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Sun M, Ma Y, Wan J, Zheng B, Shi Z, Li J. DNMT3B promotes the progression of pheochromocytoma by mediating the hypermethylation of LRP1B promoter. Epigenetics Chromatin 2025; 18:29. [PMID: 40346661 PMCID: PMC12063281 DOI: 10.1186/s13072-025-00592-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 04/23/2025] [Indexed: 05/11/2025] Open
Abstract
BACKGROUND Pheochromocytoma (Pheo) represents a potential metastatic neuroendocrine tumor. As a tumor suppressor gene, LRP1B is involved in the regulation of tumor progression. However, the precise regulatory mechanism of LRP1B in Pheo remains elusive. METHODS RT-QPCR, western blot and immunohistochemistry (IHC) were used to identify the expression levels of DNMT3B and LRP1B. Biochemistry assays including luciferase and ChIP were utilized to detect the interaction between the methyltransferase DNMT3B and LRP1B promoter. LRP1B or DNMT3B were knock-down in Pheo cell line by shRNAs. Functional experiments including clonal formation, migration, and in vivo transplantation were performed to evaluate the regulation of LRP1B or DNMT3B on tumor growth. RESULTS LRP1B was down-regulated, while DNMT3B was up-regulated in Pheo.Overexpression of LRP1B or inhibition of DNMT3B inhibited the progress of Pheo. DNMT3B was responsible for the hypermethylation of LRP1B promoter in Pheo. At the same time, overexpression of DNMT3B reversed the inhibitory effect of overexpression of LRP1B on Pheo progression. CONCLUSION DNMT3B mediated the hypermethylation of the tumor suppressive gene LRP1B and promotes Pheo progression.
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Affiliation(s)
- Min Sun
- Department of Urology Surgery Center, People's Hospital of Xinjiang Uygur Autonomous Region, No. 91, Tianchi Road, Tianshan District, Urumqi City, Xinjiang Uygur Autonomous Region, 830000, China
| | - Yanrong Ma
- Department of Endocrinology and Metabolic Diseases, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi City, Xinjiang Uygur Autonomous Region, China
| | - Jing Wan
- Department of Ultrasound, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi City, Xinjiang Uygur Autonomous Region, China
| | - Bingli Zheng
- Department of Hepatobiliary Pancreatic Center, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi City, Xinjiang Uygur Autonomous Region, China
| | - Zhenfeng Shi
- Department of Urology Surgery Center, People's Hospital of Xinjiang Uygur Autonomous Region, No. 91, Tianchi Road, Tianshan District, Urumqi City, Xinjiang Uygur Autonomous Region, 830000, China.
| | - Jiuzhi Li
- Department of Urology Surgery Center, People's Hospital of Xinjiang Uygur Autonomous Region, No. 91, Tianchi Road, Tianshan District, Urumqi City, Xinjiang Uygur Autonomous Region, 830000, China.
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2
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Jayaswal N, Srivastava S, Kumar S, Belagodu Sridhar S, Khalid A, Najmi A, Zoghebi K, Alhazmi HA, Mohan S, Tambuwala MM. Precision arrows: Navigating breast cancer with nanotechnology siRNA. Int J Pharm 2024; 662:124403. [PMID: 38944167 DOI: 10.1016/j.ijpharm.2024.124403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 06/26/2024] [Accepted: 06/26/2024] [Indexed: 07/01/2024]
Abstract
Nanotechnology-based drug delivery systems, including siRNA, present an innovative approach to treating breast cancer, which disproportionately affects women. These systems enable personalized and targeted therapies, adept at managing drug resistance and minimizing off-target effects. This review delves into the current landscape of nanotechnology-derived siRNA transport systems for breast cancer treatment, discussing their mechanisms of action, preclinical and clinical research, therapeutic applications, challenges, and future prospects. Emphasis is placed on the importance of targeted delivery and precise gene silencing in improving therapeutic efficacy and patient outcomes. The review addresses specific hurdles such as specificity, biodistribution, immunological reactions, and regulatory approval, offering potential solutions and avenues for future research. SiRNA drug delivery systems hold promise in revolutionizing cancer care and improving patient outcomes, but realizing their full potential necessitates ongoing research, innovation, and collaboration. Understanding the intricacies of siRNA delivery mechanisms is pivotal for designing effective cancer treatments, overcoming challenges, and advancing siRNA-based therapies for various diseases, including cancer. The article provides a comprehensive review of the methods involved in siRNA transport for therapeutic applications, particularly in cancer treatment, elucidating the complex journey of siRNA molecules from extracellular space to intracellular targets. Key mechanisms such as endocytosis, receptor-mediated uptake, and membrane fusion are explored, alongside innovative delivery vehicles and technologies that enhance siRNA delivery efficiency. Moreover, the article discusses challenges and opportunities in the field, including issues related to specificity, biodistribution, immune response, and clinical translation. By comprehending the mechanisms of siRNA delivery, researchers can design and develop more effective siRNA-based therapies for various diseases, including cancer.
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Affiliation(s)
- Nandani Jayaswal
- Faculty of Pharmaceutical Sciences, Mahayogi Gorakhnath University, Gorakhpur, 273007, India
| | - Shriyansh Srivastava
- Department of Pharmacology, Delhi Pharmaceutical Sciences and Research University (DPSRU), New Delhi 273007, India; Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, India.
| | - Sachin Kumar
- Department of Pharmacology, Delhi Pharmaceutical Sciences and Research University (DPSRU), New Delhi 273007, India
| | | | - Asaad Khalid
- Substance Abuse and Toxicology Research Centre, Jazan University, Jazan 45142, Saudi Arabia.
| | - Asim Najmi
- Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia
| | - Khalid Zoghebi
- Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia
| | - Hassan A Alhazmi
- Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia
| | - Syam Mohan
- Substance Abuse and Toxicology Research Centre, Jazan University, Jazan 45142, Saudi Arabia; School of Health Sciences, University of Petroleum and Energy Studies, Dehradun, Uttarakhand, India; Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, India
| | - Murtaza M Tambuwala
- Lincoln Medical School, University of Lincoln, Brayford Pool Campus, Lincoln LN6 7TS, UK; RAK College of Pharmacy, RAK Medical and Health Sciences University, Ras Al Khaimah, UAE.
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Wang D, Zhang Y, Li Q, Li Y, Li W, Zhang A, Xu J, Meng J, Tang L, Lyu S. Epigenetics: Mechanisms, potential roles, and therapeutic strategies in cancer progression. Genes Dis 2024; 11:101020. [PMID: 38988323 PMCID: PMC11233905 DOI: 10.1016/j.gendis.2023.04.040] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Revised: 02/20/2023] [Accepted: 04/14/2023] [Indexed: 07/12/2024] Open
Abstract
Mutations or abnormal expression of oncogenes and tumor suppressor genes are known to cause cancer. Recent studies have shown that epigenetic modifications are key drivers of cancer development and progression. Nevertheless, the mechanistic role of epigenetic dysregulation in the tumor microenvironment is not fully understood. Here, we reviewed the role of epigenetic modifications of cancer cells and non-cancer cells in the tumor microenvironment and recent research advances in cancer epigenetic drugs. In addition, we discussed the great potential of epigenetic combination therapies in the clinical treatment of cancer. However, there are still some challenges in the field of cancer epigenetics, such as epigenetic tumor heterogeneity, epigenetic drug heterogeneity, and crosstalk between epigenetics, proteomics, metabolomics, and other omics, which may be the focus and difficulty of cancer treatment in the future. In conclusion, epigenetic modifications in the tumor microenvironment are essential for future epigenetic drug development and the comprehensive treatment of cancer. Epigenetic combination therapy may be a novel strategy for the future clinical treatment of cancer.
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Affiliation(s)
- Dong Wang
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Yan Zhang
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Qingbo Li
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Yu Li
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Wen Li
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Ao Zhang
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Jingxuan Xu
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Jingyan Meng
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Lin Tang
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Shuhua Lyu
- Department of Pathology, Tianjin Union Medical Center, Tianjin 300121, China
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4
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Ali K, Nabeel M, Mohsin F, Iqtedar M, Islam M, Rasool MF, Hashmi FK, Hussain SA, Saeed H. Recent developments in targeting breast cancer stem cells (BCSCs): a descriptive review of therapeutic strategies and emerging therapies. Med Oncol 2024; 41:112. [PMID: 38592510 DOI: 10.1007/s12032-024-02347-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 02/27/2024] [Indexed: 04/10/2024]
Abstract
Despite recent advancements in the diagnosis and treatment of breast cancer (BC), patient outcomes in terms of survival, recurrence, and disease progression remain suboptimal. A significant factor contributing to these challenges is the cellular heterogeneity within BC, particularly the presence of breast cancer stem cells (BCSCs). These cells are thought to serve as the clonogenic nexus for new tumor growth, owing to their hierarchical organization within the tumor. This descriptive review focuses on the evolving strategies to target BCSCs, which have become a pivotal aspect of therapeutic development. We explore a variety of approaches, including targeting specific tumor surface markers (CD133 and CD44), transporters, heat shock proteins, and critical signaling pathways like Notch, Akt, Hedgehog, KLF4, and Wnt/β-catenin. Additionally, we discuss the modulation of the tumor microenvironment through the CXCR-12/CXCR4 axis, manipulation of pH levels, and targeting hypoxia-inducible factors, vascular endothelial growth factor, and CXCR1/2 receptors. Further, this review focuses on the roles of microRNA expression, strategies to induce apoptosis and differentiation in BCSCs, dietary interventions, dendritic cell vaccination, oncolytic viruses, nanotechnology, immunotherapy, and gene therapy. We particularly focused on studies reporting identification of BCSCs, their unique properties and the efficacy of various therapeutic modalities in targeting these cells. By dissecting these approaches, we aim to provide insights into the complex landscape of BC treatment and the potential pathways for improving patient outcomes through targeted BCSC therapies.
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Affiliation(s)
- Khubaib Ali
- Department of Clinical Pharmacy, Akhtar Saeed College of Pharmaceutical Sciences, Bahria Town, Lahore, Pakistan
- Department Clinical Oncology Pharmacy, Cancer Care Hospital & Research Centre, Lahore, Pakistan
| | - Muhammad Nabeel
- Department of Clinical Pharmacy, Akhtar Saeed College of Pharmaceutical Sciences, Bahria Town, Lahore, Pakistan
- Department Clinical Oncology Pharmacy, Cancer Care Hospital & Research Centre, Lahore, Pakistan
| | - Fatima Mohsin
- Department of Biological Sciences, KAM School of Life Sciences, Forman Christian College (A Chartered University), Lahore, Pakistan
| | - Mehwish Iqtedar
- Department of Bio-Technology, Lahore College for Women University, Jail Road, Lahore, Pakistan
| | - Muhammad Islam
- Department of Pharmaceutics, College of Pharmacy, University of the Punjab, Allama Iqbal Campus, Lahore, Pakistan
| | | | - Furqan K Hashmi
- Department of Pharmaceutics, College of Pharmacy, University of the Punjab, Allama Iqbal Campus, Lahore, Pakistan
| | | | - Hamid Saeed
- Department of Pharmaceutics, College of Pharmacy, University of the Punjab, Allama Iqbal Campus, Lahore, Pakistan.
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Ye C, Jiang N, Zheng J, Zhang S, Zhang J, Zhou J. Epigenetic therapy: Research progress of decitabine in the treatment of solid tumors. Biochim Biophys Acta Rev Cancer 2024; 1879:189066. [PMID: 38163523 DOI: 10.1016/j.bbcan.2023.189066] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 12/06/2023] [Accepted: 12/23/2023] [Indexed: 01/03/2024]
Abstract
Decitabine's early successful therapeutic outcomes in hematologic malignancies have led to regulatory approvals from the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for addressing myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). These approvals have sparked keen interest in exploring the potential of decitabine for treating solid tumors. Continuous preclinical and clinical trials have proved that low doses of decitabine also bring benefits in treating solid tumors, and various proposed mechanisms attempt to explain the potential efficacy. It is important to note that the application of decitabine in solid tumors is still considered investigational. This article reviews the application mechanism and current status of decitabine in the treatment of solid tumors.
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Affiliation(s)
- Chenlin Ye
- Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Nan Jiang
- Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jing Zheng
- Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Shumeng Zhang
- Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jingchen Zhang
- Department of Critical Care Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jianya Zhou
- Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
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6
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sanei M, Amirheidari B, Satarzadeh N. Mutuality of epigenetic and nanoparticles: two sides of a coin. Heliyon 2024; 10:e23679. [PMID: 38187314 PMCID: PMC10767507 DOI: 10.1016/j.heliyon.2023.e23679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 11/26/2023] [Accepted: 12/09/2023] [Indexed: 01/09/2024] Open
Abstract
Nowadays nanoparticles (NPs) due to their multidimensional applications in enormous different fields, has become an exciting research topic. In particular, they could attract a noticeable interest as drug deliver with increased bioavailability, therapeutic efficacy and drug specificity. Epigenetic can be considered as a complex network of molecular mechanism which are engaged in gene expression and have a vital role in regulation of environmental effects on ethology of different disorders like neurological disorders, cancers and cardiovascular diseases. For many of them epigenetic therapy was proposed although its application accompanied with limitations, due to drug toxicity. In this review we evaluate two aspects to epigenetic in the field of NPs: firstly, the role of epigenetic in regulation of nanotoxicity and secondly application of NPs as potential carriers for epidrugs.
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Affiliation(s)
- Maryam sanei
- Islamic Azad University, Faculty of Medicine, Mashhad branch, Mashhad, Iran
| | - Bagher Amirheidari
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
- Extremophile and Productive Microorganisms Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Naghmeh Satarzadeh
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
- Extremophile and Productive Microorganisms Research Center, Kerman University of Medical Sciences, Kerman, Iran
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7
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Ghosh A, Himaja A, Biswas S, Kulkarni O, Ghosh B. Advances in the Delivery and Development of Epigenetic Therapeutics for the Treatment of Cancer. Mol Pharm 2023; 20:5981-6009. [PMID: 37899551 DOI: 10.1021/acs.molpharmaceut.3c00610] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2023]
Abstract
Gene expression at the transcriptional level is altered by epigenetic modifications such as DNA methylation, histone methylation, and acetylation, which can upregulate, downregulate, or entirely silence genes. Pathological dysregulation of epigenetic processes can result in the development of cancer, neurological problems, metabolic disorders, and cardiovascular diseases. It is of promising therapeutic interest to find medications that target these epigenetic alterations. Despite the enormous amount of work that has been done in this area, very few molecules have been approved for clinical purposes. This article provides a comprehensive review of recent advances in epigenetic therapeutics for cancer, with a specific focus on emerging delivery and development strategies. Various delivery systems, including pro-drugs, conjugated molecules, nanoparticles (NPs), and liposomes, as well as remedial strategies such as combination therapies, and epigenetic editing, are being investigated to improve the efficacy and specificity of epigenetic drugs (epi-drugs). Furthermore, the challenges associated with available epi-drugs and the limitations of their translation into clinics have been discussed. Target selection, isoform selectivity, physiochemical properties of synthesized molecules, drug screening, and scalability of epi-drugs from preclinical to clinical fields are the major shortcomings that are addressed. This Review discusses novel strategies for the identification of new biomarkers, exploration of the medicinal chemistry of epigenetic modifiers, optimization of the dosage regimen, and design of proper clinical trials that will lead to better utilization of epigenetic modifiers over conventional therapies. The integration of these approaches holds great potential for improving the efficacy and precision of epigenetic treatments, ultimately benefiting cancer patients.
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Affiliation(s)
- Aparajita Ghosh
- Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science- Pilani, Hyderabad Campus, Jawahar Nagar, Medchal, Hyderabad 500078, Telangana, India
- Pharmacology Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Medchal, Hyderabad 500078, Telangana, India
| | - Ambati Himaja
- Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science- Pilani, Hyderabad Campus, Jawahar Nagar, Medchal, Hyderabad 500078, Telangana, India
| | - Swati Biswas
- Nanomedicine Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Medchal, Hyderabad 500078, Telangana, India
| | - Onkar Kulkarni
- Pharmacology Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Medchal, Hyderabad 500078, Telangana, India
| | - Balaram Ghosh
- Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science- Pilani, Hyderabad Campus, Jawahar Nagar, Medchal, Hyderabad 500078, Telangana, India
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8
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Yan L, Geng Q, Cao Z, Liu B, Li L, Lu P, Lin L, Wei L, Tan Y, He X, Li L, Zhao N, Lu C. Insights into DNMT1 and programmed cell death in diseases. Biomed Pharmacother 2023; 168:115753. [PMID: 37871559 DOI: 10.1016/j.biopha.2023.115753] [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: 08/07/2023] [Revised: 10/15/2023] [Accepted: 10/17/2023] [Indexed: 10/25/2023] Open
Abstract
DNMT1 (DNA methyltransferase 1) is the predominant member of the DNMT family and the most abundant DNMT in various cell types. It functions as a maintenance DNMT and is involved in various diseases, including cancer and nervous system diseases. Programmed cell death (PCD) is a fundamental mechanism that regulates cell proliferation and maintains the development and homeostasis of multicellular organisms. DNMT1 plays a regulatory role in various types of PCD, including apoptosis, autophagy, necroptosis, ferroptosis, and others. DNMT1 is closely associated with the development of various diseases by regulating key genes and pathways involved in PCD, including caspase 3/7 activities in apoptosis, Beclin 1, LC3, and some autophagy-related proteins in autophagy, glutathione peroxidase 4 (GPX4) and nuclear receptor coactivator 4 (NCOA4) in ferroptosis, and receptor-interacting protein kinase 1-receptor-interacting protein kinase 3-mixed lineage kinase domain-like protein (RIPK1-RIPK3-MLKL) in necroptosis. Our study summarizes the regulatory relationship between DNMT1 and different types of PCD in various diseases and discusses the potential of DNMT1 as a common regulatory hub in multiple types of PCD, offering a perspective for therapeutic approaches in disease.
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Affiliation(s)
- Lan Yan
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Qi Geng
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhiwen Cao
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Bin Liu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Li Li
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Peipei Lu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Lin Lin
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Lini Wei
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yong Tan
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiaojuan He
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Li Li
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Ning Zhao
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Cheng Lu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China.
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Urbanova M, Cihova M, Buocikova V, Slopovsky J, Dubovan P, Pindak D, Tomas M, García-Bermejo L, Rodríguez-Garrote M, Earl J, Kohl Y, Kataki A, Dusinska M, Sainz B, Smolkova B, Gabelova A. Nanomedicine and epigenetics: New alliances to increase the odds in pancreatic cancer survival. Biomed Pharmacother 2023; 165:115179. [PMID: 37481927 DOI: 10.1016/j.biopha.2023.115179] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 07/04/2023] [Accepted: 07/12/2023] [Indexed: 07/25/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers worldwide, primarily due to its robust desmoplastic stroma and immunosuppressive tumor microenvironment (TME), which facilitate tumor progression and metastasis. In addition, fibrous tissue leads to sparse vasculature, high interstitial fluid pressure, and hypoxia, thereby hindering effective systemic drug delivery and immune cell infiltration. Thus, remodeling the TME to enhance tumor perfusion, increase drug retention, and reverse immunosuppression has become a key therapeutic strategy. In recent years, targeting epigenetic pathways has emerged as a promising approach to overcome tumor immunosuppression and cancer progression. Moreover, the progress in nanotechnology has provided new opportunities for enhancing the efficacy of conventional and epigenetic drugs. Nano-based drug delivery systems (NDDSs) offer several advantages, including improved drug pharmacokinetics, enhanced tumor penetration, and reduced systemic toxicity. Smart NDDSs enable precise targeting of stromal components and augment the effectiveness of immunotherapy through multiple drug delivery options. This review offers an overview of the latest nano-based approaches developed to achieve superior therapeutic efficacy and overcome drug resistance. We specifically focus on the TME and epigenetic-targeted therapies in the context of PDAC, discussing the advantages and limitations of current strategies while highlighting promising new developments. By emphasizing the immense potential of NDDSs in improving therapeutic outcomes in PDAC, our review paves the way for future research in this rapidly evolving field.
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Affiliation(s)
- Maria Urbanova
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia
| | - Marina Cihova
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia
| | - Verona Buocikova
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia
| | - Jan Slopovsky
- 2nd Department of Oncology, National Cancer Institute, Klenova 1, 833 10 Bratislava, Slovakia; Faculty of Medicine, Comenius University, Spitalska 24, 813 72 Bratislava, Slovakia
| | - Peter Dubovan
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; Department of Surgical Oncology, National CancerInstitute in Bratislava, Klenova 1, 833 10 Bratislava, Slovakia; Faculty of Medicine, Slovak Medical University in Bratislava, Limbová12, 833 03 Bratislava
| | - Daniel Pindak
- Department of Surgical Oncology, National CancerInstitute in Bratislava, Klenova 1, 833 10 Bratislava, Slovakia; Faculty of Medicine, Slovak Medical University in Bratislava, Limbová12, 833 03 Bratislava
| | - Miroslav Tomas
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; Department of Surgical Oncology, National CancerInstitute in Bratislava, Klenova 1, 833 10 Bratislava, Slovakia; Faculty of Medicine, Slovak Medical University in Bratislava, Limbová12, 833 03 Bratislava
| | - Laura García-Bermejo
- Biomarkers and Therapeutic Targets Group, Area4, Ramón y Cajal Health Research Institute (IRYCIS), Carretera Colmenar Km 9100, 28034 Madrid, Spain
| | - Mercedes Rodríguez-Garrote
- Molecular Epidemiology and Predictive Tumor Markers Group, Area 3, Ramón y Cajal Health Research Institute (IRYCIS), Carretera Colmenar Km 9100, 28034 Madrid, Spain; CIBERONC, Madrid, Spain
| | - Julie Earl
- Molecular Epidemiology and Predictive Tumor Markers Group, Area 3, Ramón y Cajal Health Research Institute (IRYCIS), Carretera Colmenar Km 9100, 28034 Madrid, Spain; CIBERONC, Madrid, Spain
| | - Yvonne Kohl
- Department Bioprocessing & Bioanalytics, Fraunhofer Institute for Biomedical Engineering IBMT, 66280 Sulzbach, Germany
| | - Agapi Kataki
- 1st Department of Propaedeutic Surgery, National and Kapodistrian University of Athens, Vasilissis Sofias 114, 11527 Athens, Greece
| | - Maria Dusinska
- Health Effects Laboratory, Department of Environmental Chemistry, NILU-Norwegian Institute for Air Research, Instituttveien 18, 2002 Kjeller, Norway
| | - Bruno Sainz
- CIBERONC, Madrid, Spain; Instituto de Investigaciones Biomédicas"Alberto Sols" (IIBM), CSIC-UAM, 28029 Madrid, Spain; Biomarkers and Personalized Approach to Cancer (BIOPAC) Group, Area 3, Ramón y Cajal Health Research Institute (IRYCIS), 28034 Madrid, Spain
| | - Bozena Smolkova
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia
| | - Alena Gabelova
- Department of Nanobiology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska Cesta 9, 84505 Bratislava, Slovakia..
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Fakhri S, Moradi SZ, Faraji F, Farhadi T, Hesami O, Iranpanah A, Webber K, Bishayee A. Current advances in nanoformulations of therapeutic agents targeting tumor microenvironment to overcome drug resistance. Cancer Metastasis Rev 2023; 42:959-1020. [PMID: 37505336 DOI: 10.1007/s10555-023-10119-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 06/13/2023] [Indexed: 07/29/2023]
Abstract
The tumor microenvironment (TME) plays a pivotal role in cancer development and progression. In this line, revealing the precise mechanisms of the TME and associated signaling pathways of tumor resistance could pave the road for cancer prevention and efficient treatment. The use of nanomedicine could be a step forward in overcoming the barriers in tumor-targeted therapy. Novel delivery systems benefit from enhanced permeability and retention effect, decreasing tumor resistance, reducing tumor hypoxia, and targeting tumor-associated factors, including immune cells, endothelial cells, and fibroblasts. Emerging evidence also indicates the engagement of multiple dysregulated mediators in the TME, such as matrix metalloproteinase, vascular endothelial growth factor, cytokines/chemokines, Wnt/β-catenin, Notch, Hedgehog, and related inflammatory and apoptotic pathways. Hence, investigating novel multitargeted agents using a novel delivery system could be a promising strategy for regulating TME and drug resistance. In recent years, small molecules from natural sources have shown favorable anticancer responses by targeting TME components. Nanoformulations of natural compounds are promising therapeutic agents in simultaneously targeting multiple dysregulated factors and mediators of TME, reducing tumor resistance mechanisms, overcoming interstitial fluid pressure and pericyte coverage, and involvement of basement membrane. The novel nanoformulations employ a vascular normalization strategy, stromal/matrix normalization, and stress alleviation mechanisms to exert higher efficacy and lower side effects. Accordingly, the nanoformulations of anticancer monoclonal antibodies and conventional chemotherapeutic agents also improved their efficacy and lessened the pharmacokinetic limitations. Additionally, the coadministration of nanoformulations of natural compounds along with conventional chemotherapeutic agents, monoclonal antibodies, and nanomedicine-based radiotherapy exhibits encouraging results. This critical review evaluates the current body of knowledge in targeting TME components by nanoformulation-based delivery systems of natural small molecules, monoclonal antibodies, conventional chemotherapeutic agents, and combination therapies in both preclinical and clinical settings. Current challenges, pitfalls, limitations, and future perspectives are also discussed.
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Affiliation(s)
- Sajad Fakhri
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, 6734667149, Iran
| | - Seyed Zachariah Moradi
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, 6734667149, Iran
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, 6734667149, Iran
| | - Farahnaz Faraji
- Department of Pharmaceutics, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, 6517838678, Iran
| | - Tara Farhadi
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, 6714415153, Iran
| | - Osman Hesami
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, 6734667149, Iran
| | - Amin Iranpanah
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, 6734667149, Iran
| | - Kassidy Webber
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL, 34211, USA
| | - Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL, 34211, USA.
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11
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Chaudhuri A, Kumar DN, Dehari D, Patil R, Singh S, Kumar D, Agrawal AK. Endorsement of TNBC Biomarkers in Precision Therapy by Nanotechnology. Cancers (Basel) 2023; 15:cancers15092661. [PMID: 37174125 PMCID: PMC10177107 DOI: 10.3390/cancers15092661] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 05/05/2023] [Accepted: 05/06/2023] [Indexed: 05/15/2023] Open
Abstract
Breast cancer is a heterogeneous disease which accounts globally for approximately 1 million new cases annually, wherein more than 200,000 of these cases turn out to be cases of triple-negative breast cancer (TNBC). TNBC is an aggressive and rare breast cancer subtype that accounts for 10-15% of all breast cancer cases. Chemotherapy remains the only therapy regimen against TNBC. However, the emergence of innate or acquired chemoresistance has hindered the chemotherapy used to treat TNBC. The data obtained from molecular technologies have recognized TNBC with various gene profiling and mutation settings that have helped establish and develop targeted therapies. New therapeutic strategies based on the targeted delivery of therapeutics have relied on the application of biomarkers derived from the molecular profiling of TNBC patients. Several biomarkers have been found that are targets for the precision therapy in TNBC, such as EGFR, VGFR, TP53, interleukins, insulin-like growth factor binding proteins, c-MET, androgen receptor, BRCA1, glucocorticoid, PTEN, ALDH1, etc. This review discusses the various candidate biomarkers identified in the treatment of TNBC along with the evidence supporting their use. It was established that nanoparticles had been considered a multifunctional system for delivering therapeutics to target sites with increased precision. Here, we also discuss the role of biomarkers in nanotechnology translation in TNBC therapy and management.
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Affiliation(s)
- Aiswarya Chaudhuri
- Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi 221005, India
| | - Dulla Naveen Kumar
- Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi 221005, India
| | - Deepa Dehari
- Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi 221005, India
| | - Rohit Patil
- Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi 221005, India
| | - Sanjay Singh
- Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi 221005, India
- Department of Pharmaceutics, Babasaheb Bhimrao Ambedkar University (A Central University), Vidya Vihar, Raebareli Road, Lucknow 226025, India
| | - Dinesh Kumar
- Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi 221005, India
| | - Ashish Kumar Agrawal
- Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi 221005, India
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12
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Desai N, Hasan U, K J, Mani R, Chauhan M, Basu SM, Giri J. Biomaterial-based platforms for modulating immune components against cancer and cancer stem cells. Acta Biomater 2023; 161:1-36. [PMID: 36907233 DOI: 10.1016/j.actbio.2023.03.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 03/02/2023] [Accepted: 03/02/2023] [Indexed: 03/12/2023]
Abstract
Immunotherapy involves the therapeutic alteration of the patient's immune system to identify, target, and eliminate cancer cells. Dendritic cells, macrophages, myeloid-derived suppressor cells, and regulatory T cells make up the tumor microenvironment. In cancer, these immune components (in association with some non-immune cell populations like cancer-associated fibroblasts) are directly altered at a cellular level. By dominating immune cells with molecular cross-talk, cancer cells can proliferate unchecked. Current clinical immunotherapy strategies are limited to conventional adoptive cell therapy or immune checkpoint blockade. Targeting and modulating key immune components presents an effective opportunity. Immunostimulatory drugs are a research hotspot, but their poor pharmacokinetics, low tumor accumulation, and non-specific systemic toxicity limit their use. This review describes the cutting-edge research undertaken in the field of nanotechnology and material science to develop biomaterials-based platforms as effective immunotherapeutics. Various biomaterial types (polymer-based, lipid-based, carbon-based, cell-derived, etc.) and functionalization methodologies for modulating tumor-associated immune/non-immune cells are explored. Additionally, emphasis has been laid on discussing how these platforms can be used against cancer stem cells, a fundamental contributor to chemoresistance, tumor relapse/metastasis, and failure of immunotherapy. Overall, this comprehensive review strives to provide up-to-date information to an audience working at the juncture of biomaterials and cancer immunotherapy. STATEMENT OF SIGNIFICANCE: Cancer immunotherapy possesses incredible potential and has successfully transitioned into a clinically lucrative alternative to conventional anti-cancer therapies. With new immunotherapeutics getting rapid clinical approval, fundamental problems associated with the dynamic nature of the immune system (like limited clinical response rates and autoimmunity-related adverse effects) have remained unanswered. In this context, treatment approaches that focus on modulating the compromised immune components within the tumor microenvironment have garnered significant attention amongst the scientific community. This review aims to provide a critical discussion on how various biomaterials (polymer-based, lipid-based, carbon-based, cell-derived, etc.) can be employed along with immunostimulatory agents to design innovative platforms for selective immunotherapy directed against cancer and cancer stem cells.
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Affiliation(s)
- Nimeet Desai
- Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Kandi, Telangana, India
| | - Uzma Hasan
- Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Kandi, Telangana, India; Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, Telangana, India
| | - Jeyashree K
- Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Kandi, Telangana, India
| | - Rajesh Mani
- Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Kandi, Telangana, India
| | - Meenakshi Chauhan
- Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Kandi, Telangana, India
| | - Suparna Mercy Basu
- Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Kandi, Telangana, India
| | - Jyotsnendu Giri
- Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Kandi, Telangana, India.
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Zhao CR, Li J, Jiang ZT, Zhu JJ, Zhao JN, Yang QR, Yao W, Pang W, Li N, Yu M, Gan Y, Zhou J. Disturbed Flow-Facilitated Margination and Targeting of Nanodisks Protect against Atherosclerosis. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023; 19:e2204694. [PMID: 36403215 DOI: 10.1002/smll.202204694] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 10/22/2022] [Indexed: 06/16/2023]
Abstract
Disturbed blood flow induces endothelial pro-inflammatory responses that promote atherogenesis. Nanoparticle-based therapeutics aimed at treating endothelial inflammation in vasculature where disturbed flow occurs may provide a promising avenue to prevent atherosclerosis. By using a vertical-step flow apparatus and a microfluidic chip of vascular stenosis, herein, it is found that the disk-shaped versus the spherical nanoparticles exhibit preferential margination (localization and adhesion) to the regions with the pro-atherogenic disturbed flow. By employing a mouse model of carotid partial ligation, superior targeting and higher accumulation of the disk-shaped particles are also demonstrated within disturbed flow areas than that of the spherical particles. In hyperlipidemia mice, administration of disk-shaped particles loaded with hypomethylating agent decitabine (DAC) displays greater anti-inflammatory and anti-atherosclerotic effects compared with that of the spherical counterparts and exhibits reduced toxicity than "naked" DAC. The findings suggest that shaping nanoparticles to disk is an effective strategy for promoting their delivery to atheroprone endothelia.
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Affiliation(s)
- Chuan-Rong Zhao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Hemorheology Center, School of Basic Medical Sciences, Peking University, Beijing, 100191, China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, China
- National Health Commission Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University, Beijing, 100191, China
| | - Jingyi Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Zhi-Tong Jiang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Hemorheology Center, School of Basic Medical Sciences, Peking University, Beijing, 100191, China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, China
- National Health Commission Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University, Beijing, 100191, China
- Department of Cardiovascular Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, China
| | - Juan-Juan Zhu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Hemorheology Center, School of Basic Medical Sciences, Peking University, Beijing, 100191, China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, China
- National Health Commission Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University, Beijing, 100191, China
| | - Jia-Nan Zhao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Hemorheology Center, School of Basic Medical Sciences, Peking University, Beijing, 100191, China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, China
- National Health Commission Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University, Beijing, 100191, China
| | - Qian-Ru Yang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Hemorheology Center, School of Basic Medical Sciences, Peking University, Beijing, 100191, China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, China
- National Health Commission Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University, Beijing, 100191, China
| | - Weijuan Yao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Hemorheology Center, School of Basic Medical Sciences, Peking University, Beijing, 100191, China
| | - Wei Pang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Hemorheology Center, School of Basic Medical Sciences, Peking University, Beijing, 100191, China
| | - Ning Li
- Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory), and, Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing, 100190, China
- School of Engineering Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Miaorong Yu
- 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
| | - Yong Gan
- 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
| | - Jing Zhou
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Hemorheology Center, School of Basic Medical Sciences, Peking University, Beijing, 100191, China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, China
- National Health Commission Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University, Beijing, 100191, China
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Lee-Theilen M, Fadini DD, Hadhoud JR, van Dongen F, Kroll G, Rolle U, Fiegel HC. Hepatoblastoma Cancer Stem Cells Express PD-L1, Reveal Plasticity and Can Emerge upon Chemotherapy. Cancers (Basel) 2022; 14:5825. [PMID: 36497307 PMCID: PMC9736435 DOI: 10.3390/cancers14235825] [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: 10/26/2022] [Revised: 11/21/2022] [Accepted: 11/23/2022] [Indexed: 11/29/2022] Open
Abstract
The biology of cancer stem cells (CSCs) of pediatric cancers, such as hepatoblastoma, is sparsely explored. This is mainly due to the very immature nature of these tumors, which complicates the distinction of CSCs from the other tumor cells. Previously, we identified a CSC population in hepatoblastoma cell lines expressing the CSC markers CD34 and CD90, cell surface Vimentin (csVimentin) and binding of OV-6. In this study, we detected the co-expression of the immune escape factor PD-L1 in the CSC population, whereas the other tumor cells remained negative. FACS data revealed that non-CSCs give rise to CSCs, reflecting plasticity of CSCs and non-CSCs in hepatoblastoma as seen in other tumors. When we treated cells with cisplatin and decitabine, a new CD34+/lowOV-6lowCD90+ population emerged that lacked csVimentin and PD-L1 expression. Expression analyses showed that this new CSC subset shared similar pluripotency and EMT features with the already-known CSCs. FACS results further revealed that this subset is also generated from non-CSCs. In conclusion, we showed that hepatoblastoma CSCs express PD-L1 and that the biology of hepatoblastoma CSCs is of a plastic nature. Chemotherapeutic treatment leads to another CSC subset, which is highly chemoresistant and could be responsible for a poor prognosis after postoperative chemotherapy.
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Affiliation(s)
- Mieun Lee-Theilen
- Department of Pediatric Surgery and Pediatric Urology, University Hospital, Goethe University Frankfurt, 60590 Frankfurt, Germany
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15
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Alexandraki A, Strati K. Decitabine Treatment Induces a Viral Mimicry Response in Cervical Cancer Cells and Further Sensitizes Cells to Chemotherapy. Int J Mol Sci 2022; 23:ijms232214042. [PMID: 36430521 PMCID: PMC9692951 DOI: 10.3390/ijms232214042] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 11/04/2022] [Accepted: 11/05/2022] [Indexed: 11/16/2022] Open
Abstract
PURPOSE To investigate the anti-cancer, chemosensitizing and/or immunomodulating effects of decitabine (DAC) to be used as a potential therapeutic agent for the treatment of cervical cancer (CC). METHODS Cervical cancer cell lines were treated with low doses of DAC treatment used as a single agent or in combination with chemotherapy. End-point in vitro assays were developed as indicators of the anti-cancer and/or immunomodulating effects of DAC treatment in CC cells. These assays include cell viability, cell cycle analysis, apoptosis, induction of a viral-mimicry response pathway, expression of MHC-class I and PD-L1 and chemosensitivity. RESULTS High and low doses of DAC treatment induced reduction in cell viability in HeLa (HPV18+), CaSki (HPV16+) and C33A (HPV-) cells. Specifically, a time-dependent reduction in cell viability of HeLa and CaSki cells was observed accompanied by robust cell cycle arrest at G2/M phase and alterations in the cell cycle distribution. Decrease in cell viability was also observed in a non-transformed immortal keratinocyte (HaCat) suggesting a non-cancer specific target effect. DAC treatment also triggered a viral mimicry response through long-term induction of cytoplasmic double-stranded RNA (dsRNA) and activation of downstream IFN-related genes in both HPV+ and HPV- cells. In addition, DAC treatment increased the number of CC cells expressing MHC-class I and PD-L1. Furthermore, DAC significantly increased the proportion of early and late apoptotic CC cells quantified using FACS. Our combination treatments showed that low dose DAC treatment sensitizes cells to chemotherapy. CONCLUSIONS Low doses of DAC treatment promotes robust induction of a viral mimicry response, immunomodulating and chemosensitizing effects in CC, indicating its promising therapeutic role in CC in vitro.
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16
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Flores-Contreras EA, González-González RB, González-González E, Parra-Saldívar R, Iqbal HM. Nano-vehicles modulated delivery of therapeutic epigenetic regulators to treat Triple-Negative Breast Cancer. J Drug Deliv Sci Technol 2022; 77:103924. [DOI: 10.1016/j.jddst.2022.103924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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17
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Madej M, Kurowska N, Strzalka-Mrozik B. Polymeric Nanoparticles—Tools in a Drug Delivery System in Selected Cancer Therapies. APPLIED SCIENCES 2022; 12:9479. [DOI: 10.3390/app12199479] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
The increase in cancer cases is undoubtedly affecting the development of new therapeutic approaches. Polymeric nanoparticles are of great interest. Due to their relatively small size, the possibility of incorporating into them medicinal substances and the ease with which their physicochemical properties may be manipulated, they are being used as anticancer drug delivery systems. The aim of this review is to focus on the use of nanoscale polymeric particles in the treatment of colorectal cancer, breast cancer, ovarian cancer and glioblastoma multiforme, and to consider their potential use in cancer gene therapy. According to several reports, the use of polymer nanoparticles as drug carriers is promising in solid tumors. With their application, it is possible to precisely deliver medicinal substances to the tumor structure, to overcome the blood–brain barrier in the case of brain tumors, to reduce the side effects of anticancer agents on normal cells and to achieve a therapeutic effect with a lower drug dose. Additionally, a number of reports indicate that they can also be used in combination with other methods of cancer treatment, mainly radiotherapy.
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Affiliation(s)
- Marcel Madej
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 40-055 Katowice, Poland
| | - Natalia Kurowska
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 40-055 Katowice, Poland
| | - Barbara Strzalka-Mrozik
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 40-055 Katowice, Poland
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18
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Novel epigenetic therapeutic strategies and targets in cancer. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166552. [PMID: 36126898 DOI: 10.1016/j.bbadis.2022.166552] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 09/08/2022] [Accepted: 09/14/2022] [Indexed: 11/24/2022]
Abstract
The critical role of dysregulated epigenetic pathways in cancer genesis, development, and therapy has typically been established as a result of scientific and technical innovations in next generation sequencing. RNA interference, histone modification, DNA methylation and chromatin remodelling are epigenetic processes that control gene expression without causing mutations in the DNA. Although epigenetic abnormalities are thought to be a symptom of cell tumorigenesis and malignant events that impact tumor growth and drug resistance, physicians believe that related processes might be a key therapeutic target for cancer treatment and prevention due to the reversible nature of these processes. A plethora of novel strategies for addressing epigenetics in cancer therapy for immuno-oncological complications are currently available - ranging from basic treatment to epigenetic editing. - and they will be the subject of this comprehensive review. In this review, we cover most of the advancements made in the field of targeting epigenetics with special emphasis on microbiology, plasma science, biophysics, pharmacology, molecular biology, phytochemistry, and nanoscience.
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19
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Guha L, Bhat IA, Bashir A, Rahman JU, Pottoo FH. Nanotechnological Approaches for the Treatment of Triple-Negative Breast Cancer: A Comprehensive Review. Curr Drug Metab 2022; 23:781-799. [PMID: 35676850 DOI: 10.2174/1389200223666220608144551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 02/01/2022] [Accepted: 03/10/2022] [Indexed: 01/05/2023]
Abstract
Breast cancer is the most prevalent cancer in women around the world, having a sudden spread nowadays because of the poor sedentary lifestyle of people. Comprising several subtypes, one of the most dangerous and aggressive ones is triple-negative breast cancer or TNBC. Even though conventional surgical approaches like single and double mastectomy and preventive chemotherapeutic approaches are available, they are not selective to cancer cells and are only for symptomatic treatment. A new branch called nanotechnology has emerged in the last few decades that offers various novel characteristics, such as size in nanometric scale, enhanced adherence to multiple targeting moieties, active and passive targeting, controlled release, and site-specific targeting. Among various nanotherapeutic approaches like dendrimers, lipid-structured nanocarriers, carbon nanotubes, etc., nanoparticle targeted therapeutics can be termed the best among all for their specific cytotoxicity to cancer cells and increased bioavailability to a target site. This review focuses on the types and molecular pathways involving TNBC, existing treatment strategies, various nanotechnological approaches like exosomes, carbon nanotubes, dendrimers, lipid, and carbon-based nanocarriers, and especially various nanoparticles (NPs) like polymeric, photodynamic, peptide conjugated, antibody-conjugated, metallic, inorganic, natural product capped, and CRISPR based nanoparticles already approved for treatment or are under clinical and pre-clinical trials for TNBC.
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Affiliation(s)
- Lahanya Guha
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research Mohali, S.A.S Nagar, Punjab 160062, India
| | - Ishfaq Ahmad Bhat
- Northern Railway Hospital, Sri Mata Vaishno Devi, Katra, Reasi 182320, India
| | - Aasiya Bashir
- Department of Pharmaceutical Sciences, Faculty of Applied Sciences and Technology, University of Kashmir, Hazratbal, Srinagar-190006, J&K, India
| | - Jawad Ur Rahman
- Department of Microbiology, College of Medicine, Imam Abdulrahman Bin Faisal University, P.O.BOX 1982, Dammam 31441, Saudi Arabia
| | - Faheem Hyder Pottoo
- Department of Pharmacology, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O.BOX 1982, Dammam 31441, Saudi Arabia
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Zewail M, E Gaafar PM, Ali MM, Abbas H. Lipidic cubic-phase leflunomide nanoparticles (cubosomes) as a potential tool for breast cancer management. Drug Deliv 2022; 29:1663-1674. [PMID: 35616281 PMCID: PMC9154769 DOI: 10.1080/10717544.2022.2079770] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Despite the fact of availability of several treatments for breast cancer, most of them fail to attain the desired therapeutic response due to their poor bioavailability, high doses, non-selectivity and as a result systemic toxicity. Here in an attempt made to study the transdermal effect of leflunomide (LEF) against breast cancer. In order to improve the poor physicochemical properties of LEF, it was loaded into cubosomes. Cubosomes were prepared by the emulsification method. Colloidal characteristics of cubosomes including particle size, ζ-potential, entrapment efficiency, in-vitro release profile and ex-vivo permeation were studied. In addition, morphology, stability, cytotoxicity and cell uptake in MDA-MB-231 cell line were carried out for the selected cubosomal formulation. The selected LEF loaded cubosomal formulation showed a small particle size (168 ± 1.08) with narrow size distribution (PI 0.186 ± 0.125) and negative ζ potential (–25.5 ± 0.98). Its Entrapment efficiency (EE%) was 93.2% and showed sustained release profile that extended for 24 h. The selected formulation showed stability when stored at 25 °C for three months in terms of size and EE%. TEM images illustrated the cubic structure of the cubosome. Cell culture results revealed the superiority of LEF cubosomes compared to LEF suspension in their cytotoxic effects with an IC50 close to that of doxorubicin. Furthermore, LEF cell uptake was significantly higher for LEF cubosomes. This may be attributed to the effect of nano-encapsulation on enhancing drug pharmacological effects and uptake indicating the potential usefulness of LEF cubosomes for breast cancer management.
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Affiliation(s)
- Mariam Zewail
- Pharmaceutics Department, Faculty of Pharmacy, Damanhour University, Damanhour, Egypt
| | - Passent M E Gaafar
- Department of Pharmaceutics, Division of Pharmaceutical Sciences, College of Pharmacy, Arab Academy for Science, Technology and Maritime Transport, Alexandria, Egypt
| | - Mai M Ali
- Department of Pharmaceutics, Division of Pharmaceutical Sciences, College of Pharmacy, Arab Academy for Science, Technology and Maritime Transport, Alexandria, Egypt
| | - Haidy Abbas
- Pharmaceutics Department, Faculty of Pharmacy, Damanhour University, Damanhour, Egypt
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Buocikova V, Longhin EM, Pilalis E, Mastrokalou C, Miklikova S, Cihova M, Poturnayova A, Mackova K, Babelova A, Trnkova L, El Yamani N, Zheng C, Rios-Mondragon I, Labudova M, Csaderova L, Kuracinova KM, Makovicky P, Kucerova L, Matuskova M, Cimpan MR, Dusinska M, Babal P, Chatziioannou A, Gabelova A, Rundén-Pran E, Smolkova B. Decitabine potentiates efficacy of doxorubicin in a preclinical trastuzumab-resistant HER2-positive breast cancer models. Biomed Pharmacother 2022; 147:112662. [DOI: 10.1016/j.biopha.2022.112662] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 01/14/2022] [Accepted: 01/19/2022] [Indexed: 12/22/2022] Open
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Musolino E, Pagiatakis C, Serio S, Borgese M, Gamberoni F, Gornati R, Bernardini G, Papait R. The Yin and Yang of epigenetics in the field of nanoparticles. NANOSCALE ADVANCES 2022; 4:979-994. [PMID: 36131763 PMCID: PMC9419747 DOI: 10.1039/d1na00682g] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 12/30/2021] [Indexed: 05/02/2023]
Abstract
Nanoparticles (NPs) have become a very exciting research avenue, with multitudinous applications in various fields, including the biomedical one, whereby they have been gaining considerable interest as drug carriers able to increase bioavailability, therapeutic efficiency and specificity of drugs. Epigenetics, a complex network of molecular mechanisms involved in gene expression regulation, play a key role in mediating the effect of environmental factors on organisms and in the etiology of several diseases (e.g., cancers, neurological disorders and cardiovascular diseases). For many of these diseases, epigenetic therapies have been proposed, whose application is however limited by the toxicity of epigenetic drugs. In this review, we will analyze two aspects of epigenetics in the field of NPs: the first is the role that epigenetics play in mediating nanotoxicity, and the second is the possibility of using NPs for delivery of "epi-drugs" to overcome their limitations. We aim to stimulate discussion among specialists, specifically on the potential contribution of epigenetics to the field of NPs, and to inspire newcomers to this exciting technology.
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Affiliation(s)
- Elettra Musolino
- Department of and Life Sciences, Insubria University Via Dunant 3 21100 Varese Italy
| | - Christina Pagiatakis
- Department of Cardiovascular Medicine, Humanitas Research Hospital Rozzano MI Italy
| | - Simone Serio
- Department of Cardiovascular Medicine, Humanitas Research Hospital Rozzano MI Italy
- Department of Biomedical Sciences, Humanitas University Via Rita Levi Montalcini 4 20090 Pieve Emanuele MI Italy
| | - Marina Borgese
- Department of and Life Sciences, Insubria University Via Dunant 3 21100 Varese Italy
| | - Federica Gamberoni
- Department of and Life Sciences, Insubria University Via Dunant 3 21100 Varese Italy
| | - Rosalba Gornati
- Department of and Life Sciences, Insubria University Via Dunant 3 21100 Varese Italy
| | - Giovanni Bernardini
- Department of and Life Sciences, Insubria University Via Dunant 3 21100 Varese Italy
| | - Roberto Papait
- Department of and Life Sciences, Insubria University Via Dunant 3 21100 Varese Italy
- Department of Cardiovascular Medicine, Humanitas Research Hospital Rozzano MI Italy
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23
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Nigam K, Kaur A, Tyagi A, Manda K, Goswami N, Nematullah M, Khan F, Gabrani R, Gauba P, Dang S. In vitro & In vivo evaluations of PLGA nanoparticle based combinatorial drug therapy for Baclofen and Lamotrigine for neuropathic pain management. J Microencapsul 2022; 39:95-109. [PMID: 35147068 DOI: 10.1080/02652048.2022.2041751] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
AIM Baclofen and Lamotrigine via PLGA nanoparticles were developed for nose-to-brain delivery for treatment of Neuropathic pain. METHODS Nanoparticles were prepared using modified nano-precipitation method. The prepared NPs were characterized and further in vitro and in vivo studies were performed. RESULTS The Bcf-Ltg-PLGA-NPs were ∼177.7nm with >75%(w/w) drugs encapsulated. In vitro dissolution studies suggested zero-order release profiles following Korsmeyer-Peppas model. In vitro cytotoxicity and staining studies on mammalian cells showed dose dependant cytotoxicity where nanoparticles were significantly less toxic(>95% cell-viability). ELISA studies on RAW-macrophages showed Bcf-Ltg-PLGA-NPs as potential pro-inflammatory-cytokines inhibitor. In vivo gamma-scintigraphy studies on rats showed intra-nasal administration of 99mTc-Bcf-Ltg-PLGA-NPs showed Cmax 3.6%/g at Tmax=1.5h with DTE% as 191.23% and DTP% = 38.61% in brain. Pharmacodynamics evaluations on C57BL/6J mice showed significant reduction in licks/bites during inflammation induced phase II pain. CONCLUSION The findings concluded that combination of these drugs into single nanoparticle-based formulation has potential for pain management.
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Affiliation(s)
- Kuldeep Nigam
- Department of Biotechnology, Jaypee Institute of Information Technology, A-10, Sector-62, NOIDA, India, 201309
| | - Atinderpal Kaur
- Department of Biotechnology, Jaypee Institute of Information Technology, A-10, Sector-62, NOIDA, India, 201309
| | - Amit Tyagi
- Institute of Nuclear medicine and Allied Sciences, Defence Research and Development Organisation, Timarpur, Delhi, India, 110054
| | - Kailash Manda
- Institute of Nuclear medicine and Allied Sciences, Defence Research and Development Organisation, Timarpur, Delhi, India, 110054
| | - Nidhi Goswami
- Institute of Nuclear medicine and Allied Sciences, Defence Research and Development Organisation, Timarpur, Delhi, India, 110054
| | - Md Nematullah
- Department of Biochemistry, Faculty of Science, Jamia Hamdard, New Delhi, India, 110062
| | - Farah Khan
- Department of Biochemistry, Faculty of Science, Jamia Hamdard, New Delhi, India, 110062
| | - Reema Gabrani
- Department of Biotechnology, Jaypee Institute of Information Technology, A-10, Sector-62, NOIDA, India, 201309
| | - Pammi Gauba
- Department of Biotechnology, Jaypee Institute of Information Technology, A-10, Sector-62, NOIDA, India, 201309
| | - Shweta Dang
- Department of Biotechnology, Jaypee Institute of Information Technology, A-10, Sector-62, NOIDA, India, 201309
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24
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Gupta P, Neupane YR, Parvez S, Kohli K. Recent advances in targeted nanotherapeutic approaches for breast cancer management. Nanomedicine (Lond) 2021; 16:2605-2631. [PMID: 34854336 DOI: 10.2217/nnm-2021-0281] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Breast cancer is the most commonly occurring tumor disease worldwide. Breast cancer is currently managed by conventional chemotherapy, which is inadequate in curbing this heterogeneous disease and results in off-site toxic effects, suggesting effective treatment approaches with better therapeutic profiles are needed. This review, therefore, focuses on the recent advancements in delivering therapeutics to the target site using passive and/or active targeted nanodrug-delivery systems to ameliorate endolysosomal escape. In addition, recent strategies in targeting breast cancer stem cells are discussed. The role of naturally cell-secreted nanovesicles (exosomes) in the management of triple-negative breast cancer is also discussed.
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Affiliation(s)
- Priya Gupta
- Department of Pharmaceutics, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi, 110062, India
| | - Yub Raj Neupane
- Department of Pharmacy, National University of Singapore, Singapore, 117559
| | - Suhel Parvez
- Department of Toxicology, School of Chemical & Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Kanchan Kohli
- Department of Pharmaceutics, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi, 110062, India.,Lloyd Institute of Management & Technology (Pharm.), Plot No. 11, Knowledge Park-II, Greater Noida, 201308, Uttar Pradesh, India
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25
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Püschel J, Dubrovska A, Gorodetska I. The Multifaceted Role of Aldehyde Dehydrogenases in Prostate Cancer Stem Cells. Cancers (Basel) 2021; 13:4703. [PMID: 34572930 PMCID: PMC8472046 DOI: 10.3390/cancers13184703] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 08/27/2021] [Accepted: 09/13/2021] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) are the only tumor cells possessing self-renewal and differentiation properties, making them an engine of tumor progression and a source of tumor regrowth after treatment. Conventional therapies eliminate most non-CSCs, while CSCs often remain radiation and drug resistant, leading to tumor relapse and metastases. Thus, targeting CSCs might be a powerful tool to overcome tumor resistance and increase the efficiency of current cancer treatment strategies. The identification and isolation of the CSC population based on its high aldehyde dehydrogenase activity (ALDH) is widely accepted for prostate cancer (PCa) and many other solid tumors. In PCa, several ALDH genes contribute to the ALDH activity, which can be measured in the enzymatic assay by converting 4, 4-difluoro-4-bora-3a, 4a-diaza-s-indacene (BODIPY) aminoacetaldehyde (BAAA) into the fluorescent product BODIPY-aminoacetate (BAA). Although each ALDH isoform plays an individual role in PCa biology, their mutual functional interplay also contributes to PCa progression. Thus, ALDH proteins are markers and functional regulators of CSC properties, representing an attractive target for cancer treatment. In this review, we discuss the current state of research regarding the role of individual ALDH isoforms in PCa development and progression, their possible therapeutic targeting, and provide an outlook for the future advances in this field.
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Affiliation(s)
- Jakob Püschel
- OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, 01309 Dresden, Germany;
| | - Anna Dubrovska
- OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, 01309 Dresden, Germany;
- National Center for Tumor Diseases (NCT), Partner Site Dresden, German Cancer Research Center (DKFZ), Heidelberg, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, and Helmholtz-Zentrum Dresden-Rossendorf (HZDR), 01307 Dresden, Germany
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, 01328 Dresden, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Ielizaveta Gorodetska
- OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, 01309 Dresden, Germany;
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26
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Zhu D, Zhu XH, Ren SZ, Lu YD, Zhu HL. Manganese dioxide (MnO2) based nanomaterials for cancer therapies and theranostics. J Drug Target 2021; 29:911-924. [DOI: 10.1080/1061186x.2020.1815209] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Dan Zhu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
| | - Xiao-Hua Zhu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
| | - Shen-Zhen Ren
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
| | - Ya-Dong Lu
- Childrens Hospital, Neonatal Medical Center, Nanjing Medical University, Nanjing, China
| | - Hai-Liang Zhu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
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27
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Qayoom H, Wani NA, Alshehri B, Mir MA. An insight into the cancer stem cell survival pathways involved in chemoresistance in triple-negative breast cancer. Future Oncol 2021; 17:4185-4206. [PMID: 34342489 DOI: 10.2217/fon-2021-0172] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is the most complex, aggressive and fatal subtype of breast cancer. Owing to the lack of targeted therapy and heterogenic nature of TNBC, chemotherapy remains the sole treatment option for TNBC, with taxanes and anthracyclines representing the general chemotherapeutic regimen in TNBC therapy. But unfortunately, patients develop resistance to the existing chemotherapeutic regimen, resulting in approximately 90% treatment failure. Breast cancer stem cells (BCSCs) are one of the major causes for the development of chemoresistance in TNBC patients. After surviving the chemotherapy damage, the presence of BCSCs results in relapse and recurrence of TNBC. Several pathways are known to regulate BCSCs' survival, such as the Wnt/β-catenin, Hedgehog, JAK/STAT and HIPPO pathways. Therefore it is imperative to target these pathways in the context of eliminating chemoresistance. In this review we will discuss the novel strategies and various preclinical and clinical studies to give an insight into overcoming TNBC chemoresistance. We present a detailed account of recent studies carried out that open an exciting perspective in relation to the mechanisms of chemoresistance.
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Affiliation(s)
- Hina Qayoom
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar 190006, J&K, India
| | - Nissar A Wani
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir Nunar Ganderbal 191201, J&K, India
| | - Bader Alshehri
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah, KSA
| | - Manzoor A Mir
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar 190006, J&K, India
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28
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Kumari M, Krishnamurthy PT, Sola P. Targeted Drug Therapy to Overcome Chemoresistance in Triple-negative Breast Cancer. Curr Cancer Drug Targets 2021; 20:559-572. [PMID: 32370716 DOI: 10.2174/1568009620666200506110850] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 03/09/2020] [Accepted: 03/16/2020] [Indexed: 02/07/2023]
Abstract
Triple-negative Breast Cancer (TNBC) is the most aggressive and prevailing breast cancer subtype. The chemotherapeutics used in the treatment of TNBC suffer from chemoresistance, dose-limiting toxicities and off-target side effects. As a result, conventional chemotherapeutics are unable to prevent tumor growth, metastasis and result in failure of therapy. Various new targets such as BCSCs surface markers (CD44, CD133, ALDH1), signaling pathways (IL-6/JAK/STAT3, notch), pro and anti-apoptotic proteins (Bcl-2, Bcl-xL, DR4, DR5), hypoxic factors (HIF-1α, HIF-2α) and drug efflux transporters (ABCC1, ABCG2 and ABCB1) have been exploited to treat TNBC. Further, to improve the efficacy and safety of conventional chemotherapeutics, researchers have tried to deliver anticancer agents specifically to the TNBCs using nanocarrier based drug delivery. In this review, an effort has been made to highlight the various factors responsible for the chemoresistance in TNBC, novel molecular targets of TNBC and nano-delivery systems employed to achieve sitespecific drug delivery to improve efficacy and reduce off-target side effects.
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Affiliation(s)
- Mamta Kumari
- Department of Pharmacology, JSS College of Pharmacy, (A Constituent College of JSS Academy of Higher Education & Research), Ooty, Tamilnadu, India
| | - Praveen Thaggikuppe Krishnamurthy
- Department of Pharmacology, JSS College of Pharmacy, (A Constituent College of JSS Academy of Higher Education & Research), Ooty, Tamilnadu, India
| | - Piyong Sola
- Department of Pharmacology, JSS College of Pharmacy, (A Constituent College of JSS Academy of Higher Education & Research), Ooty, Tamilnadu, India
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29
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Local ablation of gastric cancer by reconstituted apolipoprotein B lipoparticles carrying epigenetic drugs. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2021; 37:102450. [PMID: 34332115 DOI: 10.1016/j.nano.2021.102450] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 04/28/2021] [Accepted: 07/10/2021] [Indexed: 11/21/2022]
Abstract
Epigenetic inhibitors have shown anticancer effects. Combination chemotherapy with epigenetic inhibitors has shown high effectiveness in gastric cancer clinical trials, but severe side effect and local progression are the causes of treatment failure. Therefore, we sought to develop an acidity-sensitive drug delivery system to release drugs locally to diminish unfavorable outcome of gastric cancer. In this study, we showed that, as compared with single agents, combination treatment with the demethylating agent 5'-aza-2'-deoxycytidine and HDAC inhibitors Trichostatin A or LBH589 decreased cell survival, blocked cell cycle by reducing number of S-phase cells and expression of cyclins, increased cell apoptosis by inducing expression of Bim and cleaved Caspase 3, and reexpressed tumor suppressor genes more effectively in MGCC3I cells. As a carrier, reconstituted apolipoprotein B lipoparticles (rABLs) could release drugs in acidic environments. Orally administrated embedded drugs not only showed inhibitory effects on gastric tumor growth in a syngeneic orthotopic mouse model, but also reduced the hepatic and renal toxicity. In conclusion, we have established rABL-based nanoparticles embedded epigenetic inhibitors for local treatment of gastric cancer, which have good therapeutic effects but do not cause severe side effects.
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30
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A MnO 2-coated multivariate porphyrinic metal-organic framework for oxygen self-sufficient chemo-photodynamic synergistic therapy. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2021; 37:102440. [PMID: 34256062 DOI: 10.1016/j.nano.2021.102440] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 04/14/2021] [Accepted: 04/26/2021] [Indexed: 11/21/2022]
Abstract
Lately, chemotherapy and photodynamic therapy (PDT) synergistic therapy has become a promising anti-cancer treatment mean. However, the hypoxia in tumor leads to huge impediments to the oxygen-dependentPDT effects. In this work, a multifunctional nanoplatform (TUDMP) based on a multivariable porphyrin-nMOFs core and a manganese dioxide (MnO2) shell was prepared for relieving tumor hypoxia and enhancing chemo-photodynamic synergistic therapy performance. The obtained TUDMP nanoplatform could effectively catalyze the hydrolysis of hydrogen peroxide to generate oxygen and also lead to consumption of antioxidant GSH, thereby facilitating the production of cytotoxic reactive oxygen species (ROS) by photosensitizer under laser irradiation. More importantly, the decomposition of the MnO2 shell would further promote the release of the loaded doxorubicin (DOX), and thus an efficient chemo-PDT synergistic therapy was realized. Both in vitro and in vivo experimental results demonstrated the oxygen self-sufficient multifunctional nanoplatform could exhibit significantly enhanced anticancer efficiencies compared with chemotherapy or PDT alone.
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31
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Ertas YN, Abedi Dorcheh K, Akbari A, Jabbari E. Nanoparticles for Targeted Drug Delivery to Cancer Stem Cells: A Review of Recent Advances. NANOMATERIALS 2021; 11:nano11071755. [PMID: 34361141 PMCID: PMC8308126 DOI: 10.3390/nano11071755] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 06/29/2021] [Accepted: 07/02/2021] [Indexed: 12/16/2022]
Abstract
Cancer stem cells (CSCs) are a subpopulation of cells that can initiate, self-renew, and sustain tumor growth. CSCs are responsible for tumor metastasis, recurrence, and drug resistance in cancer therapy. CSCs reside within a niche maintained by multiple unique factors in the microenvironment. These factors include hypoxia, excessive levels of angiogenesis, a change of mitochondrial activity from aerobic aspiration to aerobic glycolysis, an upregulated expression of CSC biomarkers and stem cell signaling, and an elevated synthesis of the cytochromes P450 family of enzymes responsible for drug clearance. Antibodies and ligands targeting the unique factors that maintain the niche are utilized for the delivery of anticancer therapeutics to CSCs. In this regard, nanomaterials, specifically nanoparticles (NPs), are extremely useful as carriers for the delivery of anticancer agents to CSCs. This review covers the biology of CSCs and advances in the design and synthesis of NPs as a carrier in targeting cancer drugs to the CSC subpopulation of cancer cells. This review includes the development of synthetic and natural polymeric NPs, lipid NPs, inorganic NPs, self-assembling protein NPs, antibody-drug conjugates, and extracellular nanovesicles for CSC targeting.
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Affiliation(s)
- Yavuz Nuri Ertas
- Department of Biomedical Engineering, Erciyes University, Kayseri 38039, Turkey;
- ERNAM—Nanotechnology Research and Application Center, Erciyes University, Kayseri 38039, Turkey
| | - Keyvan Abedi Dorcheh
- Department of Biomedical Engineering, Faculty of Chemical Engineering, Tarbiat Modares University, Tehran 14115, Iran;
| | - Ali Akbari
- Solid Tumor Research Center, Research Institute for Cellular and Molecular Medicine, Urmia University of Medical Sciences, Urmia 57147, Iran;
| | - Esmaiel Jabbari
- Biomaterials and Tissue Engineering Laboratory, Department of Chemical Engineering, University of South Carolina, Columbia, SC 29208, USA
- Correspondence:
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32
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Singh D, Singh P, Pradhan A, Srivastava R, Sahoo SK. Reprogramming Cancer Stem-like Cells with Nanoforskolin Enhances the Efficacy of Paclitaxel in Targeting Breast Cancer. ACS APPLIED BIO MATERIALS 2021; 4:3670-3685. [PMID: 35014452 DOI: 10.1021/acsabm.1c00141] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Cancer stem-like cells (CSCs) have emerged as an important target for breast cancer therapy owing to their self-renewability, proliferation, and elevated chemoresistance properties. Here, we present a strategy of eliminating CSCs by differentiation therapy where "forced differentiation" reprograms CSCs so that they lose their intrinsic properties and become susceptible for conventional chemotherapeutic drugs. In this study, we report that a conventional chemotherapeutic paclitaxel enhances the stemness of CSCs, while a phytochemical forskolin being essentially nontoxic to CSCs possesses the intrinsic ability to reprogram them. To achieve simultaneous targeting of CSCs and bulk tumor cells, we used a co-delivery system where liquid crystal nanoparticles (LCN) were co-encapsulated with both paclitaxel and forskolin. LCN showed higher uptake, retention, and penetration potential in CSCs overcoming their high drug efflux property. Moreover, LCN improved the pharmacokinetic parameters of forskolin, which otherwise had very low retention and bioavailability. Forskolin-loaded LCN forced CSCs to exit from their mesenchymal state, which reduced their stemness and chemosensitized them while inhibiting E-cadherin-mediated survival and tumor-initiating potential as well as reversing paclitaxel-induced stemness. We further showed that upon administration of paclitaxel and forskolin co-loaded LCN to an orthotropic xenograft mouse model, the nanomedicine showed enhanced passive tumor targeting capability with very potent antitumor activity that eradicated small solid tumor in a single dose and showed no sign of tumor relapse or systemic toxicity over a long period. Overall, these findings give a proof of concept that co-delivery of forskolin and paclitaxel in a single nanoformulation can achieve overall tumor targeting where forskolin can efficiently reprogram/differentiate CSCs and paclitaxel can induce cytotoxicity in both differentiated CSCs and bulk tumor cells simultaneously. Hence, this study can provide a nanoformulation that can offer an efficient strategy for cancer therapy.
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Affiliation(s)
- Deepika Singh
- Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, Odisha, India
| | - Priya Singh
- Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, Odisha, India
| | - Arpan Pradhan
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, India
| | - Rohit Srivastava
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, India
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33
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Ombredane AS, de Andrade LR, Bonadio RS, Pinheiro WO, de Azevedo RB, Joanitti GA. Melittin sensitizes skin squamous carcinoma cells to 5-fluorouracil by affecting cell proliferation and survival. Exp Dermatol 2021; 30:710-716. [PMID: 33523510 DOI: 10.1111/exd.14289] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 12/13/2020] [Accepted: 01/13/2021] [Indexed: 12/13/2022]
Abstract
Combined 5-fluorouracil (5-FU) and melittin (MEL) is believed to enhance cytotoxic effects on skin squamous cell carcinoma (SCC). However, the rationale underlying cytotoxicity is fundamentally important for a proper design of combination chemotherapy, and to provide translational insights for future therapeutics in the dermatology field. The aim was to elucidate the effects of 5-FU/MEL combination on the viability, proliferation and key structures of human squamous cell carcinoma (A431). Morphology, plasma membrane, DNA, mitochondria, oxidative stress, cell viability, proliferation and cell death pathways were targeted for investigation by microscopy, MTT, trypan blue assay, flow cytometry and real-time cell analysis. 5-FU/MEL (0.25 µM/0.52 µM) enhanced the cytotoxic effect in A431 cells (74.46%, p < .001) after 72 h exposure, showing greater cytotoxic effect when compared to each isolated compound (45.55% 5-FU and 61.78% MEL). The results suggest that MEL induces plasma membrane alterations that culminate in a loss of integrity at subsequent times, sensitizing the cell to 5-FU action. DNA fragmentation, S and G2/M arrest, disruption of mitochondrial metabolism, and alterations in cell morphology culminated in proliferation blockage and apoptosis. 5-FU/MEL combination design optimizes the cytotoxic effects of each drug at lower concentrations, which may represent an innovative strategy for SCC therapy.
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Affiliation(s)
- Alicia S Ombredane
- Laboratory of Bioactive Compounds and Nanobiotechnology (LBCNano, Faculty of Ceilândia, University of Brasília, Brasília, Brazil.,Post-Graduation Program in Nanoscience and Nanobiotechnology, Institute of Biological Sciences, University of Brasília, Brasília, Brazil
| | - Laise R de Andrade
- Laboratory of Nanobiotechnology, Department of Genetics and Morphology, Institute of Biological Sciences, University of Brasília, Brasília, Brazil
| | - Raphael S Bonadio
- Laboratory of Nanobiotechnology, Department of Genetics and Morphology, Institute of Biological Sciences, University of Brasília, Brasília, Brazil
| | - Willie O Pinheiro
- Post-Graduation Program in Sciences and Technologies in Health, Faculty of Ceilândia, University of Brasília, Brasília, Brazil
| | - Ricardo B de Azevedo
- Laboratory of Nanobiotechnology, Department of Genetics and Morphology, Institute of Biological Sciences, University of Brasília, Brasília, Brazil
| | - Graziella A Joanitti
- Laboratory of Bioactive Compounds and Nanobiotechnology (LBCNano, Faculty of Ceilândia, University of Brasília, Brasília, Brazil.,Post-Graduation Program in Nanoscience and Nanobiotechnology, Institute of Biological Sciences, University of Brasília, Brasília, Brazil.,Laboratory of Nanobiotechnology, Department of Genetics and Morphology, Institute of Biological Sciences, University of Brasília, Brasília, Brazil.,Post-Graduation Program in Sciences and Technologies in Health, Faculty of Ceilândia, University of Brasília, Brasília, Brazil
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34
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Zheng Q, Zhang M, Zhou F, Zhang L, Meng X. The Breast Cancer Stem Cells Traits and Drug Resistance. Front Pharmacol 2021; 11:599965. [PMID: 33584277 PMCID: PMC7876385 DOI: 10.3389/fphar.2020.599965] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 11/17/2020] [Indexed: 12/13/2022] Open
Abstract
Drug resistance is a major challenge in breast cancer (BC) treatment at present. Accumulating studies indicate that breast cancer stem cells (BCSCs) are responsible for the BC drugs resistance, causing relapse and metastasis in BC patients. Thus, BCSCs elimination could reverse drug resistance and improve drug efficacy to benefit BC patients. Consequently, mastering the knowledge on the proliferation, resistance mechanisms, and separation of BCSCs in BC therapy is extremely helpful for BCSCs-targeted therapeutic strategies. Herein, we summarize the principal BCSCs surface markers and signaling pathways, and list the BCSCs-related drug resistance mechanisms in chemotherapy (CT), endocrine therapy (ET), and targeted therapy (TT), and display therapeutic strategies for targeting BCSCs to reverse drug resistance in BC. Even more importantly, more attention should be paid to studies on BCSC-targeted strategies to overcome the drug resistant dilemma of clinical therapies in the future.
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Affiliation(s)
- Qinghui Zheng
- Department of Breast Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China
| | - Mengdi Zhang
- MOE Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Fangfang Zhou
- Institutes of Biology and Medical Science, Soochow University, Suzhou, China
| | - Long Zhang
- MOE Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Xuli Meng
- Department of Breast Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China
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Kesharwani P, Md S, Alhakamy NA, Hosny KM, Haque A. QbD Enabled Azacitidine Loaded Liposomal Nanoformulation and Its In Vitro Evaluation. Polymers (Basel) 2021; 13:250. [PMID: 33451016 PMCID: PMC7828524 DOI: 10.3390/polym13020250] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 12/23/2020] [Accepted: 12/29/2020] [Indexed: 12/13/2022] Open
Abstract
Azacitidine (AZA), an inhibitor of DNA methyltransferase, is a commonly recognized drug used in clinical treatment for myelodysplastic syndrome and breast cancer. Due to higher aqueous solubility and negative log P of AZA causes poor cancer cell permeation and controlled release. The objective of the present study was to formulate and optimize AZA-loaded liposome (AZA-LIPO) for breast cancer chemotherapy by using Box Behnken design (BBD) and in vitro evaluation using MCF-7 cells. AZA-LIPO were prepared using a thin film hydration technique and characterization study was performed by using FTIR and DSC. The prepared formulations were optimized using BBD and the optimized formulation was further subjected for particle size, surface charges, polydispersity index (PDI), drug loading, entrapment efficiency, TEM, XRD, in-vitro drug release and hemolytic toxicity. The mean particle size of optimized AZA-LIPO was 127 nm. Entrapment efficiency and drug loading of AZA-LIPO was found to be 85.2% ± 0.5 and 6.82 ± 1.6%, respectively. Further, in vitro drug release study showed preliminary burst release in 2 h followed by a sustained release for 36 h in phosphate buffer at different pH (4.0, 5.5, and 7.4) as compared to free drug. Drug release was found to be pH dependent, as the pH was increased, the drug release rate was found to be low. Time-dependent cell viability assay exhibited significant higher cell viability and higher internalization than free AZA in MCF-7 cells. AZA-LIPO were more effective than the free AZA in reducing Bcl2 expression, while increasing pro-apoptotic Bax and caspase-3 activity. The result showed that the formulated biocompatible AZA-LIPO nano-formulations may be used as an efficient anti-cancer drug delivery system for the treatment of breast cancer after establishing preclinical and clinical studies.
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Affiliation(s)
- Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
| | - Shadab Md
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (S.M.); (N.A.A.); (K.M.H.)
- Center of Excellence for Drug Research & Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Nabil A. Alhakamy
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (S.M.); (N.A.A.); (K.M.H.)
- Center of Excellence for Drug Research & Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Khaled M. Hosny
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (S.M.); (N.A.A.); (K.M.H.)
- Center of Excellence for Drug Research & Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Anzarul Haque
- Department of Pharmacognosy, College of Pharmacy, Prince Sattam bin Abdulaziz University, Al-kharj 16278, Saudi Arabia;
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Buocikova V, Rios-Mondragon I, Pilalis E, Chatziioannou A, Miklikova S, Mego M, Pajuste K, Rucins M, Yamani NE, Longhin EM, Sobolev A, Freixanet M, Puntes V, Plotniece A, Dusinska M, Cimpan MR, Gabelova A, Smolkova B. Epigenetics in Breast Cancer Therapy-New Strategies and Future Nanomedicine Perspectives. Cancers (Basel) 2020; 12:E3622. [PMID: 33287297 PMCID: PMC7761669 DOI: 10.3390/cancers12123622] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 11/30/2020] [Accepted: 11/30/2020] [Indexed: 12/12/2022] Open
Abstract
Epigenetic dysregulation has been recognized as a critical factor contributing to the development of resistance against standard chemotherapy and to breast cancer progression via epithelial-to-mesenchymal transition. Although the efficacy of the first-generation epigenetic drugs (epi-drugs) in solid tumor management has been disappointing, there is an increasing body of evidence showing that epigenome modulation, in synergy with other therapeutic approaches, could play an important role in cancer treatment, reversing acquired therapy resistance. However, the epigenetic therapy of solid malignancies is not straightforward. The emergence of nanotechnologies applied to medicine has brought new opportunities to advance the targeted delivery of epi-drugs while improving their stability and solubility, and minimizing off-target effects. Furthermore, the omics technologies, as powerful molecular epidemiology screening tools, enable new diagnostic and prognostic epigenetic biomarker identification, allowing for patient stratification and tailored management. In combination with new-generation epi-drugs, nanomedicine can help to overcome low therapeutic efficacy in treatment-resistant tumors. This review provides an overview of ongoing clinical trials focusing on combination therapies employing epi-drugs for breast cancer treatment and summarizes the latest nano-based targeted delivery approaches for epi-drugs. Moreover, it highlights the current limitations and obstacles associated with applying these experimental strategies in the clinics.
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Affiliation(s)
- Verona Buocikova
- Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (V.B.); (S.M.); (A.G.)
| | - Ivan Rios-Mondragon
- Department of Clinical Dentistry, University of Bergen, Aarstadveien 19, 5009 Bergen, Norway; (I.R.-M.); (M.R.C.)
| | - Eleftherios Pilalis
- e-NIOS Applications Private Company, Alexandrou Pantou 25, 17671 Kallithea, Greece; (E.P.); (A.C.)
- Center of Systems Biology, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece
| | - Aristotelis Chatziioannou
- e-NIOS Applications Private Company, Alexandrou Pantou 25, 17671 Kallithea, Greece; (E.P.); (A.C.)
- Center of Systems Biology, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece
| | - Svetlana Miklikova
- Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (V.B.); (S.M.); (A.G.)
| | - Michal Mego
- 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Klenova 1, 833 10 Bratislava, Slovakia;
| | - Karlis Pajuste
- Latvian Institute of Organic Synthesis, Aizkraukles str. 21, LV-1006 Riga, Latvia; (K.P.); (M.R.); (A.S.); (A.P.)
| | - Martins Rucins
- Latvian Institute of Organic Synthesis, Aizkraukles str. 21, LV-1006 Riga, Latvia; (K.P.); (M.R.); (A.S.); (A.P.)
| | - Naouale El Yamani
- Health Effects Laboratory, NILU-Norwegian Institute for Air Research, 2007 Kjeller, Norway; (N.E.Y.); (E.M.L.); (M.D.)
| | - Eleonora Marta Longhin
- Health Effects Laboratory, NILU-Norwegian Institute for Air Research, 2007 Kjeller, Norway; (N.E.Y.); (E.M.L.); (M.D.)
| | - Arkadij Sobolev
- Latvian Institute of Organic Synthesis, Aizkraukles str. 21, LV-1006 Riga, Latvia; (K.P.); (M.R.); (A.S.); (A.P.)
| | - Muriel Freixanet
- Vall d Hebron, Institut de Recerca (VHIR), 08035 Barcelona, Spain; (M.F.); (V.P.)
| | - Victor Puntes
- Vall d Hebron, Institut de Recerca (VHIR), 08035 Barcelona, Spain; (M.F.); (V.P.)
- Institut Català de Nanosciència i Nanotecnologia (ICN2), Bellaterra, 08193 Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain
| | - Aiva Plotniece
- Latvian Institute of Organic Synthesis, Aizkraukles str. 21, LV-1006 Riga, Latvia; (K.P.); (M.R.); (A.S.); (A.P.)
| | - Maria Dusinska
- Health Effects Laboratory, NILU-Norwegian Institute for Air Research, 2007 Kjeller, Norway; (N.E.Y.); (E.M.L.); (M.D.)
| | - Mihaela Roxana Cimpan
- Department of Clinical Dentistry, University of Bergen, Aarstadveien 19, 5009 Bergen, Norway; (I.R.-M.); (M.R.C.)
| | - Alena Gabelova
- Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (V.B.); (S.M.); (A.G.)
| | - Bozena Smolkova
- Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (V.B.); (S.M.); (A.G.)
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Baik J, Felices M, Yingst A, Theuer CP, Verneris MR, Miller JS, Perlingeiro R. Therapeutic effect of TRC105 and decitabine combination in AML xenografts. Heliyon 2020; 6:e05242. [PMID: 33088975 PMCID: PMC7566100 DOI: 10.1016/j.heliyon.2020.e05242] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 09/30/2020] [Accepted: 10/08/2020] [Indexed: 01/13/2023] Open
Abstract
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy, often characterized by poor prognosis following standard induction therapy. The hypomethylating agent decitabine (DAC) is an alternative treatment for elderly and relapsed/refractory AML patients, yet responses following DAC monotherapy are still modest. The transforming growth factor-β (TGF-β) receptor CD105 (endoglin) is expressed in various hematopoietic malignancies, and high CD105 expression correlates with poor prognosis in AML patients. Using a xenograft model, we have recently demonstrated that targeting CD105+ AML blasts with the TRC105 monoclonal antibody inhibits leukemia progression. Here we investigated whether administration of TRC105 along with DAC could represent a novel therapeutic option for relapsed/refractory AML. Our data show that the DAC/TRC105 combination results in a more durable anti-leukemic effect in AML xenografts compared to DAC monotherapy. Moreover, the DAC/TRC105 combination enhanced reactive oxygen species (ROS) activity, which correlated with reduced leukemia burden. RNA-sequencing studies suggest that TRC105 may alter TGF-β activity in AML blasts. Taken together, these findings provide rationale for the clinical evaluation of TRC105 in combination with DAC in AML patients.
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Affiliation(s)
- June Baik
- Dept. of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Martin Felices
- Dept. of Medicine, University of Minnesota, Minneapolis, MN, USA.,Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Ashley Yingst
- Dept. of Pediatrics, University of Denver, Colorado, CO, USA
| | | | | | - Jeffrey S Miller
- Dept. of Medicine, University of Minnesota, Minneapolis, MN, USA.,Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Rita Perlingeiro
- Dept. of Medicine, University of Minnesota, Minneapolis, MN, USA.,Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
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TPGS 2k-PLGA composite nanoparticles by depleting lipid rafts in colon cancer cells for overcoming drug resistance. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2020; 35:102307. [PMID: 32987192 DOI: 10.1016/j.nano.2020.102307] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 06/18/2020] [Accepted: 09/16/2020] [Indexed: 11/21/2022]
Abstract
Recently, studies showed that the drug-resistant cell membranes have formed high-density lipid rafts regions; traditional targeted drug delivery systems can hardly break through the hard shell and deliver drugs to drug-resistant cells. Here, α-tocopherol polyethylene glycol 2000 succinate (TPGS2k) was successfully synthesized and used to modify poly (lactic-glycolic acid) nanoparticles co-loaded with doxorubicin (DOX) and simvastatin (SV) (SV/DOX@TPGS2k-PLGA NPs). The purpose of this study is to explore the synergistic effect between SV consuming cholesterol in lipid rafts and directly down-regulating P-gp expression on the intracellular drugs retention. The research highlights these nanoparticles interrupted lipid rafts (cholesterol-rich domains, where P-gp is often located), which inhibited drug efflux by down-regulating P-gp, promoted the mitochondria apoptosis and made SW620/AD300 cells (DOX-resistant colon cancer cell line) re-sensitized to DOX. Therefore, the carrier can become a promising SV-based nano-delivery system with depleting cholesterol in lipid rafts to reverse drug resistance.
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Li C, Naveed M, Dar K, Liu Z, Baig MMFA, Lv R, Saeed M, Dingding C, Feng Y, Xiaohui Z. Therapeutic advances in cardiac targeted drug delivery: from theory to practice. J Drug Target 2020; 29:235-248. [PMID: 32933319 DOI: 10.1080/1061186x.2020.1818761] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The most commonly used administration methods in clinics and life are oral administration, intravenous injection, and other systemic administration methods. Targeted administration must be an essential long-term development direction due to the limited availability and a high incidence of systemic side effects. Cardiovascular diseases (CVD) are the leading cause of death all over the world. Targeted drug delivery (TDD) methods with the heart as the target organ have developed rapidly and are diversified. This article reviews the research progress of various TDD methods around the world with a heart as the target organ. It is mainly divided into two parts: the targeting vector represented by nanoparticles and various TDD methods such as intracoronary injection, ventricular wall injection, pericardial injection, and implantable medical device therapy and put forward some suggestions on the development of targeting. Different TDD methods described in this paper have not been widely used in clinical practice, and some have not even completed preclinical studies. Targeted drug delivery still requires long-term efforts by many researchers to realize the true meaning of the heart. HIGHLIGHTS Targeted administration can achieve a better therapeutic effect and effectively reduce the occurrence of adverse reactions. Parenteral administration or medical device implantation can be used for targeted drug delivery. Combined with new dosage forms or new technologies, better-targeted therapy can be achieved. Clinical trials have confirmed the safety and effectiveness of several administration methods.
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Affiliation(s)
- Cuican Li
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, P. R. China
| | - Muhammad Naveed
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, P. R. China.,School of Pharmacy, Nanjing Medical University, Nanjing, P. R. China
| | - Kashif Dar
- Department of Cardiology, Nanjing Drum Tower Hospital, Nanjing Medical University, Nanjing, P. R. China
| | - Ziwei Liu
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, P. R. China
| | - Mirza Muhammad Faran Ashraf Baig
- State Key Laboratory of Analytical Chemistry for Life Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, P. R. China
| | - Rundong Lv
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, P. R. China
| | - Muhammad Saeed
- Faculty of Animal Production and Technology, The Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan
| | - Chen Dingding
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, P. R. China
| | - Yu Feng
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, P. R. China
| | - Zhou Xiaohui
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, P. R. China.,Department of Heart Surgery, Nanjing Shuiximen Hospital, Nanjing, P. R. China.,Department of Cardiothoracic Surgery, Zhongda Hospital affiliated with Southeast University, Nanjing, P. R. China
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40
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Samuel SM, Varghese E, Koklesová L, Líšková A, Kubatka P, Büsselberg D. Counteracting Chemoresistance with Metformin in Breast Cancers: Targeting Cancer Stem Cells. Cancers (Basel) 2020; 12:E2482. [PMID: 32883003 PMCID: PMC7565921 DOI: 10.3390/cancers12092482] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 08/19/2020] [Accepted: 08/22/2020] [Indexed: 12/12/2022] Open
Abstract
Despite the leaps and bounds in achieving success in the management and treatment of breast cancers through surgery, chemotherapy, and radiotherapy, breast cancer remains the most frequently occurring cancer in women and the most common cause of cancer-related deaths among women. Systemic therapeutic approaches, such as chemotherapy, although beneficial in treating and curing breast cancer subjects with localized breast tumors, tend to fail in metastatic cases of the disease due to (a) an acquired resistance to the chemotherapeutic drug and (b) the development of intrinsic resistance to therapy. The existence of cancer stem cells (CSCs) plays a crucial role in both acquired and intrinsic chemoresistance. CSCs are less abundant than terminally differentiated cancer cells and confer chemoresistance through a unique altered metabolism and capability to evade the immune response system. Furthermore, CSCs possess active DNA repair systems, transporters that support multidrug resistance (MDR), advanced detoxification processes, and the ability to self-renew and differentiate into tumor progenitor cells, thereby supporting cancer invasion, metastasis, and recurrence/relapse. Hence, current research is focusing on targeting CSCs to overcome resistance and improve the efficacy of the treatment and management of breast cancer. Studies revealed that metformin (1, 1-dimethylbiguanide), a widely used anti-hyperglycemic agent, sensitizes tumor response to various chemotherapeutic drugs. Metformin selectively targets CSCs and improves the hypoxic microenvironment, suppresses the tumor metastasis and inflammation, as well as regulates the metabolic programming, induces apoptosis, and reverses epithelial-mesenchymal transition and MDR. Here, we discuss cancer (breast cancer) and chemoresistance, the molecular mechanisms of chemoresistance in breast cancers, and metformin as a chemo-sensitizing/re-sensitizing agent, with a particular focus on breast CSCs as a critical contributing factor to acquired and intrinsic chemoresistance. The review outlines the prospects and directions for a better understanding and re-purposing of metformin as an anti-cancer/chemo-sensitizing drug in the treatment of breast cancer. It intends to provide a rationale for the use of metformin as a combinatory therapy in a clinical setting.
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Affiliation(s)
- Samson Mathews Samuel
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar;
| | - Elizabeth Varghese
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar;
| | - Lenka Koklesová
- Department of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia; (L.K.); (A.L.)
| | - Alena Líšková
- Department of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia; (L.K.); (A.L.)
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia;
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar;
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Jain V, Kumar H, Anod HV, Chand P, Gupta NV, Dey S, Kesharwani SS. A review of nanotechnology-based approaches for breast cancer and triple-negative breast cancer. J Control Release 2020; 326:628-647. [PMID: 32653502 DOI: 10.1016/j.jconrel.2020.07.003] [Citation(s) in RCA: 166] [Impact Index Per Article: 33.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 07/03/2020] [Accepted: 07/04/2020] [Indexed: 12/24/2022]
Abstract
Breast cancer (BC) is one of the most prevalent cancers in women. Triple-negative breast cancer (TNBC) in which the three major receptors i.e. estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), are absent is known to express the most aggressive phenotype and increased metastasis which results in the development of resistance to chemotherapy. It offers various therapeutic advantages in treating BC and TNBC. Nanotechnology offers various unique characteristics such as small size (nanometric), active and passive targeting, and the ability to attach multiple targeting moieties, controlled release, and site-specific targeting. This review focuses on conventional drug therapies, recent treatment strategies, and unique therapeutic approaches available for BC and TNBC. The role of breast cancer stem cells in the recurrence of BC and TNBC has also been highlighted. Several chemotherapeutic agents delivered using nanocarriers such as polymeric nanoparticles/micelles, metallic/inorganic NPs, and lipid-based NPs (Liposome, solid-lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs)), etc. with excellent responses in the treatment of BC/TNBC along with breast cancer stem cells have been discussed in details. Moreover, the application of nanomedicine including CRISPR nanoparticle, exosomes for the treatment of BC/TNBC and other molecular targets available such as poly (ADP-ribose) polymerase (PARP), epidermal growth factor receptor (EGFR), Vascular endothelial growth factor (VEGF), etc. for further exploration have also been discussed.
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Affiliation(s)
- Vikas Jain
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, 570015, India.
| | - Hitesh Kumar
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, 570015, India
| | - Haritha V Anod
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, 570015, India
| | - Pallavi Chand
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, 570015, India
| | - N Vishal Gupta
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, 570015, India
| | - Surajit Dey
- College of Pharmacy, Roseman University of Health Sciences, Henderson, NV, USA
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Barzaman K, Karami J, Zarei Z, Hosseinzadeh A, Kazemi MH, Moradi-Kalbolandi S, Safari E, Farahmand L. Breast cancer: Biology, biomarkers, and treatments. Int Immunopharmacol 2020; 84:106535. [PMID: 32361569 DOI: 10.1016/j.intimp.2020.106535] [Citation(s) in RCA: 440] [Impact Index Per Article: 88.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 04/20/2020] [Accepted: 04/20/2020] [Indexed: 02/07/2023]
Abstract
During the past recent years, various therapies emerged in the era of breast cancer. Breast cancer is a heterogeneous disease in which genetic and environmental factors are involved. Breast cancer stem cells (BCSCs) are the main player in the aggressiveness of different tumors and also, these cells are the main challenge in cancer treatment. Moreover, the major obstacle to achieve an effective treatment is resistance to therapies. There are various types of treatment for breast cancer (BC) patients. Therefore, in this review, we present the current treatments, novel approaches such as antibody-drug conjugation systems (ADCs), nanoparticles (albumin-, metal-, lipid-, polymer-, micelle-based nanoparticles), and BCSCs-based therapies. Furthermore, prognostic and predictive biomarkers will be discussed also biomarkers that have been applied by some tests such as Oncotype DX, Mamm αPrint, and uPA/PAI-1 are regarded as suitable prognostic and predictive factors in breast cancer.
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Affiliation(s)
- Khadijeh Barzaman
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Jafar Karami
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Zeinab Zarei
- Department of Biomaterials and Tissue Engineering, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Aysooda Hosseinzadeh
- Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Mohammad Hossein Kazemi
- Student Research Committee, Department of Immunology, School of Medicine, Iran University of Medical Science, Tehran, Iran; ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Shima Moradi-Kalbolandi
- Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Elahe Safari
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Leila Farahmand
- Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.
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Tang Q, Yin D, Wang Y, Du W, Qin Y, Ding A, Li H. Cancer Stem Cells and Combination Therapies to Eradicate Them. Curr Pharm Des 2020; 26:1994-2008. [PMID: 32250222 DOI: 10.2174/1381612826666200406083756] [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: 11/05/2019] [Accepted: 02/13/2020] [Indexed: 12/23/2022]
Abstract
Cancer stem cells (CSCs) show self-renewal ability and multipotential differentiation, like normal stem or progenitor cells, and which proliferate uncontrollably and can escape the effects of drugs and phagocytosis by immune cells. Traditional monotherapies, such as surgical resection, radiotherapy and chemotherapy, cannot eradicate CSCs, however, combination therapy may be more effective at eliminating CSCs. The present review summarizes the characteristics of CSCs and several promising combination therapies to eradicate them.
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Affiliation(s)
- Qi Tang
- College of Pharmacy and Biological Engineering, Chengdu University, Chengdu, China.,Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu, China
| | - Dan Yin
- Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu, China
| | - Yao Wang
- College of Pharmacy and Biological Engineering, Chengdu University, Chengdu, China
| | - Wenxuan Du
- College of Pharmacy and Biological Engineering, Chengdu University, Chengdu, China
| | - Yuhan Qin
- College of Pharmacy and Biological Engineering, Chengdu University, Chengdu, China
| | - Anni Ding
- College of Pharmacy and Biological Engineering, Chengdu University, Chengdu, China
| | - Hanmei Li
- College of Pharmacy and Biological Engineering, Chengdu University, Chengdu, China
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44
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Ning F, Yang Z, Xu L, Sun Y. Targeted tumor therapy by autophagy of nanoparticles. Future Oncol 2020; 16:793-803. [DOI: 10.2217/fon-2019-0712] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Autophagy is an important biological mechanism that regulates the growth, death and energy metabolism of eukaryotic cells. It is also an active and evolutionarily conservative catabolic process to maintain homeostasis during cell stress response and cell survival. Autophagy maintains the body’s stability by degrading damaged proteins, organelles, cytoplasm and invasive microorganisms. Studies have found that autophagy also has a significant impact on the occurrence and development of tumors. Simultaneously, nanoparticles (NPs) can induce autophagy in cells, and the level of autophagy can be regulated by the synthesis design of NPs. Therefore, the study of the regulation of autophagy by NPs is of great significance for the treatment of cancer autocorrelation.
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Affiliation(s)
- Fang Ning
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266021, PR China
| | - Zhihong Yang
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266021, PR China
| | - Lisa Xu
- Department of Nutrition, School of Public Health, Qingdao University, Qingdao 266021, PR China
| | - Yong Sun
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266021, PR China
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Zhang J, An X, Zheng Y, Chen Y, Wu C, Wang S. Injectable Ovalbumin-Based Composite Implant for Photothermal Tumor Therapy. Chembiochem 2020; 21:865-873. [PMID: 31613042 DOI: 10.1002/cbic.201900556] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Indexed: 12/16/2022]
Abstract
Polymeric hydrogels with three-dimensional network structures have found tremendous applications in biomedicine. Herein, we report the synthesis of a multifunctional implant based on ovalbumin (OVA) as a carrier capable of synergistically delivering a photothermal transducing agent (polydopamine, PDA) to tumors. The formation of PDA was achieved by utilizing the basicity of OVA, whereas the formation of the hydrogel implant was achieved through the in vitro/in vivo near-infrared (NIR) laser-induced hyperthermia of PDA. The as-prepared PDA@OVA implant exhibits high photothermal conversion efficiency (38.7 %). Once implanted in vivo, the OVA-based implant shows great versatility in the treatment of malignant tumors. Furthermore, a chemotherapeutic (doxorubicin, DOX) and a contrast agent (iohexol), dispersed in the OVA solution in advance, can also be firmly entrapped in the hydrogel along with the hydrogel formation. It is anticipated that the multifunctional OVA-based implant, not showing any obvious toxicity to healthy tissue, could be a promising system for synergistic cancer treatment.
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Affiliation(s)
- Jing Zhang
- College of Science, University of Shanghai for Science and Technology, No. 334 Jungong Road, Shanghai, 200093, P. R. China
| | - Xiao An
- Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 100 Haining Road, Shanghai, 200080, P. R. China
| | - Yuting Zheng
- College of Science, University of Shanghai for Science and Technology, No. 334 Jungong Road, Shanghai, 200093, P. R. China
| | - Yongkang Chen
- College of Science, University of Shanghai for Science and Technology, No. 334 Jungong Road, Shanghai, 200093, P. R. China
| | - Chenyao Wu
- College of Science, University of Shanghai for Science and Technology, No. 334 Jungong Road, Shanghai, 200093, P. R. China
| | - Shige Wang
- College of Science, University of Shanghai for Science and Technology, No. 334 Jungong Road, Shanghai, 200093, P. R. China
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Scheetz LM, Yu M, Li D, Castro MG, Moon JJ, Schwendeman A. Synthetic HDL Nanoparticles Delivering Docetaxel and CpG for Chemoimmunotherapy of Colon Adenocarcinoma. Int J Mol Sci 2020; 21:ijms21051777. [PMID: 32150841 PMCID: PMC7084365 DOI: 10.3390/ijms21051777] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 02/19/2020] [Accepted: 03/03/2020] [Indexed: 12/13/2022] Open
Abstract
Colon carcinomas comprise over two-thirds of all colorectal cancers with an overall 5-year survival rate of 64%, which rapidly decreases to 14% when the cancer becomes metastatic. Depending on the stage of colon carcinoma at diagnosis, patients can undergo surgery to attempt complete tumor resection or move directly to chemotherapy with one or a combination of drugs. As with most cancers, colon carcinomas do not always respond to chemotherapies, so targeted therapies and immunotherapies have been developed to aid chemotherapy. We report the development of a local combination therapy for colon carcinoma whereby chemo- and immunotherapeutic entities are delivered intratumorally to maximize efficacy and minimize off-target side effects. A hydrophobic chemotherapeutic agent, docetaxel (DTX), and cholesterol-modified Toll-like receptor 9 (TLR9) agonist CpG (cho-CpG) oligonucleotide are co-loaded in synthetic HDL (sHDL) nanodiscs. In vivo survival analysis of MC-38 tumor-bearing mice treated intratumorally with DTX-sHDL/CpG (median survival; MS = 43 days) showed significant improvement in overall survival compared to mice treated with single agents, free DTX (MS = 23 days, p < 0.0001) or DTX-sHDL (MS = 28 days, p < 0.0001). Two of seven mice treated with DTX-sHDL/CpG experienced complete tumor regression. None of the mice experienced any systemic toxicity as indicated by body weight maintenance and normal serum enzyme and protein levels. In summary, we have demonstrated that chemo- and immunotherapies can be co-loaded into sHDLs, delivered locally to the tumor, and can be used to improve survival outcomes significantly compared to chemotherapy alone.
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Affiliation(s)
- Lindsay M. Scheetz
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA; (L.M.S.); (M.Y.); (D.L.)
- Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA
| | - Minzhi Yu
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA; (L.M.S.); (M.Y.); (D.L.)
- Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA
| | - Dan Li
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA; (L.M.S.); (M.Y.); (D.L.)
- Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA
| | - María G. Castro
- Department of Neurosurgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA;
- Department of Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA
| | - James J. Moon
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA; (L.M.S.); (M.Y.); (D.L.)
- Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
- Correspondence: (J.J.M.); (A.S.); Tel.: +734-763-4056 (A.S.)
| | - Anna Schwendeman
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA; (L.M.S.); (M.Y.); (D.L.)
- Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA
- Correspondence: (J.J.M.); (A.S.); Tel.: +734-763-4056 (A.S.)
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Abdel-Hakeem MA, Abdel-Haseb OM, Abdel-Ghany SE, Cevik E, Sabit H. Doxorubicin loaded on chitosan-protamine nanoparticles triggers apoptosis via downregulating Bcl-2 in breast cancer cells. J Drug Deliv Sci Technol 2020. [DOI: 10.1016/j.jddst.2019.101423] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Peng Y, Bariwal J, Kumar V, Tan C, Mahato RI. Organic Nanocarriers for Delivery and Targeting of Therapeutic Agents for Cancer Treatment. ADVANCED THERAPEUTICS 2020. [DOI: 10.1002/adtp.201900136] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Yang Peng
- Department of Pharmaceutical SciencesUniversity of Nebraska Medical Center Omaha NE 68198 USA
| | - Jitender Bariwal
- Department of Pharmaceutical SciencesUniversity of Nebraska Medical Center Omaha NE 68198 USA
| | - Virender Kumar
- Department of Pharmaceutical SciencesUniversity of Nebraska Medical Center Omaha NE 68198 USA
| | - Chalet Tan
- Department of Pharmaceutics and Drug DeliveryUniversity of Mississippi University MS 38677 USA
| | - Ram I. Mahato
- Department of Pharmaceutical SciencesUniversity of Nebraska Medical Center Omaha NE 68198 USA
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Patel P, Meghani N, Kansara K, Kumar A. Nanotherapeutics for the Treatment of Cancer and Arthritis. Curr Drug Metab 2020; 20:430-445. [PMID: 30479211 DOI: 10.2174/1389200220666181127102720] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 10/11/2018] [Accepted: 10/11/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Nanotechnology is gaining significant attention worldwide for the treatment of complex diseases such as AIDS (acquired immune deficiency syndrome), cancer and rheumatoid arthritis. Nanomedicine is the application of nanotechnology used for diagnosis and treatment for the disease that includes the preservation and improvement of human health by covering an area such as drug delivery using nanocarriers, nanotheranostics and nanovaccinology. The present article provides an insight into several aspects of nanomedicine such as usages of multiple types of nanocarriers, their status, advantages and disadvantages with reference to cancer and rheumatoid arthritis. METHODS An extensive search was performed on the bibliographic database for research article on nanotechnology and nanomedicine along with looking deeply into the aspects of these diseases, and how all of them are co-related. We further combined all the necessary information from various published articles and briefed to provide the current status. RESULTS Nanomedicine confers a unique technology against complex diseases which includes early diagnosis, prevention, and personalized therapy. The most common nanocarriers used globally are liposomes, polymeric nanoparticles, dendrimers, metallic nanoparticles, magnetic nanoparticles, solid lipid nanoparticles, polymeric micelles and nanotubes among others. CONCLUSION Nanocarriers are used to deliver drugs and biomolecules like proteins, antibody fragments, DNA fragments, and RNA fragments as the base of cancer biomarkers.
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Affiliation(s)
- Pal Patel
- Biological and Life Sciences, School of Arts and Sciences, Ahmedabad University, Central Campus, Navrangpura, Ahmedabad, 380009, Gujarat, India
| | - Nikita Meghani
- Biological and Life Sciences, School of Arts and Sciences, Ahmedabad University, Central Campus, Navrangpura, Ahmedabad, 380009, Gujarat, India
| | - Krupa Kansara
- Biological and Life Sciences, School of Arts and Sciences, Ahmedabad University, Central Campus, Navrangpura, Ahmedabad, 380009, Gujarat, India
| | - Ashutosh Kumar
- Biological and Life Sciences, School of Arts and Sciences, Ahmedabad University, Central Campus, Navrangpura, Ahmedabad, 380009, Gujarat, India
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Cancer Stem Cells: Powerful Targets to Improve Current Anticancer Therapeutics. Stem Cells Int 2019; 2019:9618065. [PMID: 31781251 PMCID: PMC6874936 DOI: 10.1155/2019/9618065] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 09/25/2019] [Accepted: 10/03/2019] [Indexed: 02/07/2023] Open
Abstract
A frequent observation in several malignancies is the development of resistance to therapy that results in frequent tumor relapse and metastasis. Much of the tumor resistance phenotype comes from its heterogeneity that halts the ability of therapeutic agents to eliminate all cancer cells effectively. Tumor heterogeneity is, in part, controlled by cancer stem cells (CSC). CSC may be considered the reservoir of cancer cells as they exhibit properties of self-renewal and plasticity and the capability of reestablishing a heterogeneous tumor cell population. The endowed resistance mechanisms of CSC are mainly attributed to several factors including cellular quiescence, accumulation of ABC transporters, disruption of apoptosis, epigenetic reprogramming, and metabolism. There is a current need to develop new therapeutic drugs capable of targeting CSC to overcome tumor resistance. Emerging in vitro and in vivo studies strongly support the potential benefits of combination therapies capable of targeting cancer stem cell-targeting agents. Clinical trials are still underway to address the pharmacokinetics, safety, and efficacy of combination treatment. This review will address the main characteristics, therapeutic implications, and perspectives of targeting CSC to improve current anticancer therapeutics.
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