancerous exosome detection towards potential non-invasive cancer diagnosis. This study aims to develop a reliable colorimetric aptasensor for sensitive and specific detection of circulating cancer-derived exosomes. In this design, target exosomes were firstly captured by latex beads via aldimine condensation, followed by bio-recognition using a specific CD63 aptamer, which was conjugated to horseradish peroxidase (HRP) through biotin-streptavidin binding. Colorimetric detection was achieved in 10 min via enzymatic catalysis to produce dark coloured polydopamine (PDA) from colourless substrate dopamine (DA) in especially prepared H2O2 reaction solution. The sensitivity was enhanced by in situ deposition of PDA around exosome particles to strengthen the developed colorimetric signal, which could be directly observed by naked eye. Signal quantification was carried out by absorbance measurement. The colour intensity correlates to the CD63 amount and the limit of detection can be as low as 7.7 × 103 particle/mL, improved by 3-5 orders of magnitude from conventional Dot-blot methods. The aptasensor showed specificity to HER2 and integrin αvβ6 positive, cell culture-derived, breast and pancreatic cancer-derived exosomes, respectively, when the correct aptamer sequence was used. Overall, a sensitive and selective colorimetric aptasensor was successfully developed for detecting cancer-derived exosomes facilitated by HRP-accelerated DA polymerization and in situ PDA deposition. This versatile aptasensor holds great potential for future development of point-of-care detection kits for cancer diagnosis in a clinical setting.
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16
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Romero AH, Sojo F, Arvelo F, Calderón C, Morales A, López SE. Anticancer potential of new 3-nitroaryl-6-(N-methyl)piperazin-1,2,4-triazolo[3,4-a]phthalazines targeting voltage-gated K + channel: Copper-catalyzed one-pot synthesis from 4-chloro-1-phthalazinyl-arylhydrazones. Bioorg Chem 2020; 101:104031. [PMID: 32629281 DOI: 10.1016/j.bioorg.2020.104031] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 06/12/2020] [Accepted: 06/17/2020] [Indexed: 11/28/2022]
Abstract
A series of six 3-aryl-6-(N-methylpiperazin)-1,2,4-triazolo[3,4-a]phthalazines were prepared through a facile and efficient one-pot copper-catalyzed procedure from 4-chloro-1-phthalazinyl-arylhydrazones with relatively good yields (62-83%). The one-pot copper-catalytic procedure consists of two simultaneous reactions: (i) a direct intramolecular dehydrogentaive cyclization between ylidenic carbon and adjacent pyrazine nitrogen to form 1,2,4-triazolo ring and, (ii) a direct N-amination on carbon-chlorine bond. Then, an in vitro anticancer evaluation was performed for the synthesized compounds against five selected human cancer cells (A549, MCF-7, SKBr3, PC-3 and HeLa). The nitro-derivatives were significantly more active against cancer strains than against the rest of tested compounds. Specifically, compound 8d was identified as the most promising anticancer agent with significant biological responses and low relative toxicities on human dermis fibroblast. The cytotoxic effect of compound 8d was more significant on PC3, MCF-7 and SKBr3 cancer cells with low-micromolar IC50 value ranging from 0.11 to 0.59 μM, superior to Adriamycin drug. Mechanistic experimental and theoretical studies demonstrated that compounds 8d act as a K+ channel inhibitor in cancer models. Further molecular docking studies suggest that the EGFR Tyrosine Kinase enzyme may be a potential target for the most active 3-aryl-6-(N-methylpiperazin)-1,2,4-triazolo[3,4-a]phthalazines.
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Affiliation(s)
- Angel H Romero
- Cátedra de Química General, Facultad de Farmacia, Universidad Central de Venezuela, Los Chaguaramos, Caracas 1041-A, Venezuela.
| | - Felipe Sojo
- Fundación Institutos de Estudios Avanzados-IDEA, Área Salud, Venezuela; Laboratorio de Cultivo de Tejidos y Biología de Tumores, Instituto de Biología Experimental-IBE, Facultad de Ciencias-UCV, Bello Monte, Caracas, Venezuela
| | - Francisco Arvelo
- Fundación Institutos de Estudios Avanzados-IDEA, Área Salud, Venezuela; Laboratorio de Cultivo de Tejidos y Biología de Tumores, Instituto de Biología Experimental-IBE, Facultad de Ciencias-UCV, Bello Monte, Caracas, Venezuela
| | - Christian Calderón
- Laboratorio de Fisiología y Biofísica, Centro de Biología Celular, Instituto de Biología Experimental-IBE, Facultad de Ciencias, UCV, Bello Monte, Caracas, Venezuela
| | - Alvaro Morales
- Laboratorio de Biotecnología Clínica Santa María, Cevalfes, Valencia, Venezuela
| | - Simón E López
- Department of Chemistry, University of Florida, Gainesville, FL, United States.
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17
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Parisa A, Roya G, Mahdi R, Shabnam R, Maryam E, Malihe T. Anti-cancer effects of Bifidobacterium species in colon cancer cells and a mouse model of carcinogenesis. PLoS One 2020; 15:e0232930. [PMID: 32401801 PMCID: PMC7219778 DOI: 10.1371/journal.pone.0232930] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 04/25/2020] [Indexed: 01/20/2023] Open
Abstract
INTRODUCTION Probiotics are suggested to prevent colorectal cancer (CRC). This study aimed to investigate the anticancer properties of some potential probiotics in vitro and in vivo. MATERIALS AND METHODS Anticancer effects of the following potential probiotic groups were investigated in LS174T cancer cells compared to IEC-18 normal cells. 1. a single strain of Bifidobacterium. breve, 2. a single strain of Lactobacillus. reuteri, 3. a cocktail of 5 strains of Lactobacilli (LC), 4. a cocktail of 5 strains of Bifidobacteria (BC), 5. a cocktail of 10 strains from Lactobacillus and Bifidobacterium (L+B). Apoptosis rate, EGFR, HER-2 and PTGS-2 (COX-2 protein) expression levels were assessed as metrics of evaluating anticancer properties. Effect of BC, as the most effective group in vitro, was further assessed in mice models. RESULTS BC induced ~21% and only ~3% apoptosis among LS174T and IEC-18 cells respectively. BC decreased the expression of EGFR by 4.4 folds, HER-2 by 6.7 folds, and PTGS-2 by 20 folds among the LS174T cells. In all these cases, BC did not interfere significantly with the expression of the genes in IEC-18 cells. This cocktail has caused only 1.1 folds decrease, 1.8 folds increase and 1.7 folds decrease in EGFR, HER-2 and PTGS-2 expression, respectively. Western blot analysis confirmed these results in the protein level. BC significantly ameliorated the disease activity index, restored colon length, inhibited the increase in incidence and progress of tumors to higher stages and grades. CONCLUSIONS BC was the most efficient treatment in this study. It had considerable "protective" anti-cancer properties and concomitantly down regulated EGFR, HER-2 and PTGS-2 (COX-2), while having significant anti-CRC effects on CRC mice models. In general, this potential probiotic could be considered as a suitable nutritional supplement to treat and prevent CRC.
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Affiliation(s)
- Asadollahi Parisa
- Microbial Biotechnology Research Centre, Iran University of Medical Sciences, Tehran, Iran
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ghanavati Roya
- Microbial Biotechnology Research Centre, Iran University of Medical Sciences, Tehran, Iran
- Behbahan Faculty of Medical Science, Behbahan, Iran
| | - Rohani Mahdi
- Department of Microbiology, Pasteur Institute of Iran, Tehran, Iran
| | - Razavi Shabnam
- Microbial Biotechnology Research Centre, Iran University of Medical Sciences, Tehran, Iran
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Esghaei Maryam
- Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Talebi Malihe
- Microbial Biotechnology Research Centre, Iran University of Medical Sciences, Tehran, Iran
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
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18
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Liu T, Wan Y, Xiao Y, Xia C, Duan G. Dual-Target Inhibitors Based on HDACs: Novel Antitumor Agents for Cancer Therapy. J Med Chem 2020; 63:8977-9002. [PMID: 32320239 DOI: 10.1021/acs.jmedchem.0c00491] [Citation(s) in RCA: 112] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Histone deacetylases (HDACs) play an important role in regulating target gene expression. They have been highlighted as a novel category of anticancer targets, and their inhibition can induce apoptosis, differentiation, and growth arrest in cancer cells. In view of the fact that HDAC inhibitors and other antitumor agents, such as BET inhibitors, topoisomerase inhibitors, and RTK pathway inhibitors, exert a synergistic effect on cellular processes in cancer cells, the combined inhibition of two targets is regarded as a rational strategy to improve the effectiveness of these single-target drugs for cancer treatment. In this review, we discuss the theoretical basis for designing HDAC-involved dual-target drugs and provide insight into the structure-activity relationships of these dual-target agents.
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Affiliation(s)
- Tingting Liu
- Department of Medicinal Chemistry, School of Pharmacy, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian 271016, Shandong, China
| | - Yichao Wan
- Key Laboratory of Theoretical Organic Chemistry and Functional Molecule, Ministry of Education, School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan 411201, Hunan, China
| | - Yuliang Xiao
- Department of Medicinal Chemistry, School of Pharmacy, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian 271016, Shandong, China
| | - Chengcai Xia
- Department of Medicinal Chemistry, School of Pharmacy, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian 271016, Shandong, China
| | - Guiyun Duan
- Department of Medicinal Chemistry, School of Pharmacy, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian 271016, Shandong, China
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19
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Weiss A, Le Roux-Bourdieu M, Zoetemelk M, Ramzy GM, Rausch M, Harry D, Miljkovic-Licina M, Falamaki K, Wehrle-Haller B, Meraldi P, Nowak-Sliwinska P. Identification of a Synergistic Multi-Drug Combination Active in Cancer Cells via the Prevention of Spindle Pole Clustering. Cancers (Basel) 2019; 11:E1612. [PMID: 31652588 PMCID: PMC6826636 DOI: 10.3390/cancers11101612] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 10/14/2019] [Accepted: 10/16/2019] [Indexed: 02/06/2023] Open
Abstract
A major limitation of clinically used cancer drugs is the lack of specificity resulting in toxicity. To address this, we performed a phenotypically-driven screen to identify optimal multidrug combinations acting with high efficacy and selectivity in clear cell renal cell carcinoma (ccRCC). The search was performed using the Therapeutically Guided Multidrug Optimization (TGMO) method in ccRCC cells (786-O) and nonmalignant renal cells and identified a synergistic low-dose four-drug combination (C2) with high efficacy and negligible toxicity. We discovered that C2 inhibits multipolar spindle pole clustering, a survival mechanism employed by cancer cells with spindle abnormalities. This phenotype was also observed in 786-O cells resistant to sunitinib, the first line ccRCC treatment, as well as in melanoma cells with distinct percentages of supernumerary centrosomes. We conclude that C2-treatment shows a high efficacy in cells prone to form multipolar spindles. Our data suggest a highly effective and selective C2 treatment strategy for malignant and drug-resistant cancers.
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Affiliation(s)
- Andrea Weiss
- Institute of Pharmaceutical Sciences of Western Switzerland, Faculty of Sciences, University of Geneva, 1 Rue Michel-Servet, CMU, 1211 Geneva 4, Switzerland.
- Translational Research Centre in Oncohaematology, 1 Rue Michel-Servet, CMU, 1211 Geneva 4, Switzerland.
| | - Morgan Le Roux-Bourdieu
- Translational Research Centre in Oncohaematology, 1 Rue Michel-Servet, CMU, 1211 Geneva 4, Switzerland.
- Department of Cell Physiology and Metabolism, University of Geneva Medical School, 1 Rue Michel-Servet, CMU, 1211 Geneva 4, Switzerland.
| | - Marloes Zoetemelk
- Institute of Pharmaceutical Sciences of Western Switzerland, Faculty of Sciences, University of Geneva, 1 Rue Michel-Servet, CMU, 1211 Geneva 4, Switzerland.
- Translational Research Centre in Oncohaematology, 1 Rue Michel-Servet, CMU, 1211 Geneva 4, Switzerland.
| | - George M Ramzy
- Institute of Pharmaceutical Sciences of Western Switzerland, Faculty of Sciences, University of Geneva, 1 Rue Michel-Servet, CMU, 1211 Geneva 4, Switzerland.
| | - Magdalena Rausch
- Institute of Pharmaceutical Sciences of Western Switzerland, Faculty of Sciences, University of Geneva, 1 Rue Michel-Servet, CMU, 1211 Geneva 4, Switzerland.
- Translational Research Centre in Oncohaematology, 1 Rue Michel-Servet, CMU, 1211 Geneva 4, Switzerland.
| | - Daniela Harry
- Department of Cell Physiology and Metabolism, University of Geneva Medical School, 1 Rue Michel-Servet, CMU, 1211 Geneva 4, Switzerland.
| | - Marijana Miljkovic-Licina
- Translational Research Centre in Oncohaematology, 1 Rue Michel-Servet, CMU, 1211 Geneva 4, Switzerland.
- Department of Pathology and Immunology, University of Geneva Medical School, 1 Rue Michel-Servet, CMU, 1211 Geneva 4, Switzerland.
| | - Katayoun Falamaki
- Department of Cell Physiology and Metabolism, University of Geneva Medical School, 1 Rue Michel-Servet, CMU, 1211 Geneva 4, Switzerland.
| | - Bernard Wehrle-Haller
- Translational Research Centre in Oncohaematology, 1 Rue Michel-Servet, CMU, 1211 Geneva 4, Switzerland.
- Department of Cell Physiology and Metabolism, University of Geneva Medical School, 1 Rue Michel-Servet, CMU, 1211 Geneva 4, Switzerland.
| | - Patrick Meraldi
- Translational Research Centre in Oncohaematology, 1 Rue Michel-Servet, CMU, 1211 Geneva 4, Switzerland.
- Department of Cell Physiology and Metabolism, University of Geneva Medical School, 1 Rue Michel-Servet, CMU, 1211 Geneva 4, Switzerland.
| | - Patrycja Nowak-Sliwinska
- Institute of Pharmaceutical Sciences of Western Switzerland, Faculty of Sciences, University of Geneva, 1 Rue Michel-Servet, CMU, 1211 Geneva 4, Switzerland.
- Translational Research Centre in Oncohaematology, 1 Rue Michel-Servet, CMU, 1211 Geneva 4, Switzerland.
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Prevalence, prognosis and predictive status of HER2 amplification in anti-EGFR-resistant metastatic colorectal cancer. Clin Transl Oncol 2019; 22:813-822. [PMID: 31587152 DOI: 10.1007/s12094-019-02213-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Accepted: 09/13/2019] [Indexed: 02/06/2023]
Abstract
Numerous inherent and acquired genetic alterations have been demonstrated with resistance to anti-epidermal growth factor receptor (anti-EGFR) therapy in metastatic colorectal cancer (mCRC) patients. Although the common oncogenic driver mutations identified include KRAS, NRAS, BRAF, and PI3K, recent studies report a vital role played by human epithelial growth factor receptor-2 (HER2) amplification in acquired resistance to anti-EGFR therapy. HER2 amplification has been associated with poor prognosis in many malignancies including breast and gastric cancer and is also a negative predictor of anti-EGFR therapy. Given the relevance of HER2 amplification in conferring an anti-EGFR resistance, this paper reviews the prevalence of HER2 amplification in mCRC while exploring the prognostic and predictive values of this biomarker. Further, we also discuss the results of the studies that explored the utilization of anti-HER2-targeted therapies in mCRC. HER2-directed therapies have the ability to change the treatment algorithm in clinically relevant small subset of patients with HER2-amplified mCRC.
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21
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Patnaik S, Anupriya. Drugs Targeting Epigenetic Modifications and Plausible Therapeutic Strategies Against Colorectal Cancer. Front Pharmacol 2019; 10:588. [PMID: 31244652 PMCID: PMC6563763 DOI: 10.3389/fphar.2019.00588] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 05/08/2019] [Indexed: 12/14/2022] Open
Abstract
Genetic variations along with epigenetic modifications of DNA are involved in colorectal cancer (CRC) development and progression. CRC is the fourth leading cause of cancer-related deaths worldwide. Initiation and progression of CRC is the cumulation of a variety of genetic and epigenetic changes in colonic epithelial cells. Colorectal carcinogenesis is associated with epigenetic aberrations including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs. Recently, epigenetic modifications have been identified like association of hypermethylated gene Claudin11 (CLDN11) with metastasis and prognosis of poor survival of CRC. DNA methylation of genes CMTM3, SSTR2, MDF1, NDRG4 and TGFB2 are potential epigenetic biomarkers for the early detection of CRC. Tumor suppressor candidate 3 (TUSC3) mRNA expression is silenced by promoter methylation, which promotes epidermal growth factor receptor (EGFR) signaling and rescues the CRC cells from apoptosis and hence leading to poor survival rate. Previous scientific evidences strongly suggest epigenetic modifications that contribute to anticancer drug resistance. Recent research studies emphasize development of drugs targeting histone deacetylases (HDACs) and DNA methyltransferase inhibitors as an emerging anticancer strategy. This review covers potential epigenetic modification targeting chemotherapeutic drugs and probable implementation for the treatment of CRC, which offers a strong rationale to explore therapeutic strategies and provides a basis to develop potent antitumor drugs.
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22
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Zhang H, Zhao X, Liu H, Jin H, Ji Y. Trichostatin A inhibits proliferation of PC3 prostate cancer cells by disrupting the EGFR pathway. Oncol Lett 2019; 18:687-693. [PMID: 31289542 PMCID: PMC6546995 DOI: 10.3892/ol.2019.10384] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Accepted: 04/04/2019] [Indexed: 01/10/2023] Open
Abstract
Prostate cancer (PC) is the most common type of malignancy to exist in men within developed countries. Androgen deprivation therapy is performed for metastatic and advanced PC. However, the majority of cases of prostate cancer become refractory during therapy, leading to castration-resistant PC (CRPC). Histone deacetylases (HDACs) are key factors in regulating gene transcription and have been associated with cancer development. In the present study the small molecule inhibitor trichostatin A (TSA), which targets HDACs, was demonstrated to inhibit the proliferation of CRPC PC3 cells by disrupting the epidermal growth factor receptor (EGFR)-STAT3 pathway. The expression of EGFR and STAT3 was downregulated following TSA treatment, and cell cycle arrest was induced by downregulating the expression of cyclin D1 and CDK6, and via retinoblastoma protein phosphorylation. Furthermore, the transcription of cyclin D1 and CDK6 was suppressed by TSA. Apoptosis of PC3 cells treated with TSA was also investigated, and it was revealed that TSA induced apoptosis by upregulating BAX and downregulating BCL-2. The combination of TSA with doxorubicin exerted a synergistic inhibitory effect on PC3 cell proliferation through the induction of apoptosis. The results of the present study revealed a promising epigenetic-based therapeutic strategy that could be implemented in cases of CRPC.
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Affiliation(s)
- Hong Zhang
- Department of Clinical Medicine, Changchun Medical College, Changchun, Jilin 130031, P.R. China
| | - Xin Zhao
- Department of Clinical Medicine, Changchun Medical College, Changchun, Jilin 130031, P.R. China
| | - Hongbo Liu
- Department of Clinical Medicine, Changchun Medical College, Changchun, Jilin 130031, P.R. China
| | - Hui Jin
- Department of Pain Medical Center, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Youbo Ji
- Department of Pain Medical Center, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
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23
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Recent advancements of 4-aminoquinazoline derivatives as kinase inhibitors and their applications in medicinal chemistry. Eur J Med Chem 2019; 170:55-72. [DOI: 10.1016/j.ejmech.2019.03.004] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Revised: 02/21/2019] [Accepted: 03/01/2019] [Indexed: 12/30/2022]
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24
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Rezapour S, Hosseinzadeh E, Marofi F, Hassanzadeh A. Epigenetic-based therapy for colorectal cancer: Prospect and involved mechanisms. J Cell Physiol 2019; 234:19366-19383. [PMID: 31020647 DOI: 10.1002/jcp.28658] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 03/21/2019] [Accepted: 03/25/2019] [Indexed: 12/15/2022]
Abstract
Epigenetic modifications are heritable variations in gene expression not encoded by the DNA sequence. According to reports, a large number of studies have been performed to characterize epigenetic modification during normal development and also in cancer. Epigenetics can be regarded more widely to contain all of the changes in expression of genes that make by adjusted interactions between the regulatory portions of DNA or messenger RNAs that lead to indirect variation in the DNA sequence. In the last decade, epigenetic modification importance in colorectal cancer (CRC) pathogenesis was demonstrated powerfully. Although developments in CRC therapy have been made in the last years, much work is required as it remains the second leading cause of cancer death. Nowadays, epigenetic programs and genetic change have pivotal roles in the CRC incidence as well as progression. While our knowledge about epigenetic mechanism in CRC is not comprehensive, selective histone modifications and resultant chromatin conformation together with DNA methylation most likely regulate CRC pathogenesis that involved genes expression. Undoubtedly, the advanced understanding of epigenetic-based gene expression regulation in the CRC is essential to make epigenetic drugs for CRC therapy. The major aim of this review is to deliver a summary of valuable results that represent evidence of principle for epigenetic-based therapeutic approaches employment in CRC with a focus on the advantages of epigenetic-based therapy in the inhibition of the CRC metastasis and proliferation.
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Affiliation(s)
- Saleheh Rezapour
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Elham Hosseinzadeh
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Faroogh Marofi
- Division of Hematology, Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Hassanzadeh
- Division of Hematology, Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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25
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He K, Xu J, Liang J, Jiang J, Tang M, Ye X, Zhang Z, Zhang L, Fu B, Li Y, Bai C, Zhang L, Tao W. Discovery of A Novel EGFR-Targeting Antibody-Drug Conjugate, SHR-A1307, for the Treatment of Solid Tumors Resistant or Refractory to Anti-EGFR Therapies. Mol Cancer Ther 2019; 18:1104-1114. [PMID: 30962319 DOI: 10.1158/1535-7163.mct-18-0854] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 12/26/2018] [Accepted: 04/03/2019] [Indexed: 11/16/2022]
Abstract
Although inhibiting EGFR-mediated signaling proved to be effective in treating certain types of cancers, a quickly evolved mechanism that either restores the EGFR signaling or activates an alternative pathway for driving the proliferation and survival of malignant cells limits the efficacy and utility of the approach via suppressing the EGFR functionality. Given the fact that overexpression of EGFR is commonly seen in many cancers, an EGFR-targeting antibody-drug conjugate (ADC) can selectively kill cancer cells independently of blocking EGFR-mediated signaling. Herein, we describe SHR-A1307, a novel anti-EGFR ADC, generated from an anti-EGFR antibody with prolonged half-life, and conjugated with a proprietary toxin payload that has increased index of EGFR targeting-dependent versus EGFR targeting-independent cytotoxicity. SHR-A1307 demonstrated strong and sustained antitumor activities in EGFR-positive tumors harboring different oncogenic mutations on EGFR, KRAS, or PIK3CA. Antitumor efficacy of SHR-A1307 correlated with EGFR expression levels in vitro and in vivo, regardless of the mutation status of EGFR signaling mediators and a resultant resistance to EGFR signaling inhibitors. Cynomolgus monkey toxicology study showed that SHR-A1307 is well tolerated with a wide therapeutic index. SHR-A1307 is a promising therapeutic option for EGFR-expressing cancers, including those resistant or refractory to the EGFR pathway inhibitors.
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Affiliation(s)
- Kaijie He
- Shanghai Hengrui Pharmaceutical Co., Ltd., Shanghai, China.
| | - Jianyan Xu
- Shanghai Hengrui Pharmaceutical Co., Ltd., Shanghai, China
| | - Jindong Liang
- Shanghai Hengrui Pharmaceutical Co., Ltd., Shanghai, China
| | - Jiahua Jiang
- Jiangsu Hengrui Medicine Co., Ltd., Shanghai, China
| | - Mi Tang
- Jiangsu Hengrui Medicine Co., Ltd., Shanghai, China
| | - Xin Ye
- Shanghai Hengrui Pharmaceutical Co., Ltd., Shanghai, China
| | - Zhebin Zhang
- Shanghai Hengrui Pharmaceutical Co., Ltd., Shanghai, China
| | - Lei Zhang
- Shanghai Hengrui Pharmaceutical Co., Ltd., Shanghai, China
| | - Beibei Fu
- Shanghai Hengrui Pharmaceutical Co., Ltd., Shanghai, China
| | - Yan Li
- Shanghai Hengrui Pharmaceutical Co., Ltd., Shanghai, China
| | - Chang Bai
- Shanghai Hengrui Pharmaceutical Co., Ltd., Shanghai, China
| | - Lianshan Zhang
- Shanghai Hengrui Pharmaceutical Co., Ltd., Shanghai, China
| | - Weikang Tao
- Shanghai Hengrui Pharmaceutical Co., Ltd., Shanghai, China
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26
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Manzotti G, Ciarrocchi A, Sancisi V. Inhibition of BET Proteins and Histone Deacetylase (HDACs): Crossing Roads in Cancer Therapy. Cancers (Basel) 2019; 11:cancers11030304. [PMID: 30841549 PMCID: PMC6468908 DOI: 10.3390/cancers11030304] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Revised: 02/18/2019] [Accepted: 02/26/2019] [Indexed: 12/14/2022] Open
Abstract
Histone DeACetylases (HDACs) are enzymes that remove acetyl groups from histones and other proteins, regulating the expression of target genes. Pharmacological inhibition of these enzymes re-shapes chromatin acetylation status, confusing boundaries between transcriptionally active and quiescent chromatin. This results in reinducing expression of silent genes while repressing highly transcribed genes. Bromodomain and Extraterminal domain (BET) proteins are readers of acetylated chromatin status and accumulate on transcriptionally active regulatory elements where they serve as scaffold for the building of transcription-promoting complexes. The expression of many well-known oncogenes relies on BET proteins function, indicating BET inhibition as a strategy to counteract their activity. BETi and HDACi share many common targets and affect similar cellular processes to the point that combined inhibition of both these classes of proteins is regarded as a strategy to improve the effectiveness of these drugs in cancer. In this work, we aim to discuss the molecular basis of the interplay between HDAC and BET proteins, pointing at chromatin acetylation as a crucial node of their functional interaction. We will also describe the state of the art of their dual inhibition in cancer therapy. Finally, starting from their mechanism of action we will provide a speculative perspective on how these drugs may be employed in combination with standard therapies to improve effectiveness and/or overcome resistance.
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Affiliation(s)
- Gloria Manzotti
- Laboratory of Translational Research, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy.
| | - Alessia Ciarrocchi
- Laboratory of Translational Research, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy.
| | - Valentina Sancisi
- Laboratory of Translational Research, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy.
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27
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Deng X, Xiong F, Li X, Xiang B, Li Z, Wu X, Guo C, Li X, Li Y, Li G, Xiong W, Zeng Z. Application of atomic force microscopy in cancer research. J Nanobiotechnology 2018; 16:102. [PMID: 30538002 PMCID: PMC6288943 DOI: 10.1186/s12951-018-0428-0] [Citation(s) in RCA: 116] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Accepted: 11/24/2018] [Indexed: 12/16/2022] Open
Abstract
Atomic force microscopy (AFM) allows for nanometer-scale investigation of cells and molecules. Recent advances have enabled its application in cancer research and diagnosis. The physicochemical properties of live cells undergo changes when their physiological conditions are altered. These physicochemical properties can therefore reflect complex physiological processes occurring in cells. When cells are in the process of carcinogenesis and stimulated by external stimuli, their morphology, elasticity, and adhesion properties may change. AFM can perform surface imaging and ultrastructural observation of live cells with atomic resolution under near-physiological conditions, collecting force spectroscopy information which allows for the study of the mechanical properties of cells. For this reason, AFM has potential to be used as a tool for high resolution research into the ultrastructure and mechanical properties of tumor cells. This review describes the working principle, working mode, and technical points of atomic force microscopy, and reviews the applications and prospects of atomic force microscopy in cancer research.
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Affiliation(s)
- Xiangying Deng
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, 410078, China
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China
| | - Fang Xiong
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, 410078, China
| | - Xiayu Li
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, 410078, China
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China
| | - Bo Xiang
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, 410078, China
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China
| | - Zheng Li
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, 410078, China
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China
| | - Xu Wu
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, 410078, China
- Department of Chemistry, University of North Dakota, Grand Forks, ND, 58202, USA
| | - Can Guo
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, 410078, China
| | - Xiaoling Li
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, 410078, China
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China
| | - Yong Li
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, 410078, China
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Guiyuan Li
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, 410078, China
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China
| | - Wei Xiong
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China.
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, 410078, China.
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China.
| | - Zhaoyang Zeng
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China.
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, 410078, China.
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China.
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He P, Li K, Li SB, Hu TT, Guan M, Sun FY, Liu WW. Upregulation of AKAP12 with HDAC3 depletion suppresses the progression and migration of colorectal cancer. Int J Oncol 2018; 52:1305-1316. [PMID: 29484387 DOI: 10.3892/ijo.2018.4284] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 02/16/2018] [Indexed: 11/05/2022] Open
Abstract
A-kinase anchor protein 12 (AKAP12; also known as Gravin) functions as a tumor suppressor in several human primary cancers. However, the potential correlation between histone deacetylase 3 (HDAC3) and AKAP12 and the underlying mechanisms remain unclear. Thus, in this study, in an aim to shed light into this matter, the expression levels of HDAC3 and AKAP12 in 96 colorectal cancer (CRC) and adjacent non-cancerous tissues, as well as in SW480 cells were examined by immunohistochemical, RT-qPCR and western blot analyses. The effects of HDAC3 and AKAP12 on the proliferation, apoptosis and metastasis of CRC cells were examined by cell counting kit-8 (CCK-8) assay, colony formation assays, flow cytometry, cell cycle analysis and Transwell assays. The results revealed that the reduction or loss of AKAP12 expression was detected in 69 (71.8%) of the 96 tissue specimens, whereas HDAC3 was upregulated in 50 (52.1%) of the 96 tumor tissue specimens. AKAP12 expression was markedly increased upon treatment with the HDAC3 inhibitors, trichostatin A (TSA) and RGFP966, at both the mRNA and protein level. Mechanistically, the direct binding of HDAC3 within the intron-1 region of AKAP12 was identified to be indispensable for the inhibition of AKAP12 expression. Moreover, the proliferation, colony-forming ability, cell cycle progression and the migration of the CRC cells were found to be promoted in response to AKAP12 silencing or AKAP12/HDAC3 co-silencing, whereas transfection with si-HDAC3 yielded opposite effects. Apart from the elevated expression of the anti-apoptotic protein, Bcl-2, after AKAP12 knockdown, the increased activity of PI3K/AKT signaling was found to be indispensable for AKAP12-mediated colony formation and migration. On the whole, these findings indicate that AKAP12 may be a potential prognostic predictor and therapeutic target for the treatment of CRC in combination with HDAC3.
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Affiliation(s)
- Ping He
- Central Laboratory, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200070, P.R. China
| | - Ke Li
- Central Laboratory, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200070, P.R. China
| | - Shi-Bao Li
- Department of Laboratory Medicine, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu 221100, P.R. China
| | - Ting-Ting Hu
- Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, P.R. China
| | - Ming Guan
- Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, P.R. China
| | - Fen-Yong Sun
- Department of Laboratory Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200070, P.R. China
| | - Wei-Wei Liu
- Central Laboratory, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200070, P.R. China
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29
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Xu W, Liu H, Liu ZG, Wang HS, Zhang F, Wang H, Zhang J, Chen JJ, Huang HJ, Tan Y, Cao MT, Du J, Zhang QG, Jiang GM. Histone deacetylase inhibitors upregulate Snail via Smad2/3 phosphorylation and stabilization of Snail to promote metastasis of hepatoma cells. Cancer Lett 2018; 420:1-13. [PMID: 29410023 DOI: 10.1016/j.canlet.2018.01.068] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Revised: 12/18/2017] [Accepted: 01/25/2018] [Indexed: 01/04/2023]
Abstract
Hepatocellular carcinoma (HCC) remains the third most common cause of cancer-related mortality. Resection and transplantation are the only curative treatments available, but are greatly hampered by high recurrence rates. Histone deacetylase inhibitors (HDACIs) are considered to be promising anticancer agents in drug development. Currently, four HDACIs have been granted Food and Drug Administration (FDA) approval for cancer. HDACIs have shown significant efficacy in hematological malignancies. However, they have limited effects in epithelial cell-derived cancers, including HCC, and the mechanisms of these are not elucidated. In this study, our results demonstrated that HDACIs were able to induce epithelial-mesenchymal transitions (EMT) in hepatoma cells which are believed to trigger tumor cell invasion and metastasis. We found that HDACIs promoted the expression of Snail and Snail-induced EMT was critical for HDACI-initiated invasion and metastasis. We indicated that HDACIs upregulated Snail in two ways. Firstly, HDACIs upregulated Snail at the transcriptional level by promoting Smad2/3 phosphorylation and nuclear translocation, then combined with the promoter to activate the transcription of Snail. Secondly, we showed that HDACIs regulated the stabilization of Snail via upregulating the expression of COP9 signalosome 2 (CSN2), which combined with Snail and exposed its acetylation site, then promoted acetylation of Snail, thereby inhibiting its phosphorylation and ubiquitination to repress the degradation of Snail. All these results highlighted that HDACIs have limited effects in HCC, and the use of HDACIs combined with other targeted strategies to inhibit EMT, which explored in this study is a promising treatment method for treating HCC.
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Affiliation(s)
- Wei Xu
- Department of Clinical Laboratory, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China; The First Affiliated Hospital of University of South China, Hengyang, Hunan, China
| | - Hao Liu
- Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Zhi-Gang Liu
- Department of Radiation Oncology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Hong-Sheng Wang
- Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Fan Zhang
- Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Hao Wang
- Department of Clinical Laboratory, Anhui Provincial Hospital, Anhui Medical University, Hefei, Anhui, China
| | - Ji Zhang
- The First Affiliated Hospital of University of South China, Hengyang, Hunan, China
| | - Jing-Jing Chen
- Sinocare Biosensing Limited Company, Changsha, Hunan, China
| | - Hong-Jun Huang
- Department of Clinical Laboratory, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Yuan Tan
- Department of Clinical Laboratory, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Meng-Ting Cao
- The First Affiliated Hospital of University of South China, Hengyang, Hunan, China
| | - Jun Du
- Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Qiu-Gui Zhang
- The First Affiliated Hospital of University of South China, Hengyang, Hunan, China.
| | - Guan-Min Jiang
- Department of Clinical Laboratory, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
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30
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Shi X, Zheng C, Li C, Hou K, Wang X, Yang Z, Liu C, Liu Y, Che X, Qu X. 4-Phenybutyric acid promotes gastric cancer cell migration via histone deacetylase inhibition-mediated HER3/HER4 up-regulation. Cell Biol Int 2017; 42:53-62. [PMID: 28851073 DOI: 10.1002/cbin.10866] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Accepted: 08/22/2017] [Indexed: 11/05/2022]
Abstract
Dysregulation of histone acetylation plays an important role in tumor development. Histone acetylation regulates gene transcription and expression, which is reversibly regulated by histone acetyltransferase (HAT) and histone deacetylase (HDAC). As an HDAC inhibitor, 4-phenylbutyric acid (4-PBA) can increase histone acetylation levels by inhibiting HDAC activity. While 4-PBA inhibits proliferation of tumor cells in vitro, clinical trials have failed to show benefits of 4-PBA for refractory solid tumors. Here, we found that 4-PBA could enhance the migration capacity of gastric cancer cells. Upregulation of HER3/HER4 and activation of HER3/HER4-ERK pathway was shown to be involved in 4-PBA-induced gastric cancer cell migration. Knockdown of HER3/HER4 blocked HER3/HER4-ERK activation and partially prevented 4-PBA-induced cell migration. Consistently, the ERK inhibitor PD98059 also partially prevented 4-PBA-induced cell migration. Moreover, enhanced levels of acetyl-histones were detected following 4-PBA-treatment, and histone3 acetylation in promoter regions of HER3 and HER4 were confirmed by ChIP. These results demonstrate that 4-PBA promotes gastric cancer cells migration through upregulation of HER3/HER4 subsequent to increased levels of acetyl-histone and activation of ERK signaling. These novel findings provide important considerations for the use of 4-PBA in cancer therapeutics.
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Affiliation(s)
- Xiaonan Shi
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China
| | - Chunlei Zheng
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China
| | - Ce Li
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China
| | - Kezuo Hou
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China
| | - Xiaoxun Wang
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China
| | - Zichang Yang
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China
| | - Chang Liu
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China
| | - Yunpeng Liu
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China
| | - Xiaofang Che
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China
| | - Xiujuan Qu
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China
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Puccini A, Berger MD, Naseem M, Tokunaga R, Battaglin F, Cao S, Hanna DL, McSkane M, Soni S, Zhang W, Lenz HJ. Colorectal cancer: epigenetic alterations and their clinical implications. Biochim Biophys Acta Rev Cancer 2017; 1868:439-448. [PMID: 28939182 DOI: 10.1016/j.bbcan.2017.09.003] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Revised: 09/16/2017] [Accepted: 09/17/2017] [Indexed: 12/20/2022]
Abstract
Colorectal cancer (CRC) is a heterogeneous disease with distinct molecular and clinical features, which reflects the wide range of prognostic outcomes and treatment responses observed among CRC patients worldwide. Our understanding of the CRC epigenome has been largely developed over the last decade and it is now believed that among thousands of epigenetic alterations present in each tumor, a small subgroup of these may be considered as a CRC driver event. DNA methylation profiles have been the most widely studied in CRC, which includes a subset of patients with distinct molecular and clinical features now categorized as CpG island methylator phenotype (CIMP). Major advances have been made in our capacity to detect epigenetic alterations, providing us with new potential biomarkers for diagnostic, prognostic and therapeutic purposes. This review aims to summarize our current knowledge about epigenetic alterations occurring in CRC, underlying their potential future clinical implications in terms of diagnosis, prognosis and therapeutic strategies for CRC patients.
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Affiliation(s)
- Alberto Puccini
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Martin D Berger
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Madiha Naseem
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Ryuma Tokunaga
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Francesca Battaglin
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Shu Cao
- Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Diana L Hanna
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Michelle McSkane
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Shivani Soni
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Wu Zhang
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA.
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Ding F, Zhang S, Gao S, Shang J, Li Y, Cui N, Zhao Q. MRGBP as a potential biomarker for the malignancy of pancreatic ductal adenocarcinoma. Oncotarget 2017; 8:64224-64236. [PMID: 28969065 PMCID: PMC5609997 DOI: 10.18632/oncotarget.19451] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Accepted: 04/12/2017] [Indexed: 12/30/2022] Open
Abstract
MORF4-related gene-binding protein (MRGBP), which is also known as chromosome 20 open reading frame 20 (C20orf20), is commonly highly expressed in several types of malignant tumors and tumor progression. However, the expression pattern and underlying mechanism of MRGBP in pancreatic ductal adenocarcinoma (PDAC) remain unknown. In the study, we found that MRGBP was frequently upregulated in PDAC tissues and cell lines. In addition, the upregulation of MRGBP was positively associated with TNM stage, T classification, and poor prognosis. Knockdown of MRGBP in the PDAC cell lines ASPC-1 and Mia PaCa-2 by transiently transfected with small interfering RNA (siRNA) drastically attenuated the proliferation, migration, and invasion of those cells, whereas ectopic MRGBP overexpression in BxPC-3 cells produced exactly the opposite effect. Furthermore, we also found that overexpression of MRGBP remarkably led to cell morphological changes and induced an increased expression of mesenchymal marker Vimentin, whereas a decreased expression of epithelial marker E-cadherin. Taken together, this study indicates that MRGBP acts as a tumor oncogene in PDAC and is a promising target of carcinogenesis.
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Affiliation(s)
- Feng Ding
- Department of Gastroenterology/Hepatology, ZhongNan Hospital of Wuhan University, Wuhan 430071, China.,The Hubei Clinical Center & Key Laboratory of Intestinal & Colorectal Diseases, Wuhan 430071, China
| | - Shuang Zhang
- Laboratory of Clinical Immunology, Wuhan No.1 Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Shaoyang Gao
- Department of Pathology, Hubei Cancer Hospital, Wuhan 430079, China
| | - Jian Shang
- Department of Gastroenterology/Hepatology, ZhongNan Hospital of Wuhan University, Wuhan 430071, China.,The Hubei Clinical Center & Key Laboratory of Intestinal & Colorectal Diseases, Wuhan 430071, China
| | - Yanxia Li
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Ning Cui
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Qiu Zhao
- Department of Gastroenterology/Hepatology, ZhongNan Hospital of Wuhan University, Wuhan 430071, China.,The Hubei Clinical Center & Key Laboratory of Intestinal & Colorectal Diseases, Wuhan 430071, China
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33
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Wang H, Sun M, Guo J, Ma L, Jiang H, Gu L, Wen H, Liao S, Chen J, Zeng B, Li Y, Li Y, Yu X, Feng Y, Zhou Y. 3-O-(Z)-coumaroyloleanolic acid overcomes Cks1b-induced chemoresistance in lung cancer by inhibiting Hsp90 and MEK pathways. Biochem Pharmacol 2017; 135:35-49. [DOI: 10.1016/j.bcp.2017.03.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Accepted: 03/06/2017] [Indexed: 02/09/2023]
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34
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Pauli C, Hopkins BD, Prandi D, Shaw R, Fedrizzi T, Sboner A, Sailer V, Augello M, Puca L, Rosati R, McNary TJ, Churakova Y, Cheung C, Triscott J, Pisapia D, Rao R, Mosquera JM, Robinson B, Faltas BM, Emerling BE, Gadi VK, Bernard B, Elemento O, Beltran H, Demichelis F, Kemp CJ, Grandori C, Cantley LC, Rubin MA. Personalized In Vitro and In Vivo Cancer Models to Guide Precision Medicine. Cancer Discov 2017; 7:462-477. [PMID: 28331002 PMCID: PMC5413423 DOI: 10.1158/2159-8290.cd-16-1154] [Citation(s) in RCA: 702] [Impact Index Per Article: 87.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Revised: 01/30/2017] [Accepted: 01/30/2017] [Indexed: 02/07/2023]
Abstract
Precision medicine is an approach that takes into account the influence of individuals' genes, environment, and lifestyle exposures to tailor interventions. Here, we describe the development of a robust precision cancer care platform that integrates whole-exome sequencing with a living biobank that enables high-throughput drug screens on patient-derived tumor organoids. To date, 56 tumor-derived organoid cultures and 19 patient-derived xenograft (PDX) models have been established from the 769 patients enrolled in an Institutional Review Board-approved clinical trial. Because genomics alone was insufficient to identify therapeutic options for the majority of patients with advanced disease, we used high-throughput drug screening to discover effective treatment strategies. Analysis of tumor-derived cells from four cases, two uterine malignancies and two colon cancers, identified effective drugs and drug combinations that were subsequently validated using 3-D cultures and PDX models. This platform thereby promotes the discovery of novel therapeutic approaches that can be assessed in clinical trials and provides personalized therapeutic options for individual patients where standard clinical options have been exhausted.Significance: Integration of genomic data with drug screening from personalized in vitro and in vivo cancer models guides precision cancer care and fuels next-generation research. Cancer Discov; 7(5); 462-77. ©2017 AACR.See related commentary by Picco and Garnett, p. 456This article is highlighted in the In This Issue feature, p. 443.
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Affiliation(s)
- Chantal Pauli
- Englander Institute for Precision Medicine, Weill Cornell Medicine-New York Presbyterian Hospital, New York, New York
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York
- Institute of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
| | | | - Davide Prandi
- Center for Integrative Biology, University of Trento, Trento, Italy
| | - Reid Shaw
- Cure First and SEngine Precision Medicine, Seattle, Washington
| | | | - Andrea Sboner
- Englander Institute for Precision Medicine, Weill Cornell Medicine-New York Presbyterian Hospital, New York, New York
- Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Institute for Computational Biomedicine, Weill Cornell Medicine, New York, New York
| | - Verena Sailer
- Englander Institute for Precision Medicine, Weill Cornell Medicine-New York Presbyterian Hospital, New York, New York
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York
| | - Michael Augello
- Englander Institute for Precision Medicine, Weill Cornell Medicine-New York Presbyterian Hospital, New York, New York
- Meyer Cancer Center, Weill Cornell Medicine, New York, New York
| | - Loredana Puca
- Englander Institute for Precision Medicine, Weill Cornell Medicine-New York Presbyterian Hospital, New York, New York
| | - Rachele Rosati
- Cure First and SEngine Precision Medicine, Seattle, Washington
| | - Terra J McNary
- Englander Institute for Precision Medicine, Weill Cornell Medicine-New York Presbyterian Hospital, New York, New York
| | - Yelena Churakova
- Englander Institute for Precision Medicine, Weill Cornell Medicine-New York Presbyterian Hospital, New York, New York
| | - Cynthia Cheung
- Englander Institute for Precision Medicine, Weill Cornell Medicine-New York Presbyterian Hospital, New York, New York
| | - Joanna Triscott
- Englander Institute for Precision Medicine, Weill Cornell Medicine-New York Presbyterian Hospital, New York, New York
| | - David Pisapia
- Englander Institute for Precision Medicine, Weill Cornell Medicine-New York Presbyterian Hospital, New York, New York
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York
| | - Rema Rao
- Englander Institute for Precision Medicine, Weill Cornell Medicine-New York Presbyterian Hospital, New York, New York
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York
| | - Juan Miguel Mosquera
- Englander Institute for Precision Medicine, Weill Cornell Medicine-New York Presbyterian Hospital, New York, New York
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York
| | - Brian Robinson
- Englander Institute for Precision Medicine, Weill Cornell Medicine-New York Presbyterian Hospital, New York, New York
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York
| | - Bishoy M Faltas
- Englander Institute for Precision Medicine, Weill Cornell Medicine-New York Presbyterian Hospital, New York, New York
- Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, New York
| | | | - Vijayakrishna K Gadi
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Brady Bernard
- Cure First and SEngine Precision Medicine, Seattle, Washington
| | - Olivier Elemento
- Englander Institute for Precision Medicine, Weill Cornell Medicine-New York Presbyterian Hospital, New York, New York
- Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Institute for Computational Biomedicine, Weill Cornell Medicine, New York, New York
| | - Himisha Beltran
- Englander Institute for Precision Medicine, Weill Cornell Medicine-New York Presbyterian Hospital, New York, New York
- Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, New York
| | - Francesca Demichelis
- Englander Institute for Precision Medicine, Weill Cornell Medicine-New York Presbyterian Hospital, New York, New York
- Center for Integrative Biology, University of Trento, Trento, Italy
| | - Christopher J Kemp
- Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Carla Grandori
- Cure First and SEngine Precision Medicine, Seattle, Washington
| | - Lewis C Cantley
- Meyer Cancer Center, Weill Cornell Medicine, New York, New York
| | - Mark A Rubin
- Englander Institute for Precision Medicine, Weill Cornell Medicine-New York Presbyterian Hospital, New York, New York.
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York
- Meyer Cancer Center, Weill Cornell Medicine, New York, New York
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Medon M, Vidacs E, Vervoort SJ, Li J, Jenkins MR, Ramsbottom KM, Trapani JA, Smyth MJ, Darcy PK, Atadja PW, Henderson MA, Johnstone RW, Haynes NM. HDAC Inhibitor Panobinostat Engages Host Innate Immune Defenses to Promote the Tumoricidal Effects of Trastuzumab in HER2 + Tumors. Cancer Res 2017; 77:2594-2606. [PMID: 28249907 DOI: 10.1158/0008-5472.can-16-2247] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Revised: 10/04/2016] [Accepted: 02/27/2017] [Indexed: 11/16/2022]
Abstract
Histone deacetylase inhibitors (HDACi) may engage host immunity as one basis for their antitumor effects. Herein, we demonstrate an application of this concept using the HDACi panobinostat to augment the antitumor efficacy of trastuzumab (anti-HER2) therapy, through both tumor cell autonomous and nonautonomous mechanisms. In HER2+ tumors that are inherently sensitive to the cytostatic effects of trastuzumab, cotreatment with panobinostat abrogated AKT signaling and triggered tumor regression in mice that lacked innate and/or adaptive immune effector cells. However, the cooperative ability of panobinostat and trastuzumab to harness host anticancer immune defenses was essential for their curative activity in trastuzumab-refractory HER2+ tumors. In trastuzumab-resistant HER2+ AU565pv xenografts and BT474 tumors expressing constitutively active AKT, panobinostat enhanced the antibody-dependent cell-mediated cytotoxicity function of trastuzumab. IFNγ-mediated, CXCR3-dependent increases in tumor-associated NK cells underpinned the combined curative activity of panobinostat and trastuzumab in these tumors. These data highlight the immune-enhancing effects of panobinostat and provide compelling evidence that this HDACi can license trastuzumab to evoke NK-cell-mediated responses capable of eradicating trastuzumab-refractory HER2+ tumors. Cancer Res; 77(10); 2594-606. ©2017 AACR.
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Affiliation(s)
- Mikolaj Medon
- Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre (VCCC), Melbourne, Victoria, Australia.,Division of Surgical Oncology, Peter MacCallum Cancer Centre, VCCC, Melbourne, Victoria, Australia
| | - Eva Vidacs
- Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre (VCCC), Melbourne, Victoria, Australia
| | - Stephin J Vervoort
- Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre (VCCC), Melbourne, Victoria, Australia
| | - Jason Li
- Bioinformatics Consulting Core Facility, Cancer Research Division, Peter MacCallum Cancer Centre, VCCC, Melbourne, Victoria, Australia
| | - Misty R Jenkins
- Cancer Immunology Research Program, Peter MacCallum Cancer Centre, VCCC, Melbourne, Victoria, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia
| | - Kelly M Ramsbottom
- Cancer Immunology Research Program, Peter MacCallum Cancer Centre, VCCC, Melbourne, Victoria, Australia
| | - Joseph A Trapani
- Cancer Immunology Research Program, Peter MacCallum Cancer Centre, VCCC, Melbourne, Victoria, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia
| | - Mark J Smyth
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Phillip K Darcy
- Cancer Immunology Research Program, Peter MacCallum Cancer Centre, VCCC, Melbourne, Victoria, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia
| | - Peter W Atadja
- China Novartis, Institute for Biomedical Research, Shanghai, China
| | - Michael A Henderson
- Division of Surgical Oncology, Peter MacCallum Cancer Centre, VCCC, Melbourne, Victoria, Australia
| | - Ricky W Johnstone
- Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre (VCCC), Melbourne, Victoria, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia
| | - Nicole M Haynes
- Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre (VCCC), Melbourne, Victoria, Australia. .,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia
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Ding C, Chen S, Zhang C, Hu G, Zhang W, Li L, Chen YZ, Tan C, Jiang Y. Synthesis and investigation of novel 6-(1,2,3-triazol-4-yl)-4-aminoquinazolin derivatives possessing hydroxamic acid moiety for cancer therapy. Bioorg Med Chem 2017; 25:27-37. [DOI: 10.1016/j.bmc.2016.10.006] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Revised: 10/06/2016] [Accepted: 10/07/2016] [Indexed: 12/25/2022]
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Obatoclax, a Pan-BCL-2 Inhibitor, Targets Cyclin D1 for Degradation to Induce Antiproliferation in Human Colorectal Carcinoma Cells. Int J Mol Sci 2016; 18:ijms18010044. [PMID: 28035994 PMCID: PMC5297679 DOI: 10.3390/ijms18010044] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Revised: 12/19/2016] [Accepted: 12/21/2016] [Indexed: 12/20/2022] Open
Abstract
Colorectal cancer is the third most common cancer worldwide. Aberrant overexpression of antiapoptotic BCL-2 (B-cell lymphoma 2) family proteins is closely linked to tumorigenesis and poor prognosis in colorectal cancer. Obatoclax is an inhibitor targeting all antiapoptotic BCL-2 proteins. A previous study has described the antiproliferative action of obatoclax in one human colorectal cancer cell line without elucidating the underlying mechanisms. We herein reported that, in a panel of human colorectal cancer cell lines, obatoclax inhibits cell proliferation, suppresses clonogenicity, and induces G1-phase cell cycle arrest, along with cyclin D1 downregulation. Notably, ectopic cyclin D1 overexpression abrogated clonogenicity suppression but also G1-phase arrest elicited by obatoclax. Mechanistically, pre-treatment with the proteasome inhibitor MG-132 restored cyclin D1 levels in all obatoclax-treated cell lines. Cycloheximide chase analyses further revealed an evident reduction in the half-life of cyclin D1 protein by obatoclax, confirming that obatoclax downregulates cyclin D1 through induction of cyclin D1 proteasomal degradation. Lastly, threonine 286 phosphorylation of cyclin D1, which is essential for initiating cyclin D1 proteasomal degradation, was induced by obatoclax in one cell line but not others. Collectively, we reveal a novel anticancer mechanism of obatoclax by validating that obatoclax targets cyclin D1 for proteasomal degradation to downregulate cyclin D1 for inducing antiproliferation.
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38
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Amin KM, Barsoum FF, Awadallah FM, Mohamed NE. Identification of new potent phthalazine derivatives with VEGFR-2 and EGFR kinase inhibitory activity. Eur J Med Chem 2016; 123:191-201. [DOI: 10.1016/j.ejmech.2016.07.049] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2016] [Revised: 07/18/2016] [Accepted: 07/20/2016] [Indexed: 01/06/2023]
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Molecular mechanisms underlying the antitumor activity of (E)-N-hydroxy-3-(1-(4-methoxyphenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)acrylamide in human colorectal cancer cells in vitro and in vivo. Oncotarget 2016; 6:35991-6002. [PMID: 26462017 PMCID: PMC4742156 DOI: 10.18632/oncotarget.5475] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Accepted: 09/24/2015] [Indexed: 01/05/2023] Open
Abstract
Upregulation of class I histone deacetylases (HDAC) correlates with poor prognosis in colorectal cancer (CRC) patients. Previous study revealed that (E)-N-hydroxy-3-(1-(4-methoxyphenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)acrylamide (Compound 11) is a potent and selective class I HDAC inhibitor, exhibited significant anti-proliferative activity in various human cancer cell lines. In current study, we demonstrated that compound 11 exhibited significant anti-proliferative and cytotoxic activity in CRC cells. Notably, compound 11 was less potent than SAHA in inhibiting HDAC6 as evident from the lower expression of acetyl-α-tubulin, suggesting higher selectivity for class I HDACs. Mechanistically, compound 11 induced cell-cycle arrest at the G2/M phase, activated both intrinsic- and extrinsic-apoptotic pathways, altered the expression of Bcl-2 family proteins and exerted a potent inhibitory effect on survival signals (p-Akt, p-ERK) in CRC cells. Moreover, we provide evidence that compound 11 suppressed motility, decreased mesenchymal markers (N-cadherin and vimentin) and increased epithelial marker (E-cadherin) through down-regulation of Akt. The anti-tumor activity and underlying molecular mechanisms of compound 11 were further confirmed using the HCT116 xenograft model in vivo. Our findings provide evidence of the significant anti-tumor activity of compound 11 in a preclinical model, supporting its potential as a novel therapeutic agent for CRC.
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40
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Fanotto V, Ongaro E, Rihawi K, Avallone A, Silvestris N, Fornaro L, Vasile E, Antonuzzo L, Leone F, Rosati G, Giuliani F, Bordonaro R, Scartozzi M, Maglio GD, Negri FV, Fasola G, Aprile G. HER-2 inhibition in gastric and colorectal cancers: tangible achievements, novel acquisitions and future perspectives. Oncotarget 2016; 7:69060-69074. [PMID: 27542243 PMCID: PMC5356612 DOI: 10.18632/oncotarget.11264] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Accepted: 06/16/2016] [Indexed: 12/20/2022] Open
Abstract
HER-2 (ErbB-2, c-erbB2 or Her2/neu), a member of the HER-family, is directly involved in the pathogenesis and progression of several human cancers; as such, it is also often considered as a poor prognostic factor. Following the revolutionary impact of anti-HER-2 therapy in breast cancer patients, the role of HER-2 and its blockade has also been extensively evaluated in other tumor types, including gastric and colorectal adenocarcinoma. The aims of this review are to recall the important results achieved with the use of HER-2 inhibitors in both gastric and colorectal cancer, and to discuss on the updates available on the role of HER-2 as prognostic and predictive factor in these malignancies.
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Affiliation(s)
- Valentina Fanotto
- Department of Oncology, University and General Hospital, Udine, Italy
| | - Elena Ongaro
- Department of Oncology, University and General Hospital, Udine, Italy
| | - Karim Rihawi
- Department of Oncology, S.Orsola-Malpighi Hospital, Bologna, Italy
| | - Antonio Avallone
- Gastrointestinal Medical Oncology Unit, National Cancer Institute “Fondazione Giovanni Pascale”-IRCCS, Napoli, Italy
| | - Nicola Silvestris
- Department of Oncology, National CancerInstitute “Giovanni Paolo II”-IRCSS, Bari, Italy
| | - Lorenzo Fornaro
- Unit of Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Enrico Vasile
- Unit of Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | | | - Francesco Leone
- Department of Medical Oncology, University of Torino, Candiolo Cancer Institute-FPO-IRCCS, Torino, Italy
| | - Gerardo Rosati
- Medical Oncology Unit, San Carlo Hospital, Potenza, Italy
| | - Francesco Giuliani
- Department of Oncology, National CancerInstitute “Giovanni Paolo II”-IRCSS, Bari, Italy
| | | | - Mario Scartozzi
- Department of Oncology, University Hospital, Cagliari, Italy
| | | | | | - Gianpiero Fasola
- Department of Oncology, University and General Hospital, Udine, Italy
| | - Giuseppe Aprile
- Department of Oncology, University and General Hospital, Udine, Italy
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41
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High-Order Drug Combinations Are Required to Effectively Kill Colorectal Cancer Cells. Cancer Res 2016; 76:6950-6963. [DOI: 10.1158/0008-5472.can-15-3425] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Revised: 06/26/2016] [Accepted: 08/02/2016] [Indexed: 11/16/2022]
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42
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Chen J, Lu X, Lu C, Wang C, Xu H, Xu X, Gou H, Zhu B, Du W. 13-Methyl-palmatrubine induces apoptosis and cell cycle arrest in A549 cells in vitro and in vivo. Oncol Rep 2016; 36:2526-2534. [PMID: 27633656 PMCID: PMC5055195 DOI: 10.3892/or.2016.5093] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Accepted: 06/24/2016] [Indexed: 12/12/2022] Open
Abstract
Corydalis yanhusuo, a well-known herbaceous plant, is commonly used in the treatment of inflammation, injury and pain. One natural agent isolated from Corydalis yanhusuo, 13-methyl-palmatrubine, was found to have a cytotoxic effect on cancer cells as reported in published studies. In the present study, we synthesized a potential anti-lung tumor agent, 13-methyl-palmatrubine and analyzed its activity. 13-Methyl-palmatrubine exhibited a cytotoxic effect on a panel of cancer cell lines in a time- and concentration-dependent manner. Among all the tested cancer cell lines, lung cancer A549 cells were most sensitive to 13-methyl-palmatrubine treatment. Meanwhile 13-methyl-palmatrubine showed less cytotoxicity in human normal cells. Our investigation revealed that 13-methyl-palmatrubine induced apoptosis and cell cycle arrest in A549 cells in a dose-dependent manner. Furthermore, 13-methyl-palmatrubine treatment caused activation of P38 and JNK pathways and blocked the EGFR pathway. In conclusion, our findings demonstrated that 13-methyl-palmatrubine inhibited the growth of A549 cells mediated by blocking of the EGFR signaling pathway and activation of the MAPK signaling pathway and provides a better understanding of the molecular mechanisms of 13-methyl-palmatrubine.
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Affiliation(s)
- Jingxian Chen
- Department of Traditional Chinese Medicine, RuiJin Hospital, JiaoTong University School of Medicine, Shanghai 200025, P.R. China
| | - Xingang Lu
- Department of Traditional Chinese Medicine, HuaDong Hospital, FuDan University School of Medicine, Shanghai 200040, P.R. China
| | - Chenghua Lu
- Department of Respiration, LongHua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China
| | - Chunying Wang
- Department of Oncology, LongHua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China
| | - Haizhu Xu
- Department of Traditional Chinese Medicine, HuaDong Hospital, FuDan University School of Medicine, Shanghai 200040, P.R. China
| | - Xiaoli Xu
- Department of Traditional Chinese Medicine, HuaDong Hospital, FuDan University School of Medicine, Shanghai 200040, P.R. China
| | - Haixin Gou
- Department of Traditional Chinese Medicine, HuaDong Hospital, FuDan University School of Medicine, Shanghai 200040, P.R. China
| | - Bing Zhu
- Department of Traditional Chinese Medicine, HuaDong Hospital, FuDan University School of Medicine, Shanghai 200040, P.R. China
| | - Wangchun Du
- Clinical Medicine College, Shanghai University of Medicine and Health Sciences, Shanghai 201318, P.R. China
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43
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Park EJ, Sang-Ngern M, Chang LC, Pezzuto JM. Induction of cell cycle arrest and apoptosis with downregulation of Hsp90 client proteins and histone modification by 4β-hydroxywithanolide E isolated from Physalis peruviana. Mol Nutr Food Res 2016; 60:1482-500. [DOI: 10.1002/mnfr.201500977] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Revised: 03/04/2016] [Accepted: 03/06/2016] [Indexed: 01/08/2023]
Affiliation(s)
- Eun-Jung Park
- Daniel K. Inouye College of Pharmacy; University of Hawai‘i at Hilo; Hilo HI USA
- Arnold and Marie Schwartz College of Pharmacy and Health Sciences; Long Island University; Brooklyn NY USA
| | - Mayuramas Sang-Ngern
- Daniel K. Inouye College of Pharmacy; University of Hawai‘i at Hilo; Hilo HI USA
| | - Leng Chee Chang
- Daniel K. Inouye College of Pharmacy; University of Hawai‘i at Hilo; Hilo HI USA
| | - John M. Pezzuto
- Daniel K. Inouye College of Pharmacy; University of Hawai‘i at Hilo; Hilo HI USA
- Arnold and Marie Schwartz College of Pharmacy and Health Sciences; Long Island University; Brooklyn NY USA
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44
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Wang D, Wang M, Jiang N, Zhang Y, Bian X, Wang X, Roberts TM, Zhao JJ, Liu P, Cheng H. Effective use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib to treat PIK3CA mutant ovarian cancer. Oncotarget 2016; 7:13153-66. [PMID: 26909613 PMCID: PMC4914348 DOI: 10.18632/oncotarget.7549] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Accepted: 01/23/2016] [Indexed: 12/19/2022] Open
Abstract
Recent preclinical studies revealed the efficacy of combined use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib in breast and prostate cancers. The current study investigated the effect of such drug combination on ovarian cancer. Here we showed that combined inhibition of PI3K and PARP effectively synergized to inhibit proliferation, survival and invasion in the majority of ovarian cancer cell lines harboring PIK3CA mutations, including SKOV3, HEYA8, and IGROV1. Mechanistically, combined treatment of PARP and PI3K inhibitors resulted in an exacerbated DNA damage response and more substantially reduced AKT/mTOR signaling when compared to single-agent. Notably, ovarian cancer cells responsive to the PI3K/PARP combination displayed decreased BRCA1/2 expression upon drug treatment. Furthermore, the effect of the drug combination was corroborated in an intraperitoneal dissemination xenograft mouse model in which SKOV3 ovarian cancer cells responded with significantly decreased BRCA1 expression, suppressed PI3K/AKT signaling and reduced tumor burden. Collectively, our data suggested that combined inhibition of PI3K and PARP may be an effective therapeutic strategy for ovarian cancers with PIK3CA mutations and that the accompanied BRCA downregulation following PI3K inhibition could serve as a biomarker for the effective response to PARP inhibition.
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Affiliation(s)
- Dong Wang
- Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
- Department of Histology and Embryology, Binzhou Medical College, Yantai 264000, China
| | - Min Wang
- Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
| | - Nan Jiang
- Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
| | - Yuan Zhang
- Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
| | - Xing Bian
- Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
| | - Xiaoqing Wang
- Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
| | - Thomas M. Roberts
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
| | - Jean J. Zhao
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
| | - Pixu Liu
- Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
| | - Hailing Cheng
- Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
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45
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Wang D, Wang M, Jiang N, Zhang Y, Bian X, Wang X, Roberts TM, Zhao JJ, Liu P, Cheng H. Effective use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib to treat PIK3CA mutant ovarian cancer. Oncotarget 2016. [PMID: 26909613 DOI: 10.18632/oncotarget.7549] [] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Recent preclinical studies revealed the efficacy of combined use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib in breast and prostate cancers. The current study investigated the effect of such drug combination on ovarian cancer. Here we showed that combined inhibition of PI3K and PARP effectively synergized to inhibit proliferation, survival and invasion in the majority of ovarian cancer cell lines harboring PIK3CA mutations, including SKOV3, HEYA8, and IGROV1. Mechanistically, combined treatment of PARP and PI3K inhibitors resulted in an exacerbated DNA damage response and more substantially reduced AKT/mTOR signaling when compared to single-agent. Notably, ovarian cancer cells responsive to the PI3K/PARP combination displayed decreased BRCA1/2 expression upon drug treatment. Furthermore, the effect of the drug combination was corroborated in an intraperitoneal dissemination xenograft mouse model in which SKOV3 ovarian cancer cells responded with significantly decreased BRCA1 expression, suppressed PI3K/AKT signaling and reduced tumor burden. Collectively, our data suggested that combined inhibition of PI3K and PARP may be an effective therapeutic strategy for ovarian cancers with PIK3CA mutations and that the accompanied BRCA downregulation following PI3K inhibition could serve as a biomarker for the effective response to PARP inhibition.
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Affiliation(s)
- Dong Wang
- Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China.,Department of Histology and Embryology, Binzhou Medical College, Yantai 264000, China
| | - Min Wang
- Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
| | - Nan Jiang
- Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
| | - Yuan Zhang
- Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
| | - Xing Bian
- Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
| | - Xiaoqing Wang
- Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
| | - Thomas M Roberts
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.,Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
| | - Jean J Zhao
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.,Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
| | - Pixu Liu
- Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
| | - Hailing Cheng
- Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
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46
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Gao JJ, Shi ZY, Xia JF, Inagaki Y, Tang W. Sorafenib-based combined molecule targeting in treatment of hepatocellular carcinoma. World J Gastroenterol 2015; 21:12059-12070. [PMID: 26576091 PMCID: PMC4641124 DOI: 10.3748/wjg.v21.i42.12059] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Revised: 07/28/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023] Open
Abstract
Sorafenib is the only and standard systematic chemotherapy drug for treatment of advanced hepatocellular carcinoma (HCC) at the current stage. Although sorafenib showed survival benefits in large randomized phase III studies, its clinical benefits remain modest and most often consist of temporary tumor stabilization, indicating that more effective first-line treatment regimens or second-line salvage therapies are required. The molecular pathogenesis of HCC is very complex, involving hyperactivated signal transduction pathways such as RAS/RAF/MEK/ERK and PI3K/AKT/mTOR and aberrant expression of molecules such as receptor tyrosine kinases and histone deacetylases. Simultaneous or sequential abrogation of these critical pathways or the functions of these key molecules involved in angiogenesis, proliferation, and apoptosis may yield major improvements in the management of HCC. In this review, we summarize the emerging sorafenib-based combined molecule targeting for HCC treatment and analyze the rationales of these combinations.
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47
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Vaish V, Khare T, Verma M, Khare S. Epigenetic therapy for colorectal cancer. Methods Mol Biol 2015; 1238:771-82. [PMID: 25421691 DOI: 10.1007/978-1-4939-1804-1_40] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Aberrations in epigenome that include alterations in DNA methylation, histone acetylation, and miRNA (microRNA) expression may govern the progression of colorectal cancer (CRC). These epigenetic changes affect every phase of tumor development from initiation to metastasis. Since epigenetic alterations can be reversed by DNA demethylating and histone acetylating agents, current status of the implication of epigenetic therapy in CRC is discussed in this article. Interestingly, DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi) have shown promising results in controlling cancer progression. The information provided here might be useful in developing personalized medicine approaches.
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Affiliation(s)
- Vivek Vaish
- Section of Gastroenterology and Hepatology, Department of Internal Medicine, University of Missouri, Columbia, MO, 65212, USA
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48
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Abstract
SIGNIFICANCE Epigenetic inactivation of pivotal genes involved in cell growth is a hallmark of human pathologies, in particular cancer. Histone acetylation balance obtained through opposing actions of histone deacetylases (HDACs) and histone acetyltransferases is one epigenetic mechanism controlling gene expression and is, thus, associated with disease etiology and progression. Interfering pharmacologically with HDAC activity can correct abnormalities in cell proliferation, migration, vascularization, and death. RECENT ADVANCES Histone deacetylase inhibitors (HDACi) represent a new class of cytostatic agents that interfere with the function of HDACs and are able to increase gene expression by indirectly inducing histone acetylation. Several HDACi, alone or in combination with DNA-demethylating agents, chemopreventive, or classical chemotherapeutic drugs, are currently being used in clinical trials for solid and hematological malignancies, and are, thus, promising candidates for cancer therapy. CRITICAL ISSUES (i) Non-specific (off-target) HDACi effects due to activities unassociated with HDAC inhibition. (ii) Advantages/disadvantages of non-selective or isoform-directed HDACi. (iii) Limited number of response-predictive biomarkers. (iv) Toxicity leading to dysfunction of critical biological processes. FUTURE DIRECTIONS Selective HDACi could achieve enhanced clinical utility by reducing or eliminating the serious side effects associated with current first-generation non-selective HDACi. Isoform-selective and pan-HDACi candidates might benefit from the identification of biomarkers, enabling better patient stratification and prediction of response to treatment.
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Affiliation(s)
- Rosaria Benedetti
- 1 Department of Biochemistry, Biophysics, and General Pathology, Seconda Università degli Studi di Napoli , Napoli, Italy
| | - Mariarosaria Conte
- 1 Department of Biochemistry, Biophysics, and General Pathology, Seconda Università degli Studi di Napoli , Napoli, Italy
| | - Lucia Altucci
- 1 Department of Biochemistry, Biophysics, and General Pathology, Seconda Università degli Studi di Napoli , Napoli, Italy .,2 Istituto di Genetica e Biofisica "Adriano Buzzati-Traverso," Napoli, Italy
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49
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Roda D, Castillo J, Telechea-Fernández M, Gil A, López-Rodas G, Franco L, González-Rodríguez P, Roselló S, Pérez-Fidalgo JA, García-Trevijano ER, Cervantes A, Zaragozá R. EGF-Induced Acetylation of Heterogeneous Nuclear Ribonucleoproteins Is Dependent on KRAS Mutational Status in Colorectal Cancer Cells. PLoS One 2015; 10:e0130543. [PMID: 26110767 PMCID: PMC4482484 DOI: 10.1371/journal.pone.0130543] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Accepted: 05/22/2015] [Indexed: 12/11/2022] Open
Abstract
KRAS mutational status is considered a negative predictive marker of the response to anti-EGFR therapies in colorectal cancer (CRC) patients. However, conflicting data exist regarding the variable response to EGFR-targeted therapy. The effects of oncogenic KRAS on downstream targets were studied in cell lines with different KRAS mutations. Cells harboring a single KRASG13D allele showed the most tumorigenic profile, with constitutive activation of the downstream pathway, rendering them EGF-unresponsive. Conversely, KRASA146T cells showed a full EGF-response in terms of signal transduction pathways, cell proliferation, migration or adhesion. Moreover, the global acetylome of CRC cells was also dependent on KRAS mutational status. Several hnRNP family members were identified within the 36 acetylated-proteins. Acetylation status is known to be involved in the modulation of EGF-response. In agreement with results presented herein, hnRNPA1 and L acetylation was induced in response to EGF in KRASA146T cells, whereas acetyl-hnRNPA1 and L levels remained unchanged after growth factor treatment in KRASG13D unresponsive cells. Our results showed that hnRNPs induced-acetylation is dependent on KRAS mutational status. Nevertheless hnRNPs acetylation might also be the point where different oncogenic pathways converge.
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Affiliation(s)
- Desamparados Roda
- Department of Haematology and Medical Oncology, INCLIVA Biomedical Research Institute / University of Valencia, Valencia, Spain
| | - Josefa Castillo
- Department of Haematology and Medical Oncology, INCLIVA Biomedical Research Institute / University of Valencia, Valencia, Spain
| | - Marcelino Telechea-Fernández
- Department of Haematology and Medical Oncology, INCLIVA Biomedical Research Institute / University of Valencia, Valencia, Spain
| | - Anabel Gil
- Department of Haematology and Medical Oncology, INCLIVA Biomedical Research Institute / University of Valencia, Valencia, Spain
| | - Gerardo López-Rodas
- Department of Biochemistry and Molecular Biology, INCLIVA Biomedical Research Institute / University of Valencia, Valencia, Spain
| | - Luís Franco
- Department of Biochemistry and Molecular Biology, INCLIVA Biomedical Research Institute / University of Valencia, Valencia, Spain
| | - Patricia González-Rodríguez
- Department of Biochemistry and Molecular Biology, INCLIVA Biomedical Research Institute / University of Valencia, Valencia, Spain
| | - Susana Roselló
- Department of Haematology and Medical Oncology, INCLIVA Biomedical Research Institute / University of Valencia, Valencia, Spain
| | - J. Alejandro Pérez-Fidalgo
- Department of Haematology and Medical Oncology, INCLIVA Biomedical Research Institute / University of Valencia, Valencia, Spain
| | - Elena R. García-Trevijano
- Department of Biochemistry and Molecular Biology, INCLIVA Biomedical Research Institute / University of Valencia, Valencia, Spain
| | - Andrés Cervantes
- Department of Haematology and Medical Oncology, INCLIVA Biomedical Research Institute / University of Valencia, Valencia, Spain
- * E-mail:
| | - Rosa Zaragozá
- Department of Haematology and Medical Oncology, INCLIVA Biomedical Research Institute / University of Valencia, Valencia, Spain
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50
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Histone Deacetylase Inhibitors Resensitize EGFR/EGFRvIII-Overexpressing, Erlotinib-Resistant Glioblastoma Cells to Tyrosine Kinase Inhibition. Target Oncol 2015; 11:29-40. [DOI: 10.1007/s11523-015-0372-y] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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