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1
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Lehrich BM, Delgado ER. Lipid Nanovesicle Platforms for Hepatocellular Carcinoma Precision Medicine Therapeutics: Progress and Perspectives. Organogenesis 2024; 20:2313696. [PMID: 38357804 PMCID: PMC10878025 DOI: 10.1080/15476278.2024.2313696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 01/04/2024] [Accepted: 01/30/2024] [Indexed: 02/16/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality globally. HCC is highly heterogenous with diverse etiologies leading to different driver mutations potentiating unique tumor immune microenvironments. Current therapeutic options, including immune checkpoint inhibitors and combinations, have achieved limited objective response rates for the majority of patients. Thus, a precision medicine approach is needed to tailor specific treatment options for molecular subsets of HCC patients. Lipid nanovesicle platforms, either liposome- (synthetic) or extracellular vesicle (natural)-derived present are improved drug delivery vehicles which may be modified to contain specific cargos for targeting specific tumor sites, with a natural affinity for liver with limited toxicity. This mini-review provides updates on the applications of novel lipid nanovesicle-based therapeutics for HCC precision medicine and the challenges associated with translating this therapeutic subclass from preclinical models to the clinic.
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Affiliation(s)
- Brandon M. Lehrich
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Medical Scientist Training Program, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Evan R. Delgado
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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2
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Rahdan F, Abedi F, Dianat-Moghadam H, Sani MZ, Taghizadeh M, Alizadeh E. Autophagy-based therapy for hepatocellular carcinoma: from standard treatments to combination therapy, oncolytic virotherapy, and targeted nanomedicines. Clin Exp Med 2024; 25:13. [PMID: 39621122 PMCID: PMC11611955 DOI: 10.1007/s10238-024-01527-5] [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: 10/09/2024] [Accepted: 11/22/2024] [Indexed: 12/06/2024]
Abstract
Human hepatocellular carcinoma (HCC) has been identified as a significant cause of mortality worldwide. In recent years, extensive research has been conducted to understand the underlying mechanisms of autophagy in the pathogenesis of the disease, with the aim of developing novel therapeutic agents. Targeting autophagy with conventional therapies in invasive HCC has opened up new opportunities for treatment. However, the emergence of resistance and the immunosuppressive tumor environment highlight the need for combination therapy or specific targeting, as well as an efficient drug delivery system to ensure targeted tumor areas receive sufficient doses without affecting normal cells or tissues. In this review, we discuss the findings of several studies that have explored autophagy as a potential therapeutic approach in HCC. We also outline the potential and limitations of standard therapies for autophagy modulation in HCC treatment. Additionally, we discuss how different combination therapies, nano-targeted strategies, and oncolytic virotherapy could enhance autophagy-based HCC treatment in future research.
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Affiliation(s)
- Fereshteh Rahdan
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Abedi
- Clinical Research Development, Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hassan Dianat-Moghadam
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, 8174673461, Iran.
- Pediatric Inherited Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, 8174673461, Iran.
| | - Maryam Zamani Sani
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Taghizadeh
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Effat Alizadeh
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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3
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Wei J, Wang X, Yu D, Tu Y, Yu Y. MicroRNA-mediated autophagy and drug resistance in cancer: mechanisms and therapeutic strategies. Discov Oncol 2024; 15:662. [PMID: 39549162 PMCID: PMC11569378 DOI: 10.1007/s12672-024-01525-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 11/04/2024] [Indexed: 11/18/2024] Open
Abstract
This paper provides an exhaustive overview of the intricate interplay between microRNAs (miRNAs) and autophagy in the context of human cancers, underscoring the pivotal role these non-coding RNAs play in modulating autophagic pathways and their implications for cancer development, progression, and resistance to therapy. MiRNAs, as critical regulators of gene expression post-transcription, influence various biological processes, including autophagy, a catabolic mechanism essential for cellular homeostasis, stress response, and survival. The review meticulously delineates the mechanisms through which miRNAs impact autophagy by targeting specific genes and signaling pathways, thereby affecting cancer cell proliferation, metastasis, and response to chemotherapy. It highlights several miRNAs with dual roles, acting either as oncogenes or tumor suppressors based on the cellular context and the specific autophagic pathways they regulate. The paper further explores the therapeutic potential of targeting miRNA-autophagy axis, offering insights into novel strategies for cancer treatment through modulation of this axis. Emphasizing the complexity of the miRNA-autophagy relationship, the review calls for more in-depth studies to unravel the nuanced regulatory networks between miRNAs and autophagy in cancer, which could pave the way for the development of innovative therapeutic interventions and diagnostic tools.
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Affiliation(s)
- Jinxing Wei
- Department of Neurosurgery, Brain Hospital Affiliated to Tongji University, No.2880, Qixin Road, Shanghai, China
| | - Xianghui Wang
- Department of Neurosurgery, Brain Hospital Affiliated to Tongji University, No.2880, Qixin Road, Shanghai, China
| | - Duo Yu
- Department of Biopharmaceutics School of Pharmacy, The Fourth Military Medical University, Xi'an, 710032, China
| | - Yanyang Tu
- Research Center, The Huizhou Central People's Hospital, Guangdong Medical University, No. 41 Eling North Road, Huizhou, Guangdong, China.
| | - Yaoyu Yu
- Department of Neurosurgery, Brain Hospital Affiliated to Tongji University, No.2880, Qixin Road, Shanghai, China.
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4
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Hefnawy A, Abdelhamid AS, Abdelaziz MM, Elzoghby AO, Khalil IA. Recent advances in nano-based drug delivery systems for treatment of liver cancer. J Pharm Sci 2024; 113:3145-3172. [PMID: 39151795 DOI: 10.1016/j.xphs.2024.08.012] [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: 04/01/2024] [Revised: 08/13/2024] [Accepted: 08/13/2024] [Indexed: 08/19/2024]
Abstract
Liver cancer is one of the aggressive primary tumors as evident by high rate of incidence and mortality. Conventional treatments (e.g. chemotherapy) suffer from various drawbacks including wide drug distribution, low localized drug concentration, and severe off-site toxicity. Therefore, they cannot satisfy the mounting need for safe and efficient cancer therapeutics, and alternative novel strategies are needed. Nano-based drug delivery systems (NDDSs) are among these novel approaches that can improve the overall therapeutic outcomes. NDDSs are designed to encapsulate drug molecules and target them specifically to liver cancer. Thus, NDDSs can selectively deliver therapeutic agents to the tumor cells and avoid distribution to off-target sites which should improve the safety profile of the active agents. Nonetheless, NDDSs should be well designed, in terms of the preparing materials, nanocarriers structure, and the targeting strategy, in order to accomplish these objectives. This review discusses the latest advances of NDDSs for cancer therapy with emphasis on the aforementioned essential design components. The review also entails the challenges associated with the clinical translation of NDDSs, and the future perspectives towards next-generation NDDSs.
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Affiliation(s)
- Amr Hefnawy
- Smyth Lab, College of Pharmacy, University of Texas at Austin, TX 78712, USA.
| | - Ahmed S Abdelhamid
- Cancer Nanotechnology Research Laboratory (CNRL), Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
| | - Moustafa M Abdelaziz
- Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS 66047, USA.
| | - Ahmed O Elzoghby
- Cancer Nanotechnology Research Laboratory (CNRL), Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt; Department of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt; Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
| | - Islam A Khalil
- Department of Pharmaceutics, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6th of October City 12582, Giza, Egypt.
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5
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Xing L, Chen Y, Zheng T. Research progress of nanoparticles in diagnosis and treatment of hepatocellular carcinoma. Open Life Sci 2024; 19:20220932. [PMID: 39220591 PMCID: PMC11365471 DOI: 10.1515/biol-2022-0932] [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: 05/09/2024] [Revised: 06/25/2024] [Accepted: 06/27/2024] [Indexed: 09/04/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is among the most common malignant liver tumors. Despite progress in anticancer drugs and surgical approaches, early detection of HCC remains challenging, often leading to late-stage diagnosis where rapid disease progression precludes surgical intervention, leaving chemotherapy as the only option. However, the systemic toxicity, low bioavailability, and significant adverse effects of chemotherapy drugs often lead to resistance, rendering treatments ineffective for many patients. This article outlines how nanoparticles, following functional modification, offer high sensitivity, reduced drug toxicity, and extended duration of action, enabling precise targeting of drugs to HCC tissues. Combined with other therapeutic modalities and imaging techniques, this significantly enhances the diagnosis, treatment, and long-term prognosis of HCC. The advent of nanomedicine provides new methodologies and strategies for the precise diagnosis and integrated treatment of HCC.
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Affiliation(s)
- Lijun Xing
- Shenzhen Key Laboratory for Drug Addiction and Medication Safety, Department of Hubei University of Medicine, Institute of Ultrasonic Medicine, Peking University Shenzhen Hospital, Shenzhen Peking University-Hong Kong University of Science and Technology Medical Center, Shenzhen, 518036, P. R. China
| | - Yun Chen
- Shenzhen Key Laboratory for Drug Addiction and Medication Safety, Department of Ultrasound, Institute of Ultrasonic Medicine, Peking University Shenzhen Hospital, Shenzhen Peking University-Hong Kong University of Science and Technology Medical Center, Shenzhen, 518036, P. R. China
| | - Tingting Zheng
- Shenzhen Key Laboratory for Drug Addiction and Medication Safety, Department of Ultrasound, Institute of Ultrasonic Medicine, Peking University Shenzhen Hospital, Shenzhen Peking University-Hong Kong University of Science and Technology Medical Center, Shenzhen, 518036, P. R. China
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6
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Wang H. A Review of Nanotechnology in microRNA Detection and Drug Delivery. Cells 2024; 13:1277. [PMID: 39120308 PMCID: PMC11311607 DOI: 10.3390/cells13151277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 07/27/2024] [Accepted: 07/28/2024] [Indexed: 08/10/2024] Open
Abstract
MicroRNAs (miRNAs) are small, non-coding RNAs that play a crucial role in regulating gene expression. Dysfunction in miRNAs can lead to various diseases, including cancers, neurological disorders, and cardiovascular conditions. To date, approximately 2000 miRNAs have been identified in humans. These small molecules have shown promise as disease biomarkers and potential therapeutic targets. Therefore, identifying miRNA biomarkers for diseases and developing effective miRNA drug delivery systems are essential. Nanotechnology offers promising new approaches to addressing scientific and medical challenges. Traditional miRNA detection methods include next-generation sequencing, microarrays, Northern blotting, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Nanotechnology can serve as an effective alternative to Northern blotting and RT-qPCR for miRNA detection. Moreover, nanomaterials exhibit unique properties that differ from larger counterparts, enabling miRNA therapeutics to more effectively enter target cells, reduce degradation in the bloodstream, and be released in specific tissues or cells. This paper reviews the application of nanotechnology in miRNA detection and drug delivery systems. Given that miRNA therapeutics are still in the developing stages, nanotechnology holds great promise for accelerating miRNA therapeutics development.
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Affiliation(s)
- Hsiuying Wang
- Institute of Statistics, National Yang Ming Chiao Tung University, Hsinchu 300093, Taiwan
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7
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Walweel N, Aydin O. Enhancing Therapeutic Efficacy in Cancer Treatment: Integrating Nanomedicine with Autophagy Inhibition Strategies. ACS OMEGA 2024; 9:27832-27852. [PMID: 38973850 PMCID: PMC11223161 DOI: 10.1021/acsomega.4c02234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 05/01/2024] [Accepted: 05/30/2024] [Indexed: 07/09/2024]
Abstract
The complicated stepwise lysosomal degradation process known as autophagy is in charge of destroying and eliminating damaged organelles and defective cytoplasmic components. This mechanism promotes metabolic adaptability and nutrition recycling. Autophagy functions as a quality control mechanism in cells that support homeostasis and redox balance under normal circumstances. However, the role of autophagy in cancer is controversial because, mostly depending on the stage of the tumor, it may either suppress or support the disease. While autophagy delays the onset of tumors and slows the dissemination of cancer in the early stages of tumorigenesis, numerous studies demonstrate that autophagy promotes the development and spread of tumors as well as the evolution and development of resistance to several anticancer drugs in advanced cancer stages. In this Review, we primarily emphasize the therapeutic role of autophagy inhibition in improving the treatment of multiple cancers and give a broad overview of how its inhibition modulates cancer responses. There have been various attempts to inhibit autophagy, including the use of autophagy inhibitor drugs, gene silencing therapy (RNA interference), and nanoparticles. In this Review, all these topics are thoroughly covered and illustrated by recent studies and field investigations.
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Affiliation(s)
- Nada Walweel
- Department
of Biomedical Engineering, Erciyes University, Kayseri 38039, Turkey
- NanoThera
Lab, ERFARMA-Drug Application and Research Center, Erciyes University, Kayseri 38280, Turkey
| | - Omer Aydin
- Department
of Biomedical Engineering, Erciyes University, Kayseri 38039, Turkey
- NanoThera
Lab, ERFARMA-Drug Application and Research Center, Erciyes University, Kayseri 38280, Turkey
- ERNAM-Nanotechnology
Research and Application Center, Erciyes
University, Kayseri 38039, Turkey
- ERKAM-Clinical-Engineering
Research and Implementation Center, Erciyes
University, Kayseri 38030, Turkey
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8
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Liu Y, Wang Y, Zhang J, Peng Q, Wang X, Xiao X, Shi K. Nanotherapeutics targeting autophagy regulation for improved cancer therapy. Acta Pharm Sin B 2024; 14:2447-2474. [PMID: 38828133 PMCID: PMC11143539 DOI: 10.1016/j.apsb.2024.03.019] [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: 11/15/2023] [Revised: 12/29/2023] [Accepted: 01/29/2024] [Indexed: 06/05/2024] Open
Abstract
The clinical efficacy of current cancer therapies falls short, and there is a pressing demand to integrate new targets with conventional therapies. Autophagy, a highly conserved self-degradation process, has received considerable attention as an emerging therapeutic target for cancer. With the rapid development of nanomedicine, nanomaterials have been widely utilized in cancer therapy due to their unrivaled delivery performance. Hence, considering the potential benefits of integrating autophagy and nanotechnology in cancer therapy, we outline the latest advances in autophagy-based nanotherapeutics. Based on a brief background related to autophagy and nanotherapeutics and their impact on tumor progression, the feasibility of autophagy-based nanotherapeutics for cancer treatment is demonstrated. Further, emerging nanotherapeutics developed to modulate autophagy are reviewed from the perspective of cell signaling pathways, including modulation of the mammalian target of rapamycin (mTOR) pathway, autophagy-related (ATG) and its complex expression, reactive oxygen species (ROS) and mitophagy, interference with autophagosome-lysosome fusion, and inhibition of hypoxia-mediated autophagy. In addition, combination therapies in which nano-autophagy modulation is combined with chemotherapy, phototherapy, and immunotherapy are also described. Finally, the prospects and challenges of autophagy-based nanotherapeutics for efficient cancer treatment are envisioned.
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Affiliation(s)
- Yunmeng Liu
- College of Pharmacy, Nankai University, Tianjin 300350, China
| | - Yaxin Wang
- College of Pharmacy, Nankai University, Tianjin 300350, China
| | - Jincheng Zhang
- College of Pharmacy, Nankai University, Tianjin 300350, China
| | - Qikai Peng
- College of Pharmacy, Nankai University, Tianjin 300350, China
| | - Xingdong Wang
- College of Pharmacy, Nankai University, Tianjin 300350, China
| | - Xiyue Xiao
- College of Pharmacy, Nankai University, Tianjin 300350, China
| | - Kai Shi
- College of Pharmacy, Nankai University, Tianjin 300350, China
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9
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Liu X, Bai Y, Zhou B, Yao W, Song S, Liu J, Zheng C. Recent advances in hepatocellular carcinoma-targeted nanoparticles. Biomed Mater 2024; 19:042004. [PMID: 38697209 DOI: 10.1088/1748-605x/ad46d3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Accepted: 05/01/2024] [Indexed: 05/04/2024]
Abstract
In the field of medicine, we often brave the unknown like interstellar explorers, especially when confronting the formidable opponent of hepatocellular carcinoma (HCC). The global burden of HCC remains significant, with suboptimal treatment outcomes necessitating the urgent development of novel drugs and treatments. While various treatments for liver cancer, such as immunotherapy and targeted therapy, have emerged in recent years, improving their transport and therapeutic efficiency, controlling their targeting and release, and mitigating their adverse effects remains challenging. However, just as we grope through the darkness, a glimmer of light emerges-nanotechnology. Recently, nanotechnology has attracted attention because it can increase the local drug concentration in tumors, reduce systemic toxicity, and has the potential to enhance the effectiveness of precision therapy for HCC. However, there are also some challenges hindering the clinical translation of drug-loaded nanoparticles (NPs). Just as interstellar explorers must overcome interstellar dust, we too must overcome various obstacles. In future researches, the design and development of nanodelivery systems for novel drugs treating HCC should be the first attention. Moreover, researchers should focus on the active targeting design of various NPs. The combination of the interventional therapies and drug-loaded NPs will greatly advance the process of precision HCC therapy.
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Affiliation(s)
- Xiaoming Liu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, People's Republic of China
| | - Yaowei Bai
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, People's Republic of China
| | - Binqian Zhou
- Department of Ultrasound, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, People's Republic of China
| | - Wei Yao
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, People's Republic of China
| | - Songlin Song
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, People's Republic of China
| | - Jiacheng Liu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, People's Republic of China
| | - Chuansheng Zheng
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, People's Republic of China
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10
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Dowaidar M. Guidelines for the role of autophagy in drug delivery vectors uptake pathways. Heliyon 2024; 10:e30238. [PMID: 38707383 PMCID: PMC11066435 DOI: 10.1016/j.heliyon.2024.e30238] [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: 01/25/2024] [Revised: 04/22/2024] [Accepted: 04/22/2024] [Indexed: 05/07/2024] Open
Abstract
The process of autophagy refers to the intracellular absorption of cytoplasm (such as proteins, nucleic acids, tiny molecules, complete organelles, and so on) into the lysosome, followed by the breakdown of that cytoplasm. The majority of cellular proteins are degraded by a process called autophagy, which is both a naturally occurring activity and one that may be induced by cellular stress. Autophagy is a system that can save cells' integrity in stressful situations by restoring metabolic basics and getting rid of subcellular junk. This happens as a component of an endurance response. This mechanism may have an effect on disease, in addition to its contribution to the homeostasis of individual cells and tissues as well as the control of development in higher species. The main aim of this study is to discuss the guidelines for the role of autophagy in drug delivery vector uptake pathways. In this paper, we discuss the meaning and concept of autophagy, the mechanism of autophagy, the role of autophagy in drug delivery vectors, autophagy-modulating drugs, nanostructures for delivery systems of autophagy modulators, etc. Later in this paper, we talk about how to deliver chemotherapeutics, siRNA, and autophagy inducers and inhibitors. We also talk about how hard it is to make a drug delivery system that takes nanocarriers' roles as autophagy modulators into account.
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Affiliation(s)
- Moataz Dowaidar
- Bioengineering Department, King Fahd University of Petroleum and Minerals (KFUPM), Dhahran, 31261, Saudi Arabia
- Interdisciplinary Research Center for Hydrogen Technologies and Carbon Management, King Fahd University of Petroleum and Minerals (KFUPM), Dhahran, 31261, Saudi Arabia
- Biosystems and Machines Research Center, King Fahd University of Petroleum and Minerals (KFUPM), Dhahran, 31261, Saudi Arabia
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Wang G, Jiang X, Torabian P, Yang Z. Investigating autophagy and intricate cellular mechanisms in hepatocellular carcinoma: Emphasis on cell death mechanism crosstalk. Cancer Lett 2024; 588:216744. [PMID: 38431037 DOI: 10.1016/j.canlet.2024.216744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 02/05/2024] [Accepted: 02/18/2024] [Indexed: 03/05/2024]
Abstract
Hepatocellular carcinoma (HCC) stands as a formidable global health challenge due to its prevalence, marked by high mortality and morbidity rates. This cancer type exhibits a multifaceted etiology, prominently linked to viral infections, non-alcoholic fatty liver disease, and genomic mutations. The inherent heterogeneity of HCC, coupled with its proclivity for developing drug resistance, presents formidable obstacles to effective therapeutic interventions. Autophagy, a fundamental catabolic process, plays a pivotal role in maintaining cellular homeostasis, responding to stressors such as nutrient deprivation. In the context of HCC, tumor cells exploit autophagy, either augmenting or impeding its activity, thereby influencing tumorigenesis. This comprehensive review underscores the dualistic role of autophagy in HCC, acting as both a pro-survival and pro-death mechanism, impacting the trajectory of tumorigenesis. The anti-carcinogenic potential of autophagy is evident in its ability to enhance apoptosis and ferroptosis in HCC cells. Pertinently, dysregulated autophagy fosters drug resistance in the carcinogenic context. Both genomic and epigenetic factors can regulate autophagy in HCC progression. Recognizing the paramount importance of autophagy in HCC progression, this review introduces pharmacological compounds capable of modulating autophagy-either inducing or inhibiting it, as promising avenues in HCC therapy.
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Affiliation(s)
- Gang Wang
- Department of Interventional, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, PR China
| | - Xiaodi Jiang
- Department of Infectious Disease, Shengjing Hospital of China Medical University, Shenyang, 110020, PR China
| | - Pedram Torabian
- Arnie Charbonneau Cancer Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4Z6, Canada; Department of Medical Sciences, University of Calgary, Calgary, AB, T2N 4Z6, Canada.
| | - Zhi Yang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, PR China.
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12
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Soliman B, Wen MM, Kandil E, El-Agamy B, Gamal-Eldeen AM, ElHefnawi M. Preparation and Optimization of MiR-375 Nano-Vector Using Two Novel Chitosan-Coated Nano-Structured Lipid Carriers as Gene Therapy for Hepatocellular Carcinoma. Pharmaceutics 2024; 16:494. [PMID: 38675155 PMCID: PMC11054685 DOI: 10.3390/pharmaceutics16040494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 12/26/2023] [Accepted: 01/08/2024] [Indexed: 04/28/2024] Open
Abstract
Currently, there is still a lack of effective carriers with minimal side effects to deliver therapeutic miRNA. Thus, it is crucial to optimize novel drug delivery systems. MiR-375 has proven superior therapeutic potency in Hepatocellular carcinoma (HCC). The purpose of this study was to fabricate 2 novel and smart nano-carriers for the transportation efficiency of miR-375 in HCC cells and enhance its anti-tumor effects. We established the miR-375 construct through the pEGP- miR expression vector. Two nano-carriers of solid/liquid lipids and chitosan (CS) were strategically selected, prepared by high-speed homogenization, and optimized by varying nano-formulation factors. Thus, the two best nano-formulations were designated as F1 (0.5% CS) and F2 (1.5% CS) and were evaluated for miR-375 conjugation efficiency by gel electrophoresis and nanodrop assessment. Then, physio-chemical characteristics and stability tests for the miR-375 nano-plexes were all studied. Next, its efficiencies as replacement therapy in HepG2 cells have been assessed by fluorescence microscopy, flow cytometry, and cytotoxicity assay. The obtained data showed that two cationic nanostructured solid/liquid lipid carriers (NSLCs); F1 and F2 typically had the best physio-chemical parameters and long-term stability. Moreover, both F1 and F2 could form nano-plexes with the anionic miR-375 construct at weight ratios 250/1 and 50/1 via electrostatic interactions. In addition, these nano-plexes exhibited physical stability after three months and protected miR-375 from degradation in the presence of 50% fetal bovine serum (FBS). Furthermore, both nano-plexes could simultaneously deliver miR-375 into HepG2 cells and they ensure miR re-expression even in the presence of 50% FBS compared to free miR-375 (p-value < 0.001). Moreover, both F1 and F2 alone significantly exhibited minimal cytotoxicity in treated cells. In contrast, the nano-plexes significantly inhibited cell growth compared to free miR-375 or doxorubicin (DOX), respectively. More importantly, F2/miR-375 nano-plex exhibited more anti-proliferative activity in treated cells although its IC50 value was 55 times lower than DOX (p-value < 0.001). Collectively, our findings clearly emphasized the multifunctionality of the two CS-coated NSLCs in terms of their enhanced biocompatibility, biostability, conjugation, and transfection efficiency of therapeutic miR-375. Therefore, the NSLCs/miR-375 nano-plexes could serve as a novel and promising therapeutic strategy for HCC.
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Affiliation(s)
- Bangly Soliman
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo 11566, Egypt; (B.S.)
- Biomedical Informatics and Chemo-Informatics Group, Informatics and Systems Department, National Research Centre, Cairo 12622, Egypt
| | - Ming Ming Wen
- Faculty of Pharmacy, Pharos University, Alexandria 21648, Egypt
| | - Eman Kandil
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo 11566, Egypt; (B.S.)
| | - Basma El-Agamy
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo 11566, Egypt; (B.S.)
| | - Amira M. Gamal-Eldeen
- Clinical Laboratory Sciences Department, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia;
| | - Mahmoud ElHefnawi
- Biomedical Informatics and Chemo-Informatics Group, Informatics and Systems Department, National Research Centre, Cairo 12622, Egypt
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Lin C, Akhtar M, Li Y, Ji M, Huang R. Recent Developments in CaCO 3 Nano-Drug Delivery Systems: Advancing Biomedicine in Tumor Diagnosis and Treatment. Pharmaceutics 2024; 16:275. [PMID: 38399329 PMCID: PMC10893456 DOI: 10.3390/pharmaceutics16020275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 02/06/2024] [Accepted: 02/13/2024] [Indexed: 02/25/2024] Open
Abstract
Calcium carbonate (CaCO3), a natural common inorganic material with good biocompatibility, low toxicity, pH sensitivity, and low cost, has a widespread use in the pharmaceutical and chemical industries. In recent years, an increasing number of CaCO3-based nano-drug delivery systems have been developed. CaCO3 as a drug carrier and the utilization of CaCO3 as an efficient Ca2+ and CO2 donor have played a critical role in tumor diagnosis and treatment and have been explored in increasing depth and breadth. Starting from the CaCO3-based nano-drug delivery system, this paper systematically reviews the preparation of CaCO3 nanoparticles and the mechanisms of CaCO3-based therapeutic effects in the internal and external tumor environments and summarizes the latest advances in the application of CaCO3-based nano-drug delivery systems in tumor therapy. In view of the good biocompatibility and in vivo therapeutic mechanisms, they are expected to become an advancing biomedicine in the field of tumor diagnosis and treatment.
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Affiliation(s)
- Chenteng Lin
- School of Pharmacy, Key Laboratory of Smart Drug Delivery (Ministry of Education), Huashan Hospital, Minhang Hospital, Fudan University, Shanghai 201203, China;
| | - Muhammad Akhtar
- Department of Pharmaceutics, Faculty of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur 63100, Pakistan;
| | - Yingjie Li
- Shanghai Yangpu District Mental Health Center, Shanghai 200090, China;
| | - Min Ji
- Shanghai Yangpu District Mental Health Center, Shanghai 200090, China;
| | - Rongqin Huang
- School of Pharmacy, Key Laboratory of Smart Drug Delivery (Ministry of Education), Huashan Hospital, Minhang Hospital, Fudan University, Shanghai 201203, China;
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14
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Li J, Bao H, Huang Z, Liang Z, Wang M, Lin N, Ni C, Xu Y. Little things with significant impact: miRNAs in hepatocellular carcinoma. Front Oncol 2023; 13:1191070. [PMID: 37274242 PMCID: PMC10235484 DOI: 10.3389/fonc.2023.1191070] [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: 03/21/2023] [Accepted: 05/09/2023] [Indexed: 06/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) has developed into one of the most lethal, aggressive, and malignant cancers worldwide. Although HCC treatment has improved in recent years, the incidence and lethality of HCC continue to increase yearly. Therefore, an in-depth study of the pathogenesis of HCC and the search for more reliable therapeutic targets are crucial to improving the survival quality of HCC patients. Currently, miRNAs have become one of the hotspots in life science research, which are widely present in living organisms and are non-coding RNAs involved in regulating gene expression. MiRNAs exert their biological roles by suppressing the expression of downstream genes and are engaged in various HCC-related processes, including proliferation, apoptosis, invasion, and metastasis. In addition, the expression status of miRNAs is related to the drug resistance mechanism of HCC, which has important implications for the systemic treatment of HCC. This paper reviews the regulatory role of miRNAs in the pathogenesis of HCC and the clinical applications of miRNAs in HCC in recent years.
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Affiliation(s)
- Jiehan Li
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Haolin Bao
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Ziyue Huang
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Zixin Liang
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Mei Wang
- Key Laboratory of Basic Pharmacology of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China
| | - Ning Lin
- Key Laboratory of Functional and Clinical Translational Medicine, Fujian Province University, Xiamen Medical College, Xiamen, Fujian, China
| | - Chunjie Ni
- Jiangsu Province Engineering Research Center of Tumor Targeted Nano Diagnostic and Therapeutic Materials, Yancheng Teachers University, Yancheng, Jiangsu, China
| | - Yi Xu
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- Key Laboratory of Basic Pharmacology of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China
- Key Laboratory of Functional and Clinical Translational Medicine, Fujian Province University, Xiamen Medical College, Xiamen, Fujian, China
- Jiangsu Province Engineering Research Center of Tumor Targeted Nano Diagnostic and Therapeutic Materials, Yancheng Teachers University, Yancheng, Jiangsu, China
- State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China
- Key Laboratory of Biomarkers and In Vitro Diagnosis Translation of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang, China
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, China
- Anhui Province Key Laboratory of Translational Cancer Research, Bengbu Medical College, Bengbu, Anhui, China
- Key Laboratory of Intelligent Pharmacy and Individualized Therapy of Huzhou, Department of Pharmacy, Changxing People’s Hospital, Changxing, Zhejiang, China
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
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15
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Tian GA, Xu WT, Zhang XL, Zhou YQ, Sun Y, Hu LP, Jiang SH, Nie HZ, Zhang ZG, Zhu L, Li J, Yang XM, Yao LL. CCBE1 promotes mitochondrial fusion by inhibiting the TGFβ-DRP1 axis to prevent the progression of hepatocellular carcinoma. Matrix Biol 2023; 117:31-45. [PMID: 36849082 DOI: 10.1016/j.matbio.2023.02.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 02/21/2023] [Accepted: 02/21/2023] [Indexed: 02/27/2023]
Abstract
The extracellular matrix (ECM), as an important component of the tumor microenvironment, exerts various roles in tumor formation. Mitochondrial dynamic disorder is closely implicated in tumorigenesis, including hyperfission in HCC. We aimed to determine the influence of the ECM-related protein CCBE1 on mitochondrial dynamics in HCC. Here, we found that CCBE1 was capable of promoting mitochondrial fusion in HCC. Initially, CCBE1 expression was found to be significantly downregulated in tumors compared with nontumor tissues, which resulted from hypermethylation of the CCBE1 promoter in HCC. Furthermore, CCBE1 overexpression or treatment with recombinant CCBE1 protein dramatically inhibited HCC cell proliferation, migration, and invasion in vitro and in vivo. Mechanistically, CCBE1 functioned as an inhibitor of mitochondrial fission by preventing the location of DRP1 on mitochondria through inhibiting its phosphorylation at Ser616 by directly binding with TGFβR2 to inhibit TGFβ signaling activity. In addition, a higher percentage of specimens with higher DRP1 phosphorylation was present in patients with lower CCBE1 expression than in patients with higher CCBE1 expression, which further confirmed the inhibitory effect of CCBE1 on DRP1 phosphorylation at Ser616. Collectively, our study highlights the crucial roles of CCBE1 in mitochondrial homeostasis, suggesting strong evidence for this process as a potential therapeutic strategy for HCC.
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Affiliation(s)
- Guang-Ang Tian
- Department of Central Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University, School of Medicine, 243 Huaihai West Road, Shanghai 200030, PR China; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China
| | - Wen-Ting Xu
- Department of Pathology, The International Peace Maternity & Child Health Hospital of China Welfare Institute, School of Medicine, Shanghai Jiao Tong University, 910 Hengshan Road, Shanghai 200030, PR China
| | - Xue-Li Zhang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China
| | - Yao-Qi Zhou
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China
| | - Yue Sun
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China
| | - Li-Peng Hu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China
| | - Shu-Heng Jiang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China
| | - Hui-Zhen Nie
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China
| | - Zhi-Gang Zhang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China
| | - Lei Zhu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China.
| | - Jun Li
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China.
| | - Xiao-Mei Yang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China.
| | - Lin-Li Yao
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China.
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16
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Xia Y, Duan S, Han C, Jing C, Xiao Z, Li C. Hypoxia-responsive nanomaterials for tumor imaging and therapy. Front Oncol 2022; 12:1089446. [PMID: 36591450 PMCID: PMC9798000 DOI: 10.3389/fonc.2022.1089446] [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: 11/04/2022] [Accepted: 11/28/2022] [Indexed: 12/23/2022] Open
Abstract
Hypoxia is an important component of tumor microenvironment and plays a pivotal role in cancer progression. With the distinctive physiochemical properties and biological effects, various nanoparticles targeting hypoxia had raised great interest in cancer imaging, drug delivery, and gene therapy during the last decade. In the current review, we provided a comprehensive view on the latest progress of novel stimuli-responsive nanomaterials targeting hypoxia-tumor microenvironment (TME), and their applications in cancer diagnosis and therapy. Future prospect and challenges of nanomaterials are also discussed.
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Affiliation(s)
- Yifei Xia
- Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shao Duan
- Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Chaozhe Han
- Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Chengwei Jing
- Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zunyu Xiao
- Department of Nuclear Medicine, The Fourth Hospital of Harbin Medical University, Harbin, China,*Correspondence: Chao Li, ; Zunyu Xiao,
| | - Chao Li
- Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, China,*Correspondence: Chao Li, ; Zunyu Xiao,
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17
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Zhao P, Tian Y, Lu Y, Zhang J, Tao A, Xiang G, Liu Y. Biomimetic calcium carbonate nanoparticles delivered IL-12 mRNA for targeted glioblastoma sono-immunotherapy by ultrasound-induced necroptosis. J Nanobiotechnology 2022; 20:525. [PMID: 36496387 PMCID: PMC9741778 DOI: 10.1186/s12951-022-01731-z] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Accepted: 11/29/2022] [Indexed: 12/13/2022] Open
Abstract
Glioblastoma (GBM) is the most aggressive brain tumor, which owns the characteristics of high recurrence, low survival rate and poor prognosis because of the existence of blood brain barrier (BBB) and complicated brain tumor microenvironment. Currently, immunotherapy has attracted much attention on account of favorable therapeutic effect. In this study, we designed a cRGD-modified cancer cell membrane (CM) coated calcium carbonate nanoparticle to deliver interleukin-12 messenger RNA (IL-12 mRNA@cRGD-CM-CaCO3 NPs). The cRGD-modified CM as the shell can endow the nanoparticles with BBB crossing and tumor homing/homotypic targeting effect in the brain tumor microenvironment. IL-12 mRNA-loaded calcium carbonate nanoparticles as the core allow synergistic immunotherapy of necroptosis-induced immune response and IL-12 mRNA transfection under ultrasound irradiation. The as-prepared biomimetic nanoparticles showed superior target and immunotherapeutic outcomes, suggesting that this biomimetic nanoplatform provides a feasible strategy for promoting BBB-penetrating and antitumor immunity.
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Affiliation(s)
- Pengxuan Zhao
- grid.33199.310000 0004 0368 7223Department of Medical Ultrasound, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China ,grid.33199.310000 0004 0368 7223School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China ,grid.443397.e0000 0004 0368 7493 School of Pharmacy, Hainan Medical University, Haikou, 571199 China
| | - Yu Tian
- Jiangsu Hengrui Pharmaceuticals Co. Ltd, Lianyungang, China
| | - Yongping Lu
- grid.440773.30000 0000 9342 2456Department of Ultrasound, The Affiliated Hospital of Yunnan University, Kunming, 650021 China
| | - Jun Zhang
- grid.33199.310000 0004 0368 7223Department of Medical Ultrasound, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Anyu Tao
- grid.33199.310000 0004 0368 7223Department of Medical Ultrasound, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Guangya Xiang
- grid.33199.310000 0004 0368 7223School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Yani Liu
- grid.33199.310000 0004 0368 7223Department of Medical Ultrasound, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
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18
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Xu W, Ye C, Qing X, Liu S, Lv X, Wang W, Dong X, Zhang Y. Multi-target tyrosine kinase inhibitor nanoparticle delivery systems for cancer therapy. Mater Today Bio 2022; 16:100358. [PMID: 35880099 PMCID: PMC9307458 DOI: 10.1016/j.mtbio.2022.100358] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 07/05/2022] [Accepted: 07/07/2022] [Indexed: 12/19/2022] Open
Abstract
Multi-target Tyrosine Kinase Inhibitors (MTKIs) have drawn substantial attention in tumor therapy. MTKIs could inhibit tumor cell proliferation and induce apoptosis by blocking the activity of tyrosine kinase. However, the toxicity and drug resistance of MTKIs severely restrict their further clinical application. The nano pharmaceutical technology based on MTKIs has attracted ever-increasing attention in recent years. Researchers deliver MTKIs through various types of nanocarriers to overcome drug resistance and improve considerably therapeutic efficiency. This review intends to summarize comprehensive applications of MTKIs nanoparticles in malignant tumor treatment. Firstly, the mechanism and toxicity were introduced. Secondly, various nanocarriers for MTKIs delivery were outlined. Thirdly, the combination treatment schemes and drug resistance reversal strategies were emphasized to improve the outcomes of cancer therapy. Finally, conclusions and perspectives were summarized to guide future research.
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Affiliation(s)
- Wenjing Xu
- School of Medicine, Southeast University, Nanjing, 210009, China
| | - Chunping Ye
- Department of Obstetrics and Gynecology, Nanjing Maternity and Child Health Care Hospital, Women's Hospital of Nanjing Medical University, Nanjing, China
| | - Xin Qing
- School of Medicine, Southeast University, Nanjing, 210009, China
| | - Shengli Liu
- Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, China
| | - Xinyi Lv
- Key Laboratory of Flexible Electronics (KLOFE) and Institute of Advanced Materials (IAM), Nanjing Tech University (NanjingTech), Nanjing, 211816, China
| | - Wenjun Wang
- School of Physical Science and Information Technology, Liaocheng University, Liaocheng, 252059, China
| | - Xiaochen Dong
- Key Laboratory of Flexible Electronics (KLOFE) and Institute of Advanced Materials (IAM), Nanjing Tech University (NanjingTech), Nanjing, 211816, China
- School of Chemistry & Materials Science, Jiangsu Normal University, Xuzhou, 221116, China
| | - Yewei Zhang
- Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, China
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19
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Zhao P, Tian Y, You J, Hu X, Liu Y. Recent Advances of Calcium Carbonate Nanoparticles for Biomedical Applications. Bioengineering (Basel) 2022; 9:691. [PMID: 36421092 PMCID: PMC9687225 DOI: 10.3390/bioengineering9110691] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 11/05/2022] [Accepted: 11/09/2022] [Indexed: 11/17/2023] Open
Abstract
Calcium carbonate nanoparticles have been widely used in biomedicine due to their biocompatibility and biodegradability. Recently, calcium carbonate nanoparticles are largely integrated with imaging contrast and therapeutic agents for various imaging and therapeutic approaches. In this review, we first described the advantages and preparation methods of calcium carbonate nanoparticles, then the state-of-the-art progress of calcium carbonate nanoparticles in diagnosis, treatment and theranostics was summarized. Finally, we discussed the challenges and recommendations for future studies of the calcium carbonate nanoparticles.
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Affiliation(s)
- Pengxuan Zhao
- Department of Medical Ultrasound, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yu Tian
- Jiangsu Hengrui Pharmaceuticals Co., Ltd., Shanghai 200000, China
| | - Jia You
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xin Hu
- Department of Medical Ultrasound, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yani Liu
- Department of Medical Ultrasound, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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20
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He Q, Guo P, Bo Z, Yu H, Yang J, Wang Y, Chen G. Noncoding RNA-mediated molecular bases of chemotherapy resistance in hepatocellular carcinoma. Cancer Cell Int 2022; 22:249. [PMID: 35945536 PMCID: PMC9361533 DOI: 10.1186/s12935-022-02643-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 06/27/2022] [Indexed: 11/10/2022] Open
Abstract
Despite the significant progress in decreasing the occurrence and mortality of hepatocellular carcinoma (HCC), it remains a public health issue worldwide on the basis of its late presentation and tumor recurrence. To date, apart from surgical interventions, such as surgical resection, liver transplantation and locoregional ablation, current standard antitumor protocols include conventional cytotoxic chemotherapy. However, due to the high chemoresistance nature, most current therapeutic agents show dismal outcomes for this refractory malignancy, leading to disease relapse. Nevertheless, the molecular mechanisms involved in chemotherapy resistance remain systematically ambiguous. Herein, HCC is hierarchically characterized by the formation of primitive cancer stem cells (CSCs), progression of epithelial-mesenchymal transition (EMT), unbalanced autophagy, delivery of extracellular vesicles (EVs), escape of immune surveillance, disruption of ferroptosis, alteration of the tumor microenvironment and multidrug resistance-related signaling pathways that mediate the multiplicity and complexity of chemoresistance. Of note, anecdotal evidence has corroborated that noncoding RNAs (ncRNAs) extensively participate in the critical physiological processes mentioned above. Therefore, understanding the detailed regulatory bases that underlie ncRNA-mediated chemoresistance is expected to yield novel insights into HCC treatment. In the present review, a comprehensive summary of the latest progress in the investigation of chemotherapy resistance concerning ncRNAs will be elucidated to promote tailored individual treatment for HCC patients.
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Affiliation(s)
- Qikuan He
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Pengyi Guo
- Department of Cardiothoracic Surgery, Ningbo Yinzhou No. 2 Hospital, Ningbo, 315199, Zhejiang, China
| | - Zhiyuan Bo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Haitao Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Jinhuan Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Yi Wang
- Department of Epidemiology and Biostatistics, School of Public Health and Management, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Gang Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
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21
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Lei Y, Chen L, Liu J, Zhong Y, Deng L. The MicroRNA-Based Strategies to Combat Cancer Chemoresistance via Regulating Autophagy. Front Oncol 2022; 12:841625. [PMID: 35211417 PMCID: PMC8861360 DOI: 10.3389/fonc.2022.841625] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 01/13/2022] [Indexed: 12/12/2022] Open
Abstract
Chemoresistance frequently occurs in cancer treatment, which results in chemotherapy failure and is one of the most leading causes of cancer-related death worldwide. Understanding the mechanism of chemoresistance and exploring strategies to overcome chemoresistance have become an urgent need. Autophagy is a highly conserved self-degraded process in cells. The dual roles of autophagy (pro-death or pro-survival) have been implicated in cancers and chemotherapy. MicroRNA (miRNA) is a class of small non-coding molecules that regulate autophagy at the post-transcriptional level in cancer cells. The association between miRNAs and autophagy in cancer chemoresistance has been emphasized. In this review, we focus on the dual roles of miRNA-mediated autophagy in facilitating or combating chemoresistance, aiming to shed lights on the potential role of miRNAs as targets to overcome chemoresistance.
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Affiliation(s)
- Yuhe Lei
- Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Lei Chen
- Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Junshan Liu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.,Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yinqin Zhong
- Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Lijuan Deng
- Formula-Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, China
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22
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The Role of Macroautophagy and Chaperone-Mediated Autophagy in the Pathogenesis and Management of Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:cancers14030760. [PMID: 35159028 PMCID: PMC8833636 DOI: 10.3390/cancers14030760] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/24/2022] [Accepted: 01/25/2022] [Indexed: 02/05/2023] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is a major health problem with the second highest mortality among all cancers and a continuous increase worldwide. HCC is highly resistant to available chemotherapeutic agents, leaving patients with no effective therapeutic option and a poor prognosis. Although an increasing number of studies have elucidated the potential role of autophagy underlying HCC, the complete regulation is far from understood. The different forms of autophagy constitute important cell survival mechanisms that could prevent hepatocarcinogenesis by limiting hepatocyte death and the associated hepatitis and fibrosis at early stages of chronic liver diseases. On the other hand, at late stages of hepatocarcinogenesis, they could support the malignant transformation of (pre)neoplastic cells by facilitating their survival. Abstract Hepatocarcinogenesis is a long process with a complex pathophysiology. The current therapeutic options for HCC management, during the advanced stage, provide short-term survival ranging from 10–14 months. Autophagy acts as a double-edged sword during this process. Recently, two main autophagic pathways have emerged to play critical roles during hepatic oncogenesis, macroautophagy and chaperone-mediated autophagy. Mounting evidence suggests that upregulation of macroautophagy plays a crucial role during the early stages of carcinogenesis as a tumor suppressor mechanism; however, it has been also implicated in later stages promoting survival of cancer cells. Nonetheless, chaperone-mediated autophagy has been elucidated as a tumor-promoting mechanism contributing to cancer cell survival. Moreover, the autophagy pathway seems to have a complex role during the metastatic stage, while induction of autophagy has been implicated as a potential mechanism of chemoresistance of HCC cells. The present review provides an update on the role of autophagy pathways in the development of HCC and data on how the modulation of the autophagic pathway could contribute to the most effective management of HCC.
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23
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Zhang X, He C, Xiang G. Engineering nanomedicines to inhibit hypoxia-inducible Factor-1 for cancer therapy. Cancer Lett 2022; 530:110-127. [PMID: 35041892 DOI: 10.1016/j.canlet.2022.01.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 12/18/2021] [Accepted: 01/10/2022] [Indexed: 11/02/2022]
Abstract
Hypoxia-inducible factor-1 (HIF-1), an essential promoter of tumor progression, has attracted increasing attention as a therapeutic target. In addition to hypoxic cellular conditions, HIF-1 activation can be triggered by cancer treatment, which causes drug tolerance and therapeutic failure. To date, a series of effective strategies have been explored to suppress HIF-1 function, including silencing the HIF-1α gene, inhibiting HIF-1α protein translation, degrading HIF-1α protein, and inhibiting HIF-1 transcription. Furthermore, nanoparticle-based drug delivery systems have been widely developed to improve the stability and pharmacokinetics of HIF-1 inhibitors or achieve HIF-1-targeted combination therapies as a nanoplatform. In this review, we summarize the current literature on nanomedicines targeting HIF-1 to combat cancer and discuss their potential for future development.
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Affiliation(s)
- Xiaojuan Zhang
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Chuanchuan He
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Guangya Xiang
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Ladju RB, Ulhaq ZS, Soraya GV. Nanotheranostics: A powerful next-generation solution to tackle hepatocellular carcinoma. World J Gastroenterol 2022; 28:176-187. [PMID: 35110943 PMCID: PMC8776531 DOI: 10.3748/wjg.v28.i2.176] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 07/15/2021] [Accepted: 12/31/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is an epidemic burden and remains highly prevalent worldwide. The significant mortality rates of HCC are largely due to the tendency of late diagnosis and the multifaceted, complex nature of treatment. Meanwhile, current therapeutic modalities such as liver resection and transplantation are only effective for resolving early-stage HCC. Hence, alternative approaches are required to improve detection and enhance the efficacy of current treatment options. Nanotheranostic platforms, which utilize biocompatible nanoparticles to perform both diagnostics and targeted delivery, has been considered a potential approach for cancer management in the past few decades. Advancement of nanomaterials and biomedical engineering techniques has led to rapid expansion of the nanotheranostics field, allowing for more sensitive and specific diagnosis, real-time monitoring of drug delivery, and enhanced treatment efficacies across various malignancies. The focus of this review is on the applications of nanotheranostics for HCC. The review first explores the current epidemiology and the commonly encountered obstacles in HCC diagnosis and treatment. It then presents the current technological and functional advancements in nanotheranostic technology for cancer in general, and then specifically explores the use of nanotheranostic modalities as a promising option to address the key challenges present in HCC management.
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Affiliation(s)
- Rusdina Bte Ladju
- Department of Anatomic Pathology, Faculty of Medicine, Hasanuddin University, Makassar 90245, Indonesia
| | - Zulvikar Syambani Ulhaq
- Department of Biochemistry, Faculty of Medicine and Health Sciences, Maulana Malik Ibrahim Islamic State University, Malang 65151, Indonesia
- National Research and Innovation Agency, Central Jakarta 10340, Indonesia
| | - Gita Vita Soraya
- Department of Biochemistry, Faculty of Medicine, Hasanuddin University, Makassar 90245, Indonesia
- Department of Neurology, Faculty of Medicine, Hasanuddin University, Makassar 90245, Indonesia
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25
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Saveleva M, Lengert E, Verkhovskii RA, Abalymov A, Pavlov AM, Ermakov A, Prikhozhdenko E, Shtykov SN, Svenskaya YI. CaCO 3-based carriers with prolonged release property for antifungal drug delivery to hair follicles. Biomater Sci 2022; 10:3323-3345. [DOI: 10.1039/d2bm00539e] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Superficial fungal infections are of serious concern worldwide due to their morbidity and increasing distribution across the globe in this era of growing antimicrobial resistance. Delivery of antifungals to target...
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26
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Feng X, Zou B, Nan T, Zheng X, Zheng L, Lan J, Chen W, Yu J. MiR-25 enhances autophagy and promotes sorafenib resistance of hepatocellular carcinoma via targeting FBXW7. Int J Med Sci 2022; 19:257-266. [PMID: 35165511 PMCID: PMC8795798 DOI: 10.7150/ijms.67352] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 12/07/2021] [Indexed: 12/25/2022] Open
Abstract
Sorafenib resistance is a major challenge in the treatment of patients with advanced hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) are a large family of non-coding RNA molecules, which is an important mechanism of drug resistance. We previously found that knockdown of miR-25 increased the sensitivity of TRAIL-induced apoptosis in liver cancer stem cells. We aimed to study the effects of miR-25 on sorafenib resistance of HCC and the underlying mechanisms. In the present study, we analyzed the expression of miR-25 between HCC and normal tissues and predicted miR-25 target genes through databases. After transfecting miR-25 mimics, inhibitor or FBXW7 Plasmid, CCK-8 and flow cytometry assay was performed to determine the sorafenib resistance. We performed LC3-dual-fluorescence assay and Western blotting to detect the autophagy levels. The expression of miR-25 was upregulated in human HCC tissues and was associated with tumor pathological grade, clinic staging, and lymphatic metastasis. MiR-25 enhanced sorafenib resistance of HCC cells and autophagy. FBXW7 is the direct target of miR-25. Overexpression of FBXW7 could reverse the increase of sorafenib resistance caused by miR-25 mimics. Our results suggested that miR-25 increased the sorafenib resistance of HCC via inducing autophagy. In addition, miR-25 decreases the expression of FBXW7 protein to regulate autophagy. Therefore, miR-25 may represent a novel therapeutic target for the treatment of HCC.
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Affiliation(s)
- Xiaoning Feng
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Bei Zou
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Tianhao Nan
- College of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Xiaoxiao Zheng
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine of Zhejiang Province, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang, China
| | - Li Zheng
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine of Zhejiang Province, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang, China
| | - Jiahua Lan
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine of Zhejiang Province, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang, China
| | - Wei Chen
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine of Zhejiang Province, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang, China
| | - Jun Yu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
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Bakrania A, Zheng G, Bhat M. Nanomedicine in Hepatocellular Carcinoma: A New Frontier in Targeted Cancer Treatment. Pharmaceutics 2021; 14:41. [PMID: 35056937 PMCID: PMC8779722 DOI: 10.3390/pharmaceutics14010041] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/17/2021] [Accepted: 12/22/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death and is associated with a dismal median survival of 2-9 months. The fundamental limitations and ineffectiveness of current HCC treatments have led to the development of a vast range of nanotechnologies with the goal of improving the safety and efficacy of treatment for HCC. Although remarkable success has been achieved in nanomedicine research, there are unique considerations such as molecular heterogeneity and concomitant liver dysfunction that complicate the translation of nanotheranostics in HCC. This review highlights the progress, challenges, and targeting opportunities in HCC nanomedicine based on the growing literature in recent years.
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Affiliation(s)
- Anita Bakrania
- Toronto General Hospital Research Institute, Toronto, ON M5G 2C4, Canada;
- Ajmera Transplant Program, University Health Network, Toronto, ON M5G 2N2, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada;
| | - Gang Zheng
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada;
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
| | - Mamatha Bhat
- Toronto General Hospital Research Institute, Toronto, ON M5G 2C4, Canada;
- Ajmera Transplant Program, University Health Network, Toronto, ON M5G 2N2, Canada
- Division of Gastroenterology, Department of Medicine, University Health Network, Toronto, ON M5G 2C4, Canada
- Department of Medical Sciences, University of Toronto, Toronto, ON M5S 1A1, Canada
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Das S, Shukla N, Singh SS, Kushwaha S, Shrivastava R. Mechanism of interaction between autophagy and apoptosis in cancer. Apoptosis 2021; 26:512-533. [PMID: 34510317 DOI: 10.1007/s10495-021-01687-9] [Citation(s) in RCA: 128] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/24/2021] [Indexed: 12/13/2022]
Abstract
The mechanisms of two programmed cell death pathways, autophagy, and apoptosis, are extensively focused areas of research in the context of cancer. Both the catabolic pathways play a significant role in maintaining cellular as well as organismal homeostasis. Autophagy facilitates this by degradation and elimination of misfolded proteins and damaged organelles, while apoptosis induces canonical cell death in response to various stimuli. Ideally, both autophagy and apoptosis have a role in tumor suppression, as autophagy helps in eliminating the tumor cells, and apoptosis prevents their survival. However, as cancer proceeds, autophagy exhibits a dual role by enhancing cancer cell survival in response to stress conditions like hypoxia, thereby promoting chemoresistance to the tumor cells. Thus, any inadequacy in either of their levels can lead to tumor progression. A complex array of biomarkers is involved in maintaining coordination between the two by acting as either positive or negative regulators of one or both of these pathways of cell death. The resulting crosstalk between the two and its role in influencing the survival or death of malignant cells makes it quintessential, among other challenges facing chemotherapeutic treatment of cancer. In view of this, the present review aims to highlight some of the factors involved in maintaining their diaphony and stresses the importance of inhibition of cytoprotective autophagy and deletion of the intermediate pathways involved to facilitate tumor cell death. This will pave the way for future prospects in designing drug combinations facilitating the synergistic effect of autophagy and apoptosis in achieving cancer cell death.
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Affiliation(s)
- Shreya Das
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS), Pilani Campus, Pilani, Rajasthan, 333031, India
| | - Nidhi Shukla
- Department of Pathology, Case Western Reserve University, Cleveland, OH, USA
| | | | - Sapana Kushwaha
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow, 226025, India
| | - Richa Shrivastava
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS), Pilani Campus, Pilani, Rajasthan, 333031, India.
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29
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Mintz KJ, Leblanc RM. The use of nanotechnology to combat liver cancer: Progress and perspectives. Biochim Biophys Acta Rev Cancer 2021; 1876:188621. [PMID: 34454983 DOI: 10.1016/j.bbcan.2021.188621] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 08/21/2021] [Accepted: 08/24/2021] [Indexed: 01/04/2023]
Abstract
Liver cancer is one of the most common cancers worldwide and is also one of the most difficult cancers to treat, resulting in almost one million deaths per year, and the danger of this cancer is compounded when the tumor is nonresectable. Hepatocellular carcinoma (HCC) is the most common type of liver cancer and has the third highest mortality rate worldwide. Considering the morbid statistics surrounding this cancer it is a popular research topic to target for better therapy practices. This review summarizes the role of nanotechnology in these endeavors. Nanoparticles (NPs) are a very broad class of material and many different kinds have been used to potentially combat liver cancer. Gold, silver, platinum, metal oxide, calcium, and selenium NPs as well as less common materials are all inorganic NPs that have been used as a therapeutic, carrier, or imaging agent in drug delivery systems (DDS) and these efforts are described. Carbon-based NPs, including polymeric, polysaccharide, and lipid NPs as well as carbon dots, have also been widely studied for this purpose and the role they play in DDS for the treatment of liver cancer is illustrated in this review. The multifunctional nature of many NPs described herein, allows these systems to display high anticancer activity in vitro and in vivo and highlights the advantage of and need for combinatorial therapy in treating this difficult cancer. These works are summarized, and future directions are presented for this promising field.
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Affiliation(s)
- Keenan J Mintz
- Department of Chemistry, University of Miami, Coral Gables, FL 33146, USA; Department of Materials Science and Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Roger M Leblanc
- Department of Chemistry, University of Miami, Coral Gables, FL 33146, USA.
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30
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Li L, Yu S, Hu Q, Hai Y, Li Y. Genome-scale CRISPRa screening identifies MTX1 as a contributor for sorafenib resistance in hepatocellular carcinoma by augmenting autophagy. Int J Biol Sci 2021; 17:3133-3144. [PMID: 34421355 PMCID: PMC8375235 DOI: 10.7150/ijbs.62393] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 07/09/2021] [Indexed: 12/29/2022] Open
Abstract
Sorafenib is the standard first-line drug for the treatment of advanced hepatocellular carcinoma (HCC), however, its therapeutic efficacy is not satisfactory due to primary or secondary resistance of HCC cells. In the present study, we identified Metaxin 1 (MTX1) as a new regulator of sorafenib resistance in HCC through genome-scale CRISPR activation (CRISPRa) screening. We found that MTX1 was frequently upregulated in HCC tissues and overexpression of MTX1 promoted HCC cell proliferation in vitro and in vivo. As well, MTX1 overexpression increased cell growth rate and decreased cell apoptosis upon sorafenib treatment. Consistently, the resistance induced by MTX1 was also observed in subcutaneous xenograft tumor model. Clinically, high expression of MTX1 was closely related with poor outcomes in HCC patients who received sorafenib treatment. Mechanistically, overexpression of MTX1 could promote HCC cell autophagy via interacting with and inhibiting CDGSH iron sulfur domain 1 (CISD1), an autophagy negative regulator. Taken together, our findings suggest that MTX1 is upregulated in HCC and contributes to sorafenib resistance via a possible mechanism involving CISD1 mediated autophagy.
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Affiliation(s)
- Li Li
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China
| | - Shijun Yu
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China
| | - Qingqing Hu
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China
| | - Yanan Hai
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China
| | - Yandong Li
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China
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31
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Hu X, Zhu H, Shen Y, Zhang X, He X, Xu X. The Role of Non-Coding RNAs in the Sorafenib Resistance of Hepatocellular Carcinoma. Front Oncol 2021; 11:696705. [PMID: 34367979 PMCID: PMC8340683 DOI: 10.3389/fonc.2021.696705] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Accepted: 06/28/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death. Sorafenib is approved by the U.S. Food and Drug Administration to be a first-line chemotherapy agent for patients with advanced HCC. A portion of advanced HCC patients can benefit from the treatment with sorafenib, but many patients ultimately develop sorafenib resistance, leading to a poor prognosis. The molecular mechanisms of sorafenib resistance are sophisticated and indefinite. Notably, non-coding RNAs (ncRNAs), which include long ncRNAs (lncRNAs), microRNAs (miRNAs) and circular RNAs (circRNAs), are critically participated in the occurrence and progression of tumors. Moreover, growing evidence has suggested that ncRNAs are crucial regulators in the development of resistance to sorafenib. Herein, we integrally and systematically summarized the molecular mechanisms and vital role of ncRNAs impact sorafenib resistance of HCC, and ultimately explored the potential clinical administrations of ncRNAs as new prognostic biomarkers and therapeutic targets for HCC.
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Affiliation(s)
- Xinyao Hu
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China.,Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Hua Zhu
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yang Shen
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China.,Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xiaoyu Zhang
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China.,Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xiaoqin He
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China.,Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Ximing Xu
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China.,Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
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32
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Romero EL, Morilla MJ. Preclinical autophagy modulatory nanomedicines: big challenges, slow advances. Expert Opin Drug Deliv 2021; 18:1415-1434. [PMID: 34030559 DOI: 10.1080/17425247.2021.1933428] [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: 12/12/2022]
Abstract
INTRODUCTION Autophagy is a critical housekeeping pathway to remove toxic protein aggregates, damaged organelles, providing cells with bioenergetic substrates needed to survive under adverse conditions. Since altered autophagy is associated with diverse diseases, its pharmacological modulation is considered of therapeutic interest. Nanomedicines may reduce the toxicity and improve the activity of toxic autophagy modulatory drugs (amd). AREAS COVERED The status of the most relevant anti-tumor, anti-inflammatory, and anti-infectious treatments mediated by autophagy modulatory nanomedicines (amN) published in the last 5 years is discussed. EXPERT OPINION Antitumor and anti-inflammatory treatments may be improved by administering amN for selective, massive, and targeted delivery of amd to diseased tissues. The use of amN as antimicrobial agent remains almost underexploited. Assessing the effect of amN on the complex autophagy machinery operating under different basal diseases, however, is not a trivial task. Besides structural reproducibility, nanomedicines must grant higher efficiency, and lower adverse effects than conventional medication. Simplicity of design, carefully chosen (scalable) preparation techniques, and rigorous monitoring of preclinical efficacy and nanotoxicity will improve the chances of clinical success. Currently, available data are not sufficient to envisage a fast-succeeding translation. Application of quality by design criteria would help to reach such milestones.
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Affiliation(s)
- Eder Lilia Romero
- Department of Science and Technology, Nanomedicines Research and Development Center, Quilmes National University, Bernal, Buenos Aires, Argentina
| | - Maria Jose Morilla
- Department of Science and Technology, Nanomedicines Research and Development Center, Quilmes National University, Bernal, Buenos Aires, Argentina
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Assessment of a New Nanostructured Microemulsion System for Ocular Delivery of Sorafenib to Posterior Segment of the Eye. Int J Mol Sci 2021; 22:ijms22094404. [PMID: 33922399 PMCID: PMC8122816 DOI: 10.3390/ijms22094404] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 04/16/2021] [Accepted: 04/21/2021] [Indexed: 12/12/2022] Open
Abstract
Eye drop formulations allowing topical treatment of retinal pathologies have long been sought as alternatives to intravitreal administration. This study aimed to assess whether a novel nanostructured microemulsions system (NaMESys) could be usefully employed to deliver sorafenib to the retina following topical instillation. NaMESys carrying 0.3% sorafenib (NaMESys-SOR) proved to be cytocompatible in vitro on rabbit corneal cells, and well-tolerated following b.i.d. ocular administration to rabbits during a 3-month study. In rats subject to retinal ischemia-reperfusion, NaMESys-SOR significantly inhibited retinal expression of tumor necrosis factor-alpha (TNFα, 20.7%) and inducible nitric oxide synthase (iNos, 87.3%) mRNAs in comparison to controls. Similarly, in streptozotocin-induced diabetic rats, NaMESys-SOR inhibited retinal expression of nuclear factor kappa B (NFκB), TNFα, insulin like growth factor 1 (IGF1), IGF1 receptor (IGF1R), vascular endothelial growth factor receptor 1 (VEGFR1) and 2 (VEGFR2) mRNAs by three-fold on average compared to controls. Furthermore, a reduction in TNFα, VEGFR1 and VEGFR2 protein expression was observed by western blot. Moreover, in mice subject to laser-induced choroidal neovascularization, NaMESys-SOR significantly inhibited neovascular lesions by 54%. In conclusion, NaMESys-SOR was shown to be a well-tolerated ophthalmic formulation able to deliver effective amounts of sorafenib to the retina, reducing proinflammatory and pro-angiogenic mediators in reliable models of proliferative retinopathies. These findings warrant further investigations on the full therapeutic potential of NaMESys-SOR eye drops, aiming to address unmet needs in the pharmacotherapy of retinal neovascular diseases.
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Chen Y, Li JX, Shu N, Zheng SJ, Ma M, Zhao ZB, Cao ZT, Zhou Q, Du JZ, Wang J. A polymeric nanoformulation improves the bioavailability and efficacy of sorafenib for hepatocellular carcinoma therapy. Biomater Sci 2021; 9:2508-2518. [PMID: 33459733 DOI: 10.1039/d0bm01881c] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Sorafenib (sfb) is widely used in clinics for advanced HCC therapy. However, the therapeutic efficacy of sfb is suboptimal due to its poor water solubility, low bioavailability, and side effects. Here, we employed a clinically safe polymer poly(ethylene glycol)-b-poly(lactic acid) (PEG-b-PLA) to prepare a nanoparticle (NP)-based sfb formulation (NP-sfb) and tested its antitumor effect in multiple HCC models. NP-sfb could achieve effective drug loading and remain stable under physiological conditions. NP-sfb could be taken up by HepG2, Hepa1-6, and H22 cells and could efficiently inhibit cell proliferation and/or promote cell apoptosis. In vivo studies indicated that NP-sfb showed significantly improved therapeutic efficacy compared with free-sfb at the same dose or even higher doses. Mechanistic studies demonstrated that NP-sfb not only inhibited tumor proliferation and angiogenesis but also stimulated the tumor microenvironment by reducing the infiltration of immunosuppressive myeloid cells and increasing the ratio of cytotoxic T cells. This study demonstrates that the NP-based formulation is a promising strategy to improve the clinical application of sfb.
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Affiliation(s)
- Yang Chen
- Guangzhou First People's Hospital, and Institutes for Life Sciences, School of Medicine, South China University of Technology, Guangzhou 510006, China.
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Lai H, Zhong L, Huang Y, Zhao Y, Qian Z. Progress in Application of Nanotechnology in Sorafenib. J Biomed Nanotechnol 2021; 17:529-557. [DOI: 10.1166/jbn.2021.3061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Dysregulation of the tyrosine kinase signaling pathway is closely related to tumor development, and tyrosine kinase inhibitors are important targets for potential anticancer strategies. In particular, sorafenib, as a representative drug of multitarget tyrosine kinase inhibitors, has
an important clinical status and is widely used for treating various solid tumors and diabetic complications. However, poor aqueous solubility of sorafenib, poor bioavailability of commonly used oral dose forms, poor accumulation at tumor sites, and severe off-target effects that tend to induce
intolerable systemic side effects in patients have greatly reduced its therapeutic efficiency and limited its extensive clinical application. To improve the properties of sorafenib, increase the efficiency of clinical treatment, and overcome the increasingly prominent phenomenon of sorafenib
resistance, multiple investigations have been conducted. Numerous studies have reported that the properties of nanomaterials, such as small particle size, large specific surface area, high surface activity and high adsorption capacity, make nanotechnology promising for the construction of
ideal sorafenib nanodelivery systems to achieve timed and targeted delivery of sorafenib to tumors, prolong the blood circulation time of the drug, improve the utilization efficiency of the drug and reduce systemic toxic side effects. This review summarizes the progress of research applications
in nanotechnology related to sorafenib, discusses the current problems, and expresses expectations for the prospect of clinical applications of sorafenib with improved performance.
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Affiliation(s)
- Huili Lai
- National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting
Theranostics, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Liping Zhong
- National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting
Theranostics, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Yong Huang
- National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting
Theranostics, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Yongxiang Zhao
- National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting
Theranostics, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Zhiyong Qian
- National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting
Theranostics, Guangxi Medical University, Nanning, Guangxi, 530021, China
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Chmurska A, Matczak K, Marczak A. Two Faces of Autophagy in the Struggle against Cancer. Int J Mol Sci 2021; 22:2981. [PMID: 33804163 PMCID: PMC8000091 DOI: 10.3390/ijms22062981] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/10/2021] [Accepted: 03/12/2021] [Indexed: 12/12/2022] Open
Abstract
Autophagy can play a double role in cancerogenesis: it can either inhibit further development of the disease or protect cells, causing stimulation of tumour growth. This phenomenon is called "autophagy paradox", and is characterised by the features that the autophagy process provides the necessary substrates for biosynthesis to meet the cell's energy needs, and that the over-programmed activity of this process can lead to cell death through apoptosis. The fight against cancer is a difficult process due to high levels of resistance to chemotherapy and radiotherapy. More and more research is indicating that autophagy may play a very important role in the development of resistance by protecting cancer cells, which is why autophagy in cancer therapy can act as a "double-edged sword". This paper attempts to analyse the influence of autophagy and cancer stem cells on tumour development, and to compare new therapeutic strategies based on the modulation of these processes.
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Affiliation(s)
- Anna Chmurska
- Doctoral School of Exact and Natural Sciences, University of Lodz, Banacha Street 12/16, 90-237 Lodz, Poland
| | - Karolina Matczak
- Department of Medical Biophysics, Faculty of Biology and Environmental Protection, Institute of Biophysics, University of Lodz, Pomorska Street 141/143, 90-236 Lodz, Poland; (K.M.); (A.M.)
| | - Agnieszka Marczak
- Department of Medical Biophysics, Faculty of Biology and Environmental Protection, Institute of Biophysics, University of Lodz, Pomorska Street 141/143, 90-236 Lodz, Poland; (K.M.); (A.M.)
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Kong FH, Ye QF, Miao XY, Liu X, Huang SQ, Xiong L, Wen Y, Zhang ZJ. Current status of sorafenib nanoparticle delivery systems in the treatment of hepatocellular carcinoma. Am J Cancer Res 2021; 11:5464-5490. [PMID: 33859758 PMCID: PMC8039945 DOI: 10.7150/thno.54822] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 02/17/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of liver cancer and one of the leading causes of cancer-related death worldwide. Advanced HCC displays strong resistance to chemotherapy, and traditional chemotherapy drugs do not achieve satisfactory therapeutic efficacy. Sorafenib is an oral kinase inhibitor that inhibits tumor cell proliferation and angiogenesis and induces cancer cell apoptosis. It also improves the survival rates of patients with advanced liver cancer. However, due to its poor solubility, fast metabolism, and low bioavailability, clinical applications of sorafenib have been substantially restricted. In recent years, various studies have been conducted on the use of nanoparticles to improve drug targeting and therapeutic efficacy in HCC. Moreover, nanoparticles have been extensively explored to improve the therapeutic efficacy of sorafenib, and a variety of nanoparticles, such as polymer, lipid, silica, and metal nanoparticles, have been developed for treating liver cancer. All these new technologies have improved the targeted treatment of HCC by sorafenib and promoted nanomedicines as treatments for HCC. This review provides an overview of hot topics in tumor nanoscience and the latest status of treatments for HCC. It further introduces the current research status of nanoparticle drug delivery systems for treatment of HCC with sorafenib.
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Ahiwale RJ, Chellampillai B, Pawar AP. Investigation of novel sorafenib tosylate loaded biomaterial based nano-cochleates dispersion system for treatment of hepatocellular carcinoma. J DISPER SCI TECHNOL 2021. [DOI: 10.1080/01932691.2021.1878034] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Raj J. Ahiwale
- Department of Pharmaceutics, Poona College of Pharmacy, Bharati Vidyapeeth University, Pune, Maharashtra, India
| | - Bothiraja Chellampillai
- Department of Pharmaceutics, Poona College of Pharmacy, Bharati Vidyapeeth University, Pune, Maharashtra, India
| | - Atmaram P. Pawar
- Department of Pharmaceutics, Poona College of Pharmacy, Bharati Vidyapeeth University, Pune, Maharashtra, India
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39
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Kouroumalis E, Voumvouraki A, Augoustaki A, Samonakis DN. Autophagy in liver diseases. World J Hepatol 2021; 13:6-65. [PMID: 33584986 PMCID: PMC7856864 DOI: 10.4254/wjh.v13.i1.6] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 12/10/2020] [Accepted: 12/26/2020] [Indexed: 02/06/2023] Open
Abstract
Autophagy is the liver cell energy recycling system regulating a variety of homeostatic mechanisms. Damaged organelles, lipids and proteins are degraded in the lysosomes and their elements are re-used by the cell. Investigations on autophagy have led to the award of two Nobel Prizes and a health of important reports. In this review we describe the fundamental functions of autophagy in the liver including new data on the regulation of autophagy. Moreover we emphasize the fact that autophagy acts like a two edge sword in many occasions with the most prominent paradigm being its involvement in the initiation and progress of hepatocellular carcinoma. We also focused to the implication of autophagy and its specialized forms of lipophagy and mitophagy in the pathogenesis of various liver diseases. We analyzed autophagy not only in well studied diseases, like alcoholic and nonalcoholic fatty liver and liver fibrosis but also in viral hepatitis, biliary diseases, autoimmune hepatitis and rare diseases including inherited metabolic diseases and also acetaminophene hepatotoxicity. We also stressed the different consequences that activation or impairment of autophagy may have in hepatocytes as opposed to Kupffer cells, sinusoidal endothelial cells or hepatic stellate cells. Finally, we analyzed the limited clinical data compared to the extensive experimental evidence and the possible future therapeutic interventions based on autophagy manipulation.
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Affiliation(s)
- Elias Kouroumalis
- Liver Research Laboratory, University of Crete Medical School, Heraklion 71110, Greece
| | - Argryro Voumvouraki
- 1 Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54636, Greece
| | - Aikaterini Augoustaki
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion 71110, Greece
| | - Dimitrios N Samonakis
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion 71110, Greece.
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40
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Toden S, Zumwalt TJ, Goel A. Non-coding RNAs and potential therapeutic targeting in cancer. Biochim Biophys Acta Rev Cancer 2021; 1875:188491. [PMID: 33316377 PMCID: PMC7856203 DOI: 10.1016/j.bbcan.2020.188491] [Citation(s) in RCA: 175] [Impact Index Per Article: 43.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 12/02/2020] [Accepted: 12/02/2020] [Indexed: 12/11/2022]
Abstract
Recent advances have begun to clarify the physiological and pathological roles of non-coding RNAs (ncRNAs) in various diseases, including cancer. Among these, microRNAs (miRNAs) have been the most studied and have emerged as key players that are involved in the regulation of important growth regulatory pathways in cancer pathogenesis. The ability of a single ncRNA to modulate the expression of multiple downstream gene targets and associated pathways, have provided a rationale to pursue them for therapeutic drug development in cancer. In this context, early data from pre-clinical studies have demonstrated that synthetic miRNA-based therapeutic molecules, along with various protective coating approaches, has allowed for their efficient delivery and anti-tumor activity. In fact, some of the miRNA-based cancer therapeutic strategies have shown promising results even in early-phase human clinical trials. While the enthusiasm for ncRNA-based cancer therapeutics continue to evolve, the field is still in the midst of unraveling a more precise understanding of the molecular mechanisms and specific downstream therapeutic targets of other lesser studied ncRNAs such as the long-non-coding RNAs, transfer RNAs, circular RNAs, small nucleolar RNAs, and piwi-interacting RNAs. This review article provides the current state of knowledge and the evolving principles for ncRNA-based therapeutic approaches in cancer, and specifically highlights the importance of data to date and the approaches that are being developed to overcome the challenges associated with their delivery and mitigating the off-target effects in human cancers.
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Affiliation(s)
- Shusuke Toden
- Center for Gastrointestinal Research; Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, USA
| | - Timothy J Zumwalt
- Center for Gastrointestinal Research; Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, USA
| | - Ajay Goel
- Center for Gastrointestinal Research; Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, USA; Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
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41
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Ezhilarasan D. Advantages and challenges in nanomedicines for chronic liver diseases: A hepatologist's perspectives. Eur J Pharmacol 2021; 893:173832. [PMID: 33359144 DOI: 10.1016/j.ejphar.2020.173832] [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] [Received: 10/17/2020] [Revised: 12/01/2020] [Accepted: 12/18/2020] [Indexed: 12/11/2022]
Abstract
Chronic liver diseases (CLD) are responsible for significant morbidity and mortality worldwide. CLD patients are at a high risk of developing progressive liver fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and subsequent liver failure. To date, there is no specific and effective therapies exist for patients with various forms of CLD. The application of nanotechnology has emerged as a rapidly developing area of interest for the safe and target-specific delivery of poorly aqueous soluble hepatoprotective agents and nucleic acids (siRNA/miRNAs) in CLD. The nanoparticle combination improves bioavailability and plasma stability of drugs with poor aqueous solubility. However, the extent of successful functional delivery of nanoparticles into hepatocytes is often surprisingly low. High Kupffer cells interaction reduces the nanomedicine efficacy. During fibrosis, the extracellular matrix accumulation in the perisinusoidal space restricts nanoparticle delivery to hepatocytes. The availability and uptake of nanoparticles exposure to different cells in the liver microenvironment is as Kupffer cells > sinusoidal endothelial cells > HSCs > hepatocytes. The most widely used strategy to reduce nanoparticles and macrophages interaction is to coat the particle surface with polyethylene glycol. The cationic charged nanoparticles have increased hepatocyte delivery by increased cellular interaction by disrupting the endosomal system via their pH buffering capacity. The immune clearance and toxicity of nanoparticles are mainly unpredictable. Therefore, more elaborate knowledge on exact cellular uptake and intracellular accumulation, trafficking, and endosomal sorting of nanoparticle is the need of the hour to improve the rational carrier design.
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Affiliation(s)
- Devaraj Ezhilarasan
- Department of Pharmacology, Drug and Molecular Medicine Laboratory (The Blue Lab), Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), No.162, PH Road, Chennai, Tamil Nadu, 600 077, India.
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42
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Li Q, Huyan T, Cai S, Huang Q, Zhang M, Peng H, Zhang Y, Liu N, Zhang W. The role of exosomal miR-375-3p: A potential suppressor in bladder cancer via the Wnt/β-catenin pathway. FASEB J 2020; 34:12177-12196. [PMID: 32716585 DOI: 10.1096/fj.202000347r] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 06/09/2020] [Accepted: 06/29/2020] [Indexed: 12/24/2022]
Abstract
miR-375-3p is a significantly downregulated miRNA in bladder cancer (BC). However, its role in BC regulation is still unclear. In this study, we reported that miR-375-3p overexpression inhibited proliferation and migration and promoted apoptosis in BC cells. Frizzled-8 (FZD8) gene is identified as the direct miR-375-3p targeting gene. miR-375-3p blocks the Wnt/β-catenin pathway and downstream molecules Cyclin D1 and c-Myc by inhibiting the expression of FZD8 directly, it could increase caspase 1 and caspase 3 expression and promote T24 cell apoptosis as well. miR-375-3p also showed a significant inhibitory effect in vivo in bladder tumor-bearing nude mice, as demonstrated by the reduced tumor volume and Ki67 proliferation index in tumor tissue. Collectively, miR-375-3p is a suppressor of BC that inhibits proliferation and metastasis, and promotes apoptosis in BC cells as well as suppresses tumor growth in a T24 xenograft mouse model, which could be used as a potential therapeutic approach for BC in future.
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Affiliation(s)
- Qi Li
- Key Laboratory for Space Bioscience and Space Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Ting Huyan
- Key Laboratory for Space Bioscience and Space Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China.,Institute of Flexible Electronics, Northwestern Polytechnical University, Xi'an, China
| | - Suna Cai
- Key Laboratory for Space Bioscience and Space Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Qiuping Huang
- Key Laboratory for Space Bioscience and Space Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Mengzhao Zhang
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Hourong Peng
- Key Laboratory for Space Bioscience and Space Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Yujun Zhang
- Key Laboratory for Space Bioscience and Space Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Ningjing Liu
- Key Laboratory for Space Bioscience and Space Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Wei Zhang
- Department of Anesthesiology, Henan Provincial People's Hospital (People's Hospital of Zhengzhou University), Zhengzhou, China
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43
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Xu WP, Liu JP, Feng JF, Zhu CP, Yang Y, Zhou WP, Ding J, Huang CK, Cui YL, Ding CH, Zhang X, Lu B, Xie WF. miR-541 potentiates the response of human hepatocellular carcinoma to sorafenib treatment by inhibiting autophagy. Gut 2020; 69:1309-1321. [PMID: 31727683 DOI: 10.1136/gutjnl-2019-318830] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 10/15/2019] [Accepted: 10/23/2019] [Indexed: 12/23/2022]
Abstract
OBJECTIVE Autophagy participates in the progression of hepatocellular carcinoma (HCC) and the resistance of HCC cells to sorafenib. We investigated the feasibility of sensitising HCC cells to sorafenib by modulating miR-541-initiated microRNA-autophagy axis. DESIGN Gain- and loss-of-function assays were performed to evaluate the effects of miR-541 on the malignant properties and autophagy of human HCC cells. Autophagy was quantified by western blotting of LC3, transmission electron microscopy analyses and confocal microscopy scanning of mRFP-GFP-LC3 reporter construct. Luciferase reporter assays were conducted to confirm the targets of miR-541. HCC xenograft tumours were established to analyse the role of miR-541 in sorafenib-induced lethality. RESULTS The expression of miR-541 was downregulated in human HCC tissues and was associated with malignant clinicopathologic phenotypes, recurrence and survival of patients with HCC. miR-541 inhibited the growth, metastasis and autophagy of HCC cells both in vitro and in vivo. Prediction software and luciferase reporter assays identified autophagy-related gene 2A (ATG2A) and Ras-related protein Rab-1B (RAB1B) as the direct targets of miR-541. Consistent with the effects of the miR-541 mimic, inhibition of ATG2A or RAB1B suppressed the malignant phenotypes and autophagy of HCC cells. Furthermore, siATG2A and siRAB1B partially reversed the enhancement of the malignant properties and autophagy in HCC cells mediated by the miR-541 inhibitor. More interestingly, higher miR-541 expression predicted a better response to sorafenib treatment, and the combination of miR-541 and sorafenib further suppressed the growth of HCC cells in vivo compared with the single treatment. CONCLUSIONS Dysregulation of miR-541-ATG2A/RAB1B axis plays a critical role in patients' responses to sorafenib treatment. Manipulation of this axis might benefit survival of patients with HCC, especially in the context of the highly pursued strategies to eliminate drug resistance.
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Affiliation(s)
- Wen-Ping Xu
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Jin-Pei Liu
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Ji-Feng Feng
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Chang-Peng Zhu
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Yuan Yang
- Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Wei-Ping Zhou
- Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Jin Ding
- The International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Institute, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Chen-Kai Huang
- Department of Gastroenterology, First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Ya-Lu Cui
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Chen-Hong Ding
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Xin Zhang
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Bin Lu
- Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Wei-Fen Xie
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
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44
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Liang Y, Liang Q, Qiao L, Xiao F. MicroRNAs Modulate Drug Resistance-Related Mechanisms in Hepatocellular Carcinoma. Front Oncol 2020; 10:920. [PMID: 32695666 PMCID: PMC7338562 DOI: 10.3389/fonc.2020.00920] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Accepted: 05/11/2020] [Indexed: 12/24/2022] Open
Abstract
Primary liver cancer [hepatocellular carcinoma (HCC)] is one of the most common malignant tumors worldwide, causing serious health threats because of its high morbidity and mortality, rapid growth, and strong invasiveness. Patients with HCC frequently develop resistance to the current chemotherapeutic drugs, and this is largely attributed to the high-level heterogeneity of the tumor tissue. MicroRNAs (miRNAs) are a group of master regulators for multiple physiological and pathological processes and play important roles in the tumorigenesis. More recent studies have indicated that miRNAs also play a non-negligible role in the development of drug resistance in liver cancer. In this review, we summarize the data from the latest studies on the mechanisms of drug resistance in liver cancer, including autophagy, membrane transporters, epithelial-mesenchymal transitions (EMTs), tumor microenvironment, and genes and proteins that are associated with apoptosis. The data herein will provide valuable information for the development of novel approaches to tackle drug resistance in the management of liver cancer.
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Affiliation(s)
- Yuehui Liang
- Department of Health Toxicology, Xiangya School of Public Health, Central South University, Changsha, China
| | - Qi Liang
- Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Liang Qiao
- Storr Liver Center, Westmead Institute for Medical Research, University of Sydney and Westmead Hospital, Westmead, NSW, Australia
| | - Fang Xiao
- Department of Health Toxicology, Xiangya School of Public Health, Central South University, Changsha, China
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45
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Cheng Z, Wei-Qi J, Jin D. New insights on sorafenib resistance in liver cancer with correlation of individualized therapy. Biochim Biophys Acta Rev Cancer 2020; 1874:188382. [PMID: 32522600 DOI: 10.1016/j.bbcan.2020.188382] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 05/11/2020] [Accepted: 05/28/2020] [Indexed: 12/19/2022]
Abstract
Liver cancer is highly malignant and insensitive to cytotoxic chemotherapy and is associated with very poor patient prognosis. In 2007, the small-molecule targeted drug sorafenib was approved for the treatment of advanced liver cancer. In the subsequent ten years, sorafenib has been the only first-line therapeutic targeted drug for advanced hepatocellular carcinoma (HCC). However, a number of clinical studies show that a considerable percentage of patients with liver cancer are insensitive to sorafenib. The number of patients who actually benefit significantly from sorafenib treatment is very limited, and the overall efficacy of sorafenib is far from satisfactory, which has attracted the attention of researchers. Based on previous studies and reports, this article reviews the potential mechanisms of sorafenib resistance (SR) and summarizes the biomarkers and clinicopathological indicators that might be used for predicting sorafenib response and developing personalized therapy.
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Affiliation(s)
- Zhang Cheng
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai 200433, China; National Center for Liver Cancer, Shanghai 200433, China
| | - Jiang Wei-Qi
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai 200433, China
| | - Ding Jin
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai 200433, China; National Center for Liver Cancer, Shanghai 200433, China.
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46
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Li H, Li Z, Pi Y, Chen Y, Mei L, Luo Y, Xie J, Mao X. MicroRNA-375 exacerbates knee osteoarthritis through repressing chondrocyte autophagy by targeting ATG2B. Aging (Albany NY) 2020; 12:7248-7261. [PMID: 32335541 PMCID: PMC7202526 DOI: 10.18632/aging.103073] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 03/24/2020] [Indexed: 12/12/2022]
Abstract
Objective: This study aimed to explore the underlying mechanism of miR-375 in exacerbating osteoarthritis (OA). Results: MiR-375 expression were upregulated in OA cartilage tissues, whereas ATG2B expression was decreased. MiR-375 targeted ATG2B 3’ UTR and inhibited its expression in the chondrocytes, and then suppressed autophagy and promoted endoplasmic reticulum stress (ERs). The apoptosis rate of chondrocytes was increased after being transfected with miR-375 mimics. In vivo results further verified that inhibition of miR-375 could relieve OA-related symptoms. Conclusion: miR-375 can inhibit the expression of ATG2B in chondrocytes, suppress autophagy and promote the ERs. It suggests that miR-375 could be considered to be a key therapy target for OA. Methods: Differential expression analyses for mRNA and miRNA microarray datasets from ArrayExpress were performed. MiR-375 and ATG2B expressions in cartilage tissues were detected by qRT-PCR. Dual luciferase assay was applied to verify the targeting relationship between ATG2B and miR-375. In vitro, the role of miR-375 on chondrocyte autophagy and ERs was investigated by western blot and immunofluorescence. The apoptotic rate was quantified by flow cytometry. In vivo, OA mice model was established, HE and Safranin O and Fast Green staining, as well as the OARSI and modified Mankin scores, were applied to measure the OA cartilage damage severity.
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Affiliation(s)
- Hongxing Li
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Zhiling Li
- Center of Health Management, The Central Hospital of Shaoyang, Shaoyang 422000, Hunan, China
| | - Yigang Pi
- Department of Orthopedics, The Central Hospital of Shaoyang, Shaoyang 422000, Hunan, China
| | - Yang Chen
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Lin Mei
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Yong Luo
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Jingping Xie
- Department of Orthopedics, The Central Hospital of Shaoyang, Shaoyang 422000, Hunan, China
| | - Xinzhan Mao
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
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Ozcan M, Altay O, Lam S, Turkez H, Aksoy Y, Nielsen J, Uhlen M, Boren J, Mardinoglu A. Improvement in the Current Therapies for Hepatocellular Carcinoma Using a Systems Medicine Approach. ACTA ACUST UNITED AC 2020; 4:e2000030. [PMID: 32529800 DOI: 10.1002/adbi.202000030] [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: 01/24/2020] [Revised: 03/02/2020] [Accepted: 03/09/2020] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death primarily due to the lack of effective targeted therapies. Despite the distinct morphological and phenotypic patterns of HCC, treatment strategies are restricted to relatively homogeneous therapies, including multitargeted tyrosine kinase inhibitors and immune checkpoint inhibitors. Therefore, more effective therapy options are needed to target dysregulated metabolic and molecular pathways in HCC. Integrative genomic profiling of HCC patients provides insight into the most frequently mutated genes and molecular targets, including telomerase reverse transcriptase, the TP53 gene, and the Wnt/β-catenin signaling pathway oncogene (CTNNB1). Moreover, emerging techniques, such as genome-scale metabolic models may elucidate the underlying cancer-specific metabolism, which allows for the discovery of potential drug targets and identification of biomarkers. De novo lipogenesis has been revealed as consistently upregulated since it is required for cell proliferation in all HCC patients. The metabolic network-driven stratification of HCC patients in terms of redox responses, utilization of metabolites, and subtype-specific pathways may have clinical implications to drive the development of personalized medicine. In this review, the current and emerging therapeutic targets in light of molecular approaches and metabolic network-based strategies are summarized, prompting effective treatment of HCC patients.
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Affiliation(s)
- Mehmet Ozcan
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, SE 17121, Sweden.,Department of Medical Biochemistry, Faculty of Medicine, Hacettepe University, Ankara, 06100, Turkey
| | - Ozlem Altay
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, SE 17121, Sweden
| | - Simon Lam
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, SE1 9RT, UK
| | - Hasan Turkez
- Department of Medical Biology, Faculty of Medicine, Atatürk University, Erzurum, 25240, Turkey
| | - Yasemin Aksoy
- Department of Medical Biochemistry, Faculty of Medicine, Hacettepe University, Ankara, 06100, Turkey
| | - Jens Nielsen
- Prof. J. Nielsen, Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, SE-41296, Sweden
| | - Mathias Uhlen
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, SE 17121, Sweden
| | - Jan Boren
- Department of Molecular and Clinical Medicine, University of Gothenburg, The Wallenberg Laboratory, Sahlgrenska University Hospital, Gothenburg, SE-413 45, Sweden
| | - Adil Mardinoglu
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, SE 17121, Sweden.,Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, SE1 9RT, UK
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48
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Liu T, Zhang J, Li K, Deng L, Wang H. Combination of an Autophagy Inducer and an Autophagy Inhibitor: A Smarter Strategy Emerging in Cancer Therapy. Front Pharmacol 2020; 11:408. [PMID: 32322202 PMCID: PMC7156970 DOI: 10.3389/fphar.2020.00408] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 03/18/2020] [Indexed: 01/08/2023] Open
Abstract
Autophagy is considered a cytoprotective function in cancer therapy under certain conditions and is a drug resistance mechanism that represents a clinical obstacle to successful cancer treatment and leads to poor prognosis in cancer patients. Because certain clinical drugs and agents in development have cytoprotective autophagy effects, targeting autophagic pathways has emerged as a potential smarter strategy for cancer therapy. Multiple preclinical and clinical studies have demonstrated that autophagy inhibition augments the efficacy of anticancer agents in various cancers. Autophagy inhibitors, such as chloroquine and hydroxychloroquine, have already been clinically approved, promoting drug combination treatment by targeting autophagic pathways as a means of discovering and developing more novel and more effective cancer therapeutic approaches. We summarize current studies that focus on the antitumor efficiency of agents that induce cytoprotective autophagy combined with autophagy inhibitors. Furthermore, we discuss the challenge and development of targeting cytoprotective autophagy as a cancer therapeutic approach in clinical application. Thus, we need to facilitate the exploitation of appropriate autophagy inhibitors and coadministration delivery system to cooperate with anticancer drugs. This review aims to note optimal combination strategies by modulating autophagy for therapeutic advantage to overcome drug resistance and enhance the effect of antitumor therapies on cancer patients.
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Affiliation(s)
- Ting Liu
- The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Zhang
- The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kangdi Li
- College of Life Sciences, Wuhan University, Wuhan, China
| | - Lingnan Deng
- Department of Digestion, The Second Affiliated Hospital of Jiangxi University TCM, Nanchang, China
| | - Hongxiang Wang
- The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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49
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Xu F, Ye ML, Zhang YP, Li WJ, Li MT, Wang HZ, Qiu X, Xu Y, Yin JW, Hu Q, Wei WH, Chang Y, Liu L, Zhao Q. MicroRNA-375-3p enhances chemosensitivity to 5-fluorouracil by targeting thymidylate synthase in colorectal cancer. Cancer Sci 2020; 111:1528-1541. [PMID: 32073706 PMCID: PMC7226198 DOI: 10.1111/cas.14356] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 02/04/2020] [Accepted: 02/06/2020] [Indexed: 12/19/2022] Open
Abstract
Resistance to chemotherapy is a major challenge for the treatment of patients with colorectal cancer (CRC). Previous studies have found that microRNAs (miRNAs) play key roles in drug resistance; however, the role of miRNA‐373‐3p (miR‐375‐3p) in CRC remains unclear. The current study aimed to explore the potential function of miR‐375‐3p in 5‐fluorouracil (5‐FU) resistance. MicroRNA‐375‐3p was found to be widely downregulated in human CRC cell lines and tissues and to promote the sensitivity of CRC cells to 5‐FU by inducing colon cancer cell apoptosis and cycle arrest and by inhibiting cell growth, migration, and invasion in vitro. Thymidylate synthase (TYMS) was found to be a direct target of miR‐375‐3p, and TYMS knockdown exerted similar effects as miR‐375‐3p overexpression on the CRC cellular response to 5‐FU. Lipid‐coated calcium carbonate nanoparticles (NPs) were designed to cotransport 5‐FU and miR‐375‐3p into cells efficiently and rapidly and to release the drugs in a weakly acidic tumor microenvironment. The therapeutic effect of combined miR‐375 + 5‐FU/NPs was significantly higher than that of the individual treatments in mouse s.c. xenografts derived from HCT116 cells. Our results suggest that restoring miR‐375‐3p levels could be a future novel therapeutic strategy to enhance chemosensitivity to 5‐FU.
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Affiliation(s)
- Fei Xu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
| | - Ming-Liang Ye
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
| | - Yu-Peng Zhang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
| | - Wen-Jie Li
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
| | - Meng-Ting Li
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
| | - Hai-Zhou Wang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
| | - Xiao Qiu
- Department of Hematology, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, Shenzhen, China
| | - Yan Xu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
| | - Jin-Wen Yin
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
| | - Qian Hu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
| | - Wan-Hui Wei
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
| | - Ying Chang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
| | - Lan Liu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
| | - Qiu Zhao
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
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Liver Cancer: Current and Future Trends Using Biomaterials. Cancers (Basel) 2019; 11:cancers11122026. [PMID: 31888198 PMCID: PMC6966667 DOI: 10.3390/cancers11122026] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 12/11/2019] [Accepted: 12/13/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common type of cancer diagnosed and the second leading cause of death worldwide. Despite advancement in current treatments for HCC, the prognosis for this cancer is still unfavorable. This comprehensive review article focuses on all the current technology that applies biomaterials to treat and study liver cancer, thus showing the versatility of biomaterials to be used as smart tools in this complex pathologic scenario. Specifically, after introducing the liver anatomy and pathology by focusing on the available treatments for HCC, this review summarizes the current biomaterial-based approaches for systemic delivery and implantable tools for locally administrating bioactive factors and provides a comprehensive discussion of the specific therapies and targeting agents to efficiently deliver those factors. This review also highlights the novel application of biomaterials to study HCC, which includes hydrogels and scaffolds to tissue engineer 3D in vitro models representative of the tumor environment. Such models will serve to better understand the tumor biology and investigate new therapies for HCC. Special focus is given to innovative approaches, e.g., combined delivery therapies, and to alternative approaches-e.g., cell capture-as promising future trends in the application of biomaterials to treat HCC.
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