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Sharma R, Kashyap M, Zayed H, Krishnia L, Kashyap MK. Artificial blood-hope and the challenges to combat tumor hypoxia for anti-cancer therapy. Med Biol Eng Comput 2025; 63:933-957. [PMID: 39614063 DOI: 10.1007/s11517-024-03233-6] [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: 03/13/2024] [Accepted: 10/22/2024] [Indexed: 12/01/2024]
Abstract
The blood plays a vital role in the human body and serves as an intermediary between various physiological systems and organs. White blood cells, which are a part of the immune system, defend against infections and regulate the body temperature and pH balance. Blood platelets play a crucial role in clotting, the prevention of excessive bleeding, and the promotion of healing. Blood also serves as a courier system that transports hormones to facilitate communication and synchronization between different organs and systems in the body. The circulatory system, comprised of arteries, veins, and capillaries, plays a crucial role in the efficient transportation and connection of vital nutrients and oxygen. Despite the importance of natural blood, there are often supply shortages, compatibility issues, and medical conditions, which make alternatives such as artificial blood necessary. This is particularly relevant in cancer treatment, which was the focus of our study. In this study, we investigated the potential of artificial blood in cancer therapy, specifically to address tumor hypoxia. We also examined the potential of red blood cell substitutes such as hemoglobin-based oxygen carriers and perfluorocarbons. Additionally, we examined the production of hemoglobin using E. coli and the role of hemoglobin in oncogenesis. Furthermore, we explored the potential use of artificial platelets for cancer treatment. Our study emphasizes the significance of artificial blood in improving cancer treatment outcomes.
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Affiliation(s)
- Rishabh Sharma
- Amity Stem Cell Institute, Amity Medical School, Amity University Haryana, Amity Education Valley, Panchgaon, Manesar (Gurugram), Haryana, 122413, India
| | - Manju Kashyap
- Amity Stem Cell Institute, Amity Medical School, Amity University Haryana, Amity Education Valley, Panchgaon, Manesar (Gurugram), Haryana, 122413, India
| | - Hatem Zayed
- Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha, Qatar
| | - Lucky Krishnia
- Amity Institute of Nanotechnology, Amity School of Applied Sciences, Amity University Haryana, Panchgaon, Manesar (Gurugram), Haryana, 122413, India.
| | - Manoj Kumar Kashyap
- Amity Stem Cell Institute, Amity Medical School, Amity University Haryana, Amity Education Valley, Panchgaon, Manesar (Gurugram), Haryana, 122413, India.
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Xu Y, Zhu K, Wu J, Zheng S, Zhong R, Zhou W, Cao Y, Liu J, Wang H. HBOC alleviated tumour hypoxia during radiotherapy more intensely in large solid tumours than regular ones. ARTIFICIAL CELLS, NANOMEDICINE, AND BIOTECHNOLOGY 2024; 52:1-14. [PMID: 37994792 DOI: 10.1080/21691401.2023.2276768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Accepted: 09/07/2023] [Indexed: 11/24/2023]
Abstract
Radiotherapy (RT) is a highly valuable method in cancer therapy, but its therapeutic efficacy is limited by its side effects and tumour radiation resistance. The resistance is mainly induced by hypoxia in the tumour microenvironment (TME). As a nano-oxygen carrier, Haemoglobin-based oxygen carriers (HBOCs) administration is a promising strategy to alleviate tumour hypoxia which may remodel TME to ameliorate radiation resistance and enable RT more effective. In this study, we administered fractionated RT combined with HBOC to treat Miapaca-2 cell and Hela cell xenografts on nude mice. The study found that HBOC relieved hypoxic environment and down-regulate expression of hypoxia-inducible factor-1α (Hif-1α) both in regular (100 mm3) and large (360/400 mm3) tumours. The proliferation and metastasis of tumour tissue also decreased after HBOC application. Nevertheless, in vivo RT combined with HBOC performed more effectively to suppress tumour growth in large tumours than in regular tumours. This is due to more severe hypoxic regions exist in the large solid tumours compared to the regular counterparts, and HBOC administration may be more effective in alleviating hypoxia in large tumours. Thus, HBOC sensitization therapy is more suitable for large solid tumours.
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Affiliation(s)
- Yingcan Xu
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences, Peking Union Medical College, Chengdu, China
| | - Kehui Zhu
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences, Peking Union Medical College, Chengdu, China
| | - Jiakang Wu
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences, Peking Union Medical College, Chengdu, China
| | - Shifan Zheng
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences, Peking Union Medical College, Chengdu, China
| | - Rui Zhong
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences, Peking Union Medical College, Chengdu, China
| | - Wentao Zhou
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences, Peking Union Medical College, Chengdu, China
| | - Ye Cao
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences, Peking Union Medical College, Chengdu, China
| | - Jiaxin Liu
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences, Peking Union Medical College, Chengdu, China
| | - Hong Wang
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences, Peking Union Medical College, Chengdu, China
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Vaghari-Tabari M, Qujeq D, Hashemzadeh MS. Long noncoding RNAs as potential targets for overcoming chemoresistance in upper gastrointestinal cancers. Biomed Pharmacother 2024; 179:117368. [PMID: 39214010 DOI: 10.1016/j.biopha.2024.117368] [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: 05/27/2024] [Revised: 08/16/2024] [Accepted: 08/26/2024] [Indexed: 09/04/2024] Open
Abstract
In the last decade, researchers have paid much attention to the role of noncoding RNA molecules in human diseases. Among the most important of these molecules are LncRNAs, which are RNA molecules with a length of more than 200 nucleotides. LncRNAs can regulate gene expression through various mechanisms, such as binding to DNA sequences and interacting with miRNAs. Studies have shown that LncRNAs may be valuable therapeutic targets in treating various cancers, including upper-gastrointestinal cancers. Upper gastrointestinal cancers, mainly referring to esophageal and gastric cancers, are among the deadliest gastrointestinal cancers. Despite notable advances, traditional chemotherapy remains a common strategy for treating these cancers. However, chemoresistance poses a significant obstacle to the effective treatment of upper gastrointestinal cancers, resulting in a low survival rate. Chemoresistance arises from various events, such as the enhancement of efflux and detoxification of chemotherapy agents, reduction of drug uptake, alteration of drug targeting, reduction of prodrug activation, strengthening of EMT and stemness, and the attenuation of apoptosis in cancerous cells. Tumor microenvironment also plays an important role in chemoresistance. Interestingly, a series of studies have revealed that LncRNAs can influence important mechanisms associated with some of the aforementioned events and may serve as promising targets for mitigating chemoresistance in upper gastrointestinal cancers. In this review paper, following a concise overview of chemoresistance mechanisms in upper gastrointestinal cancers, we will review the most intriguing findings of these investigations in detail.
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Affiliation(s)
- Mostafa Vaghari-Tabari
- Department of Paramedicine, Amol School of Paramedical Sciences, Mazandaran University of Medical Sciences, Sari, Iran
| | - Durdi Qujeq
- Cellular and Molecular Biology Research Center (CMBRC), Health Research Institute, Babol University of Medical Sciences, Babol, Iran; Department of Clinical Biochemistry, Babol University of Medical Sciences, Babol, Iran
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Zhou W, Li S, Hao S, Xie X, Zhang H, Liu J, Wang H, Yang C. Preparation and exchange transfusion effect of a double polymerization human umbilical cord haemoglobin of red blood cell substitute. ARTIFICIAL CELLS, NANOMEDICINE, AND BIOTECHNOLOGY 2023; 51:286-296. [PMID: 37224191 DOI: 10.1080/21691401.2023.2201599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/28/2022] [Accepted: 04/04/2023] [Indexed: 05/26/2023]
Abstract
The development of haemoglobin-based oxygen carrier (HBOC) is an excellent supplement to pre-hospital emergency blood transfusions. In this study, a new type of HBOC was prepared by using human cord haemoglobin (HCHb) and glutaraldehyde (GDA) and Bis(3,5-dibromosalicyl) fumarate (DBBF) to modify (DBBF-GDA-HCHb), the changes of physicochemical indexes during its preparation were evaluated, while a traditional type of GDA-HCHb was prepared, and the oxygen-carrying capacity of two type of HBOC was evaluated by a rat model of 135.0% exchange transfusion (ET). Eighteen SD male rats were selected, and were randomly divided into control group (5.0% albumin), DBBF-GDA-HCHb group and GDA-HCHb group. The 12 h survival rate of the C group was 16.67%, and the two HBOC groups were both 83.33%. Compared with GDA-HCHb, DBBF-GDA-HCHb can reduce lactic acid content by supplying oxygen to hypoxic tissues in a more timely manner, and can also can improve the reduction of MAP due to ischaemia.
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Affiliation(s)
- Wentao Zhou
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences, Chengdu, PR China
| | - Shen Li
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences, Chengdu, PR China
| | - Shasha Hao
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences, Chengdu, PR China
| | - Xintong Xie
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences, Chengdu, PR China
| | - Honghui Zhang
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences, Chengdu, PR China
| | - Jiaxin Liu
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences, Chengdu, PR China
| | - Hong Wang
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences, Chengdu, PR China
| | - Chengmin Yang
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences, Chengdu, PR China
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Luan S, Zeng X, Zhang C, Qiu J, Yang Y, Mao C, Xiao X, Zhou J, Zhang Y, Yuan Y. Advances in Drug Resistance of Esophageal Cancer: From the Perspective of Tumor Microenvironment. Front Cell Dev Biol 2021; 9:664816. [PMID: 33816512 PMCID: PMC8017339 DOI: 10.3389/fcell.2021.664816] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Accepted: 02/28/2021] [Indexed: 02/05/2023] Open
Abstract
Drug resistance represents the major obstacle to get the maximum therapeutic benefit for patients with esophageal cancer since numerous patients are inherently or adaptively resistant to therapeutic agents. Notably, increasing evidence has demonstrated that drug resistance is closely related to the crosstalk between tumor cells and the tumor microenvironment (TME). TME is a dynamic and ever-changing complex biological network whose diverse cellular and non-cellular components influence hallmarks and fates of tumor cells from the outside, and this is responsible for the development of resistance to conventional therapeutic agents to some extent. Indeed, the formation of drug resistance in esophageal cancer should be considered as a multifactorial process involving not only cancer cells themselves but cancer stem cells, tumor-associated stromal cells, hypoxia, soluble factors, extracellular vesicles, etc. Accordingly, combination therapy targeting tumor cells and tumor-favorable microenvironment represents a promising strategy to address drug resistance and get better therapeutic responses for patients with esophageal cancer. In this review, we mainly focus our discussion on molecular mechanisms that underlie the role of TME in drug resistance in esophageal cancer. We also discuss the opportunities and challenges for therapeutically targeting tumor-favorable microenvironment, such as membrane proteins, pivotal signaling pathways, and cytokines, to attenuate drug resistance in esophageal cancer.
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Affiliation(s)
- Siyuan Luan
- Department of Thoracic Surgery, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoxi Zeng
- West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China
| | - Chao Zhang
- West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China
| | - Jiajun Qiu
- West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yushang Yang
- Department of Thoracic Surgery, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Chengyi Mao
- Department of Thoracic Surgery, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Xin Xiao
- Department of Thoracic Surgery, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Jianfeng Zhou
- Department of Thoracic Surgery, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Yonggang Zhang
- Department of Periodical Press, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
- Nursing Key Laboratory of Sichuan Province, Chengdu, China
| | - Yong Yuan
- Department of Thoracic Surgery, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
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Lucas A, Belcher DA, Munoz C, Williams AT, Palmer AF, Cabrales P. Polymerized human hemoglobin increases the effectiveness of cisplatin-based chemotherapy in non-small cell lung cancer. Oncotarget 2020; 11:3770-3781. [PMID: 33144918 PMCID: PMC7584239 DOI: 10.18632/oncotarget.27776] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 06/15/2020] [Indexed: 11/25/2022] Open
Abstract
Cisplatin is a promising therapeutic for the treatment of non-small cell lung cancer (NSCLC). Unfortunately, a significant portion of NSCLC patients relapse due to cisplatin chemoresistance. This chemoresistance is thought to be primarily associated with hypoxia in the tumor microenvironment. Administration of hemoglobin (Hb)-based oxygen (O2) carriers (HBOCs) is a promising strategy to alleviate hypoxia in the tumor, which may make cisplatin more effective. In this study, we administered a high O2 affinity, relaxed state (R-state) polymerized hemoglobin (PolyHb) to three different NSCLC cell lines cultured in vitro and implanted in vivo into healthy mice. The R-state PolyHb administered in this study is unable to deliver O2 unless under severe hypoxia which significantly limits its oxygenation potential. In vitro sensitivity studies indicate that the administration of PolyHb increases the effectiveness of cisplatin under hypoxic conditions. Additional animal studies revealed that co-administration of PolyHb with cisplatin attenuated tumor growth without alleviating hypoxia. Analysis of reactive O2 species production in the presence of hypoxic culture indicates that exogenous ROS production by oxidized PolyHb may the mechanism of chemosensitization. This ROS mechanism, coupled with oxygenation, may be a potential chemosensitizing strategy for use in NSCLC treatment.
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Affiliation(s)
- Alfredo Lucas
- Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA
| | - Donald A. Belcher
- William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH 43210, USA
| | - Carlos Munoz
- Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA
| | - Alexander T. Williams
- Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA
| | - Andre F. Palmer
- William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH 43210, USA
| | - Pedro Cabrales
- Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA
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Belcher DA, Lucas A, Cabrales P, Palmer AF. Tumor vascular status controls oxygen delivery facilitated by infused polymerized hemoglobins with varying oxygen affinity. PLoS Comput Biol 2020; 16:e1008157. [PMID: 32817659 PMCID: PMC7462268 DOI: 10.1371/journal.pcbi.1008157] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 09/01/2020] [Accepted: 07/16/2020] [Indexed: 11/19/2022] Open
Abstract
Oxygen (O2) delivery facilitated by hemoglobin (Hb)-based O2 carriers (HBOCs) is a promising strategy to increase the effectiveness of chemotherapeutics for treatment of solid tumors. However, the heterogeneous vascular structures present within tumors complicates evaluating the oxygenation potential of HBOCs within the tumor microenvironment. To account for spatial variations in the vasculature and tumor tissue that occur during tumor growth, we used a computational model to develop artificial tumor constructs. With these simulated tumors, we performed a polymerized human hemoglobin (hHb) (PolyhHb) enhanced oxygenation simulation accounting for differences in the physiologic characteristics of human and mouse blood. The results from this model were used to determine the potential effectiveness of different treatment options including a top load (low volume) and exchange (large volume) infusion of a tense quaternary state (T-State) PolyhHb, relaxed quaternary state (R-State) PolyhHb, and a non O2 carrying control. Principal component analysis (PCA) revealed correlations between the different regimes of effectiveness within the different simulated dosage options. In general, we found that infusion of T-State PolyhHb is more likely to decrease tissue hypoxia and modulate the metabolic rate of O2 consumption. Though the developed models are not a definitive descriptor of O2 carrier interaction in tumor capillary networks, we accounted for factors such as non-uniform vascular density and permeability that limit the applicability of O2 carriers during infusion. Finally, we have used these validated computational models to establish potential benchmarks to guide tumor treatment during translation of PolyhHb mediated therapies into clinical applications.
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Affiliation(s)
- Donald A. Belcher
- William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, Ohio, United States of America
| | - Alfredo Lucas
- Department of Bioengineering, University of California, San Diego, La Jolla, California, United States of America
| | - Pedro Cabrales
- Department of Bioengineering, University of California, San Diego, La Jolla, California, United States of America
| | - Andre F. Palmer
- William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, Ohio, United States of America
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Niu H, Li C, Guan Y, Dang Y, Li X, Fan Z, Shen J, Ma L, Guan J. High oxygen preservation hydrogels to augment cell survival under hypoxic condition. Acta Biomater 2020; 105:56-67. [PMID: 31954189 PMCID: PMC7098391 DOI: 10.1016/j.actbio.2020.01.017] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 12/18/2019] [Accepted: 01/13/2020] [Indexed: 12/29/2022]
Abstract
Cell therapy is a promising approach for ischemic tissue regeneration. However, high death rate of delivered cells under low oxygen condition, and poor cell retention in tissues largely limit the therapeutic efficacy. Using cell carriers with high oxygen preservation has potential to improve cell survival. To increase cell retention, cell carriers that can quickly solidify at 37 °C so as to efficiently immobilize the carriers and cells in the tissues are necessary. Yet there lacks cell carriers with these combined properties. In this work, we have developed a family of high oxygen preservation and fast gelation hydrogels based on N-isopropylacrylamide (NIPAAm) copolymers. The hydrogels were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization of NIPAAm, acrylate-oligolactide (AOLA), 2-hydroxyethyl methacrylate (HEMA), and methacrylate-poly(ethylene glycol)-perfluorooctane (MAPEGPFC). The hydrogel solutions exhibited sol-gel temperatures around room temperature and were flowable and injectable at 4°C. They can quickly solidify (≤6 s) at 37°C to form flexible gels. These hydrogels lost 9.4~29.4% of their mass after incubation in Dulbecco's Phosphate-Buffered Saline (DPBS) for 4 weeks. The hydrogels exhibited a greater oxygen partial pressure than DPBS after being transferred from a 21% O2 condition to a 1% O2 condition. When bone marrow mesenchymal stem cells (MSCs) were encapsulated in the hydrogels and cultured under 1% O2, the cells survived and proliferated during the 14-day culture period. In contrast, the cells experienced extensive death in the control hydrogel that had low oxygen preservation capability. The hydrogels possessed excellent biocompatibility. The final degradation products did not provoke cell death even when the concentration was as high as 15 mg/ml, and the hydrogel implantation did not induce substantial inflammation. These hydrogels are promising as cell carriers for cell transplantation into ischemic tissues. STATEMENT OF SIGNIFICANCE: Stem cell therapy for ischemic tissues experiences low therapeutic efficacy largely due to poor cell survival under low oxygen condition. Using cell carriers with high oxygen preservation capability has potential to improve cell survival. In this work, we have developed a family of hydrogels with this property. These hydrogels promoted the encapsulated stem cell survival and growth under low oxygen condition.
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Affiliation(s)
- Hong Niu
- Department of Materials Science and Engineering, The Ohio State University, Columbus, OH 43210, USA; Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO 63130, USA
| | - Chao Li
- Department of Materials Science and Engineering, The Ohio State University, Columbus, OH 43210, USA
| | - Ya Guan
- Department of Materials Science and Engineering, The Ohio State University, Columbus, OH 43210, USA; Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO 63130, USA
| | - Yu Dang
- Department of Materials Science and Engineering, The Ohio State University, Columbus, OH 43210, USA; Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO 63130, USA
| | - Xiaofei Li
- Department of Materials Science and Engineering, The Ohio State University, Columbus, OH 43210, USA
| | - Zhaobo Fan
- Department of Materials Science and Engineering, The Ohio State University, Columbus, OH 43210, USA
| | - Jie Shen
- Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO, 631310, USA
| | - Liang Ma
- Division of Dermatology, Washington University School of Medicine, St. Louis, MO, 631310, USA
| | - Jianjun Guan
- Department of Materials Science and Engineering, The Ohio State University, Columbus, OH 43210, USA; Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO 63130, USA.
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Méndez-Blanco C, Fondevila F, García-Palomo A, González-Gallego J, Mauriz JL. Sorafenib resistance in hepatocarcinoma: role of hypoxia-inducible factors. Exp Mol Med 2018; 50:1-9. [PMID: 30315182 PMCID: PMC6185986 DOI: 10.1038/s12276-018-0159-1] [Citation(s) in RCA: 230] [Impact Index Per Article: 32.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 06/05/2018] [Accepted: 06/18/2018] [Indexed: 12/14/2022] Open
Abstract
Sorafenib, a multikinase inhibitor with antiproliferative, antiangiogenic, and proapoptotic properties, constitutes the only effective first-line drug approved for the treatment of advanced hepatocellular carcinoma (HCC). Despite its capacity to increase survival in HCC patients, its success is quite low in the long term owing to the development of resistant cells through several mechanisms. Among these mechanisms, the antiangiogenic effects of sustained sorafenib treatment induce a reduction of microvessel density, promoting intratumoral hypoxia and hypoxia-inducible factors (HIFs)-mediated cellular responses that favor the selection of resistant cells adapted to the hypoxic microenvironment. Clinical data have demonstrated that overexpressed HIF-1α and HIF-2α in HCC patients are reliable markers of a poor prognosis. Thus, the combination of current sorafenib treatment with gene therapy or inhibitors against HIFs have been documented as promising approaches to overcome sorafenib resistance both in vitro and in vivo. Because the depletion of one HIF-α subunit elevates the expression of the other HIF-α isoform through a compensatory loop, targeting both HIF-1α and HIF-2α would be a more interesting strategy than therapies that discriminate among HIF-α isoforms. In conclusion, there is a marked correlation between the hypoxic microenvironment and sorafenib resistance, suggesting that targeting HIFs is a promising way to increase the efficiency of treatment. Targeting hypoxia-inducible factors (HIFs), regulatory proteins induced by low oxygen levels, could increase the effectiveness of sorafenib, the only systemic therapy approved for advanced liver cancer. Long-term treatment with sorafenib starves tumors of oxygen, which can lead to the proliferation of cancer cells that are able to survive low oxygen levels. HIFs regulate genes involved in this adaptation and HIF levels are increased in sorafenib-resistant cells. José Mauriz at the University of León, Spain, and colleagues review recent studies on the effects of HIF inhibition on sorafenib efficacy. They conclude that HIF-1α and HIF-2α are predictive markers of sorafenib resistance and that using inhibitors of both these factors as an add-on therapy could improve patient survival. This strategy may be applicable to other types of cancer in which reduced oxygen conditions lead to drug resistance.
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Affiliation(s)
- Carolina Méndez-Blanco
- Institute of Biomedicine, University of León, León, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Flavia Fondevila
- Institute of Biomedicine, University of León, León, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Andrés García-Palomo
- Institute of Biomedicine, University of León, León, Spain.,Service of Oncology, Complejo Asistencial Universitario de León, León, Spain
| | - Javier González-Gallego
- Institute of Biomedicine, University of León, León, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - José L Mauriz
- Institute of Biomedicine, University of León, León, Spain. .,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
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Zhou Z, Zhang B, Wang H, Yuan A, Hu Y, Wu J. Two-stage oxygen delivery for enhanced radiotherapy by perfluorocarbon nanoparticles. Theranostics 2018; 8:4898-4911. [PMID: 30429876 PMCID: PMC6217071 DOI: 10.7150/thno.27598] [Citation(s) in RCA: 95] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 08/21/2018] [Indexed: 02/06/2023] Open
Abstract
Tumors are usually hypoxic, which limits the efficacy of current tumor therapies, especially radiotherapy in which oxygen is essential to promote radiation-induced cell damage. Herein, by taking advantage of the ability of perfluorocarbon (PFC) to promote red blood cell penetration, we developed a simple but effective two-stage oxygen delivery strategy to modulate the hypoxic tumor microenvironment using PFC nanoparticles. Methods: We first examined the two-stage oxygen delivery ability of PFC nanoparticles on relieving tumor hypoxia through platelet inhibition. To evaluate the effect of PFC nanoparticles on radiation sensitization, CT26 tumor and SUM49PT tumor model were used. Results: In this study, PFC was encapsulated into albumin and intravenously injected into tumor-bearing mice without hyperoxic breathing. After accumulation in the tumor, PFC nanoparticles rapidly released the oxygen that was physically dissolved in PFC as the first-stage of oxygen delivery. Then, PFC subsequently promoted red blood cell infiltration, which further released O2 as the second-stage of oxygen delivery. Conclusion: The hypoxic tumor microenvironment was rapidly relieved via two-stage oxygen delivery, effectively increasing radiotherapy efficacy. The safety of all substances used in this study has been clinically demonstrated, ensuring that this simple strategy could be rapidly and easily translated into clinical applications to solve the clinical problems associated with tumor hypoxia.
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Affiliation(s)
- Zaigang Zhou
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University & School of Life Sciences, Nanjing University, Nanjing 210093, China
- Institute of Drug R&D, Nanjing University, Nanjing 210093, China
| | - Baoli Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University & School of Life Sciences, Nanjing University, Nanjing 210093, China
- Institute of Drug R&D, Nanjing University, Nanjing 210093, China
| | - Haoran Wang
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University & School of Life Sciences, Nanjing University, Nanjing 210093, China
- Institute of Drug R&D, Nanjing University, Nanjing 210093, China
| | - Ahu Yuan
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University & School of Life Sciences, Nanjing University, Nanjing 210093, China
- Institute of Drug R&D, Nanjing University, Nanjing 210093, China
| | - Yiqiao Hu
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University & School of Life Sciences, Nanjing University, Nanjing 210093, China
- Institute of Drug R&D, Nanjing University, Nanjing 210093, China
- Jiangsu Provincial Key Laboratory for Nano Technology, Nanjing University, Nanjing 210093, China
| | - Jinhui Wu
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University & School of Life Sciences, Nanjing University, Nanjing 210093, China
- Institute of Drug R&D, Nanjing University, Nanjing 210093, China
- Jiangsu Provincial Key Laboratory for Nano Technology, Nanjing University, Nanjing 210093, China
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Lee NP, Chan CM, Tung LN, Wang HK, Law S. Tumor xenograft animal models for esophageal squamous cell carcinoma. J Biomed Sci 2018; 25:66. [PMID: 30157855 PMCID: PMC6116446 DOI: 10.1186/s12929-018-0468-7] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2018] [Accepted: 08/24/2018] [Indexed: 12/12/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is the predominant subtype of esophageal cancer worldwide and highly prevalent in less developed regions. Management of ESCC is challenging and involves multimodal treatments. Patient prognosis is generally poor especially for those diagnosed in advanced disease stage. One factor contributing to this clinical dismal is the incomplete understanding of disease mechanism, for which this situation is further compounded by the presence of other limiting factors for disease diagnosis, patient prognosis and treatments. Tumor xenograft animal models including subcutaneous tumor xenograft model, orthotopic tumor xenograft model and patient-derived tumor xenograft model are vital tools for ESCC research. Establishment of tumor xenograft models involves the implantation of human ESCC cells/xenografts/tissues into immunodeficient animals, in which mice are most commonly used. Different tumor xenograft models have their own advantages and limitations, and these features serve as key factors to determine the use of these models at different stages of research. Apart from their routine use on basic research to understand disease mechanism of ESCC, tumor xenograft models are actively employed for undertaking preclinical drug screening project and biomedical imaging research.
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Affiliation(s)
- Nikki P Lee
- Department of Surgery, The University of Hong Kong, Faculty of Medicine Building, 21 Sassoon Road, Pokfulam, Hong Kong.
| | - Chung Man Chan
- Department of Surgery, The University of Hong Kong, Faculty of Medicine Building, 21 Sassoon Road, Pokfulam, Hong Kong
| | - Lai Nar Tung
- Department of Surgery, The University of Hong Kong, Faculty of Medicine Building, 21 Sassoon Road, Pokfulam, Hong Kong
| | - Hector K Wang
- Department of Surgery, The University of Hong Kong, Faculty of Medicine Building, 21 Sassoon Road, Pokfulam, Hong Kong
| | - Simon Law
- Department of Surgery, The University of Hong Kong, Faculty of Medicine Building, 21 Sassoon Road, Pokfulam, Hong Kong
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12
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Tung LN, Song S, Chan KT, Choi MY, Lam HY, Chan CM, Chen Z, Wang HK, Leung HT, Law S, Huang Y, Song H, Lee NP. Preclinical Study of Novel Curcumin Analogue SSC-5 Using Orthotopic Tumor Xenograft Model for Esophageal Squamous Cell Carcinoma. Cancer Res Treat 2018; 50:1362-1377. [PMID: 29361818 PMCID: PMC6192909 DOI: 10.4143/crt.2017.353] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Accepted: 01/16/2018] [Indexed: 02/07/2023] Open
Abstract
Purpose Tumor xenograft model is an indispensable animal cancer model. In esophageal squamous cell carcinoma (ESCC) research, orthotopic tumor xenograft model establishes tumor xenograft in the animal esophagus, which allows the study of tumorigenesis in its native microenvironment. Materials and Methods In this study,we described two simple and reproducible methods to develop tumor xenograft at the cervical or the abdominal esophagus in nude mice by direct injection of ESCC cells in the esophageal wall. Results In comparing these two methods, the cervical one presented with more clinically relevant features, i.e., esophageal stricture, body weight loss and poor survival. In addition, the derived tumor xenografts accompanied a rapid growth rate and a high tendency to invade into the surrounding structures. This model was subsequently used to study the anti-tumor effect of curcumin, which is known for its potential therapeutic effects in various diseases including cancers, and its analogue SSC-5. SSC-5 was selected among the eight newly synthesized curcumin analogues based on its superior anti-tumor effect demonstrated in an MTT cell proliferation assay and its effects on apoptosis induction and cell cycle arrest in cultured ESCC cells. Treatment of orthotopic tumor-bearing mice with SSC-5 resulted in an inhibition in tumor growth and invasion. Conclusion Taken together, we have established a clinically relevant orthotopic tumor xenograft model that can serve as a preclinical tool for screening new anti-tumor compounds, e.g., SSC-5, in ESCC.
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Affiliation(s)
- Lai Nar Tung
- Department of Surgery, The University of Hong Kong, Hong Kong.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China
| | - Senchuan Song
- School of Chemical Engineering and Technology, Sun Yat-Sen University, Guangzhou, China.,Guangdong Petrochemical Research Institute, Guangzhou, China
| | - Kin Tak Chan
- Department of Surgery, The University of Hong Kong, Hong Kong
| | - Mei Yuk Choi
- Department of Surgery, The University of Hong Kong, Hong Kong
| | - Ho Yu Lam
- Department of Surgery, The University of Hong Kong, Hong Kong
| | - Chung Man Chan
- Department of Surgery, The University of Hong Kong, Hong Kong.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China
| | - Zhiyong Chen
- Guangdong Petrochemical Research Institute, Guangzhou, China
| | - Hector K Wang
- Department of Surgery, The University of Hong Kong, Hong Kong
| | - Hoi Ting Leung
- Department of Surgery, The University of Hong Kong, Hong Kong
| | - Simon Law
- Department of Surgery, The University of Hong Kong, Hong Kong
| | - Yanmin Huang
- Guangxi Teachers Education University, College of Chemistry and Materials Science, Nanning, China
| | - Huacan Song
- School of Chemical Engineering and Technology, Sun Yat-Sen University, Guangzhou, China
| | - Nikki P Lee
- Department of Surgery, The University of Hong Kong, Hong Kong.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China
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Qi X, Wong BL, Lau SH, Ng KTP, Kwok SY, Kin-Wai Sun C, Tzang FC, Shao Y, Li CX, Geng W, Ling CC, Ma YY, Liu XB, Liu H, Liu J, Yeung WH, Lo CM, Man K. A hemoglobin-based oxygen carrier sensitized Cisplatin based chemotherapy in hepatocellular carcinoma. Oncotarget 2017; 8:85311-85325. [PMID: 29156721 PMCID: PMC5689611 DOI: 10.18632/oncotarget.19672] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 05/11/2017] [Indexed: 12/13/2022] Open
Abstract
Background and Objective Our previous study showed that liver graft injury not only promotes tumor recurrence, but also induces chemoresistance in recurrent HCC after liver transplantation. Recently, we found that the hemoglobin-based oxygen carrier“YQ23” significantly ameliorates hepatic IR injury and prevent tumor recurrence. Here, we intended to explore the novel therapeutic strategy using oxygen carrier “YQ23”to sensitize chemotherapy in HCC. Methods To investigate the role of YQ23 combined with Cisplatin, the proliferation of HCC cells was examined under combined treatment by MTT and colony formation. To explore the effect of YQ23 on sensitization of Cisplatin based chemotherapy, the orthotopic liver cancer model was established. To characterize the delivery of YQ23 in tumor tissue, the intravital imaging system was applied for longitudinal observation in ectopic liver cancer model. The distribution of YQ23 was examined by IVIS spectrum. Results YQ23 significantly suppressed the proliferation of HCC cells under Cisplatin treatment in a dose and time dependent manner. Moreover, YQ23 administration significantly sensitized Cisplatin based chemotherapy in orthotopic liver cancer model. Down-regulation of DHFR may be one of the reasons for YQ23 sensitizing Cisplatin based chemotherapy. Real-time intravital imaging showed that YQ23 accumulated in the tumor tissue and maintained as long as 3 days in ectopic liver cancer model. The IVIS spectrum examination showed that YQ23 distributed mainly at liver and bladder within the first 36 hours after administration in orthotopic liver cancer model. Conclusion YQ23 treatment may be a potential therapeutic strategy to sensitize chemotherapy in HCC.
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Affiliation(s)
- Xiang Qi
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Bing L Wong
- New β Innovation Limited, 18/F Chevalier Commercial Centre, Hong Kong, China
| | - Sze Hang Lau
- New β Innovation Limited, 18/F Chevalier Commercial Centre, Hong Kong, China
| | - Kevin Tak-Pan Ng
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Sui Yi Kwok
- New β Innovation Limited, 18/F Chevalier Commercial Centre, Hong Kong, China
| | - Chris Kin-Wai Sun
- New β Innovation Limited, 18/F Chevalier Commercial Centre, Hong Kong, China
| | - Fei Chuen Tzang
- New β Innovation Limited, 18/F Chevalier Commercial Centre, Hong Kong, China
| | - Yan Shao
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Chang Xian Li
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Wei Geng
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Chang Chun Ling
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Yuen Yuen Ma
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Xiao Bing Liu
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Hui Liu
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Jiang Liu
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Wai Ho Yeung
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Chung Mau Lo
- Department of Surgery, The University of Hong Kong, Hong Kong, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Kwan Man
- Department of Surgery, The University of Hong Kong, Hong Kong, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
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Hou XF, Xu LP, Song HY, Li S, Wu C, Wang JF. ECRG2 enhances the anti-cancer effects of cisplatin in cisplatin-resistant esophageal cancer cells via upregulation of p53 and downregulation of PCNA. World J Gastroenterol 2017; 23:1796-1803. [PMID: 28348485 PMCID: PMC5352920 DOI: 10.3748/wjg.v23.i10.1796] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 01/06/2017] [Accepted: 01/18/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To explore the anti-tumor effects of esophageal cancer-related gene 2 (ECRG2) in combination with cisplatin (DDP) in DDP-resistant esophageal cancer cells (EC9706/DDP).
METHODS A drug-resistant cell model was established, with EC9706/DDP cells being treated with ECRG2 and/or DDP. Cell viability was examined by MTT assay. The rate of cell apoptosis was determined by flow cytometry. The mRNA expression levels of proliferating cell nuclear antigen (PCNA), metallothionein (MT), and p53 were determined by RT-PCR and PCNA, while MT and p53 protein expression levels were determined by western blotting.
RESULTS The anti-proliferative effect of ECRG2 in combination with DDP was superior when compared to ECRG2 or DDP alone. The inhibition rate for the combination reached its peak (51.33%) at 96 h. The early apoptotic rates of the control, ECRG2 alone, DDP alone, and ECRG2 plus DDP groups were 5.71% ± 0.27%, 12.68% ± 0.61%, 14.15% ± 0.87%, and 27.96% ± 0.36%, respectively. Although all treatment groups were significantly different from the control group (P < 0.05), the combination treatment of ECRG2 plus DDP performed significantly better when compared to either ECRG2 or DDP alone (P < 0.05). The combination of ECRG2 and DDP significantly upregulated p53 mRNA and protein levels and downregulated PCNA mRNA and protein levels compared to ECRG2 or DDP alone (P < 0.05). However, no changes were seen in the expression of MT mRNA or protein.
CONCLUSION ECRG2 in combination with DDP can inhibit viability and induce apoptosis in esophageal cancer DDP-resistant cells, possibly via upregulation of p53 expression and downregulation of PCNA expression. These findings suggest that the combination of ECRG2 and DDP may be a promising strategy for the clinical treatment of esophageal cancers that are resistant to DDP.
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