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Yu S, Jiang Y, Li Q, Li M, Su J, Lai S, Gan Z, Ding Z, Yu Q. Nano-sensitizer with self-amplified drug release and hypoxia normalization properties potentiates efficient chemoradiotherapy of pancreatic cancer. Biomaterials 2024; 310:122634. [PMID: 38823195 DOI: 10.1016/j.biomaterials.2024.122634] [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: 12/15/2023] [Revised: 04/29/2024] [Accepted: 05/26/2024] [Indexed: 06/03/2024]
Abstract
The hypoxic nature of pancreatic cancer, one of the most lethal malignancies worldwide, significantly impedes the effectiveness of chemoradiotherapy. Although the development of oxygen carriers and hypoxic sensitizers has shown promise in overcoming tumor hypoxia. The heterogeneity of hypoxia-primarily caused by limited oxygen penetration-has posed challenges. In this study, we designed a hypoxia-responsive nano-sensitizer by co-loading tirapazamine (TPZ), KP372-1, and MK-2206 in a metronidazole-modified polymeric vesicle. This nano-sensitizer relies on efficient endogenous NAD(P)H quinone oxidoreductase 1-mediated redox cycling induced by KP372-1, continuously consuming periphery oxygen and achieving evenly distributed hypoxia. Consequently, the normalized tumor microenvironment facilitates the self-amplified release and activation of TPZ without requiring deep penetration. The activated TPZ and metronidazole further sensitize radiotherapy, significantly reducing the radiation dose needed for extensive cell damage. Additionally, the coloaded MK-2206 complements inhibition of therapeutic resistance caused by Akt activation, synergistically enhancing the hypoxic chemoradiotherapy. This successful hypoxia normalization strategy not only overcomes hypoxia resistance in pancreatic cancer but also provides a potential universal approach to sensitize hypoxic tumor chemoradiotherapy by reshaping the hypoxic distribution.
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Affiliation(s)
- Shuchen Yu
- Beijing Laboratory of Biomedical Materials, The State Key Laboratory of Organic-Inorganic Composites, Key Laboratory of Biomedical Materials of Natural Macromolecules (Ministry of Education), College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Yitong Jiang
- Beijing Laboratory of Biomedical Materials, The State Key Laboratory of Organic-Inorganic Composites, Key Laboratory of Biomedical Materials of Natural Macromolecules (Ministry of Education), College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Qian Li
- Beijing Laboratory of Biomedical Materials, The State Key Laboratory of Organic-Inorganic Composites, Key Laboratory of Biomedical Materials of Natural Macromolecules (Ministry of Education), College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Mengmeng Li
- Beijing Laboratory of Biomedical Materials, The State Key Laboratory of Organic-Inorganic Composites, Key Laboratory of Biomedical Materials of Natural Macromolecules (Ministry of Education), College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Jiamin Su
- Beijing Laboratory of Biomedical Materials, The State Key Laboratory of Organic-Inorganic Composites, Key Laboratory of Biomedical Materials of Natural Macromolecules (Ministry of Education), College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Shicong Lai
- Department of Urology, Peking University People's Hospital, Peking University, Beijing, 100044, China
| | - Zhihua Gan
- Beijing Laboratory of Biomedical Materials, The State Key Laboratory of Organic-Inorganic Composites, Key Laboratory of Biomedical Materials of Natural Macromolecules (Ministry of Education), College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Zhenshan Ding
- Department of Urology, China-Japan Friendship Hospitals, Beijing, 100029, China.
| | - Qingsong Yu
- Beijing Laboratory of Biomedical Materials, The State Key Laboratory of Organic-Inorganic Composites, Key Laboratory of Biomedical Materials of Natural Macromolecules (Ministry of Education), College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China.
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Wang L, Xiao K, Dong Z, Meng T, Cheng X, Xu Y. A novel copper-induced cell death-related lncRNA prognostic signature associated with immune infiltration and clinical value in gastric cancer. J Cancer Res Clin Oncol 2023; 149:10543-10559. [PMID: 37291405 PMCID: PMC10423106 DOI: 10.1007/s00432-023-04916-7] [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: 05/04/2023] [Accepted: 05/22/2023] [Indexed: 06/10/2023]
Abstract
BACKGROUND Gastric cancer (GC) is one of the most important malignancies and has a poor prognosis. Copper-induced cell death, recently termed cuproptosis, may directly affect the outcome of GC. Long noncoding RNAs (lncRNAs), possessing stable structures, can influence the prognosis of cancer and may serve as potential prognostic prediction factors for various cancers. However, the role of copper cell death-related lncRNAs (CRLs) in GC has not been thoroughly investigated. Here, we aim to elucidate the role of CRLs in predicting prognosis, diagnosis, and immunotherapy in GC patients. METHODS RNA expression data for 407 GC patients from The Cancer Genome Atlas (TCGA) were gathered, and differentially expressed CRLs were identified. Subsequently, the researchers applied univariate, LASSO, and multivariate Cox regression to construct a prognostic signature consisting of 5 lncRNAs based on the CRLs. Stratified by the median CRLSig risk score, Kaplan-Meier analysis was utilized to compare overall survival (OS) between the high- and low-risk groups. Among the two groups, gene set enrichment analysis (GSEA), tumor microenvironment (TME), drug sensitivity analysis, and immune checkpoint analysis were conducted. In addition, consensus clustering and nomogram analysis were performed to predict OS. Cell experiments and 112 human serum samples were employed to verify the effect of lncRNAs on GC. Furthermore, the diagnostic value of the CRLSig in the serum of GC patients was analyzed by the receiver operating characteristic (ROC) curve. RESULTS A prognostic signature for GC patients was constructed based on CRLs, composed of AC129926.1, AP002954.1, AC023511.1, LINC01537, and TMEM75. According to the K-M survival analysis, high-risk GC patients had a lower OS rate and progression-free survival rate than low-risk GC patients. Further support for the model's accuracy was provided by ROC, principal component analysis, and the validation set. The area under the curve (AUC) of 0.772 for GC patients showed a better prognostic value than any other clinicopathological variable. Furthermore, immune infiltration analysis showed that the high-risk group had greater antitumor immune responses in the tumor microenvironment. In the high-risk subgroup, 23 immune checkpoint genes had significantly higher expression levels than in the low-risk subgroup (p < 0.05). The half-maximal inhibitory concentrations (IC50) of 86 drugs were found to be significantly different in the two groups. Accordingly, the model is capable of predicting the effectiveness of immunotherapy. In addition, the five CRLs in GC serum exhibited statistically significant expression levels. The AUC of this signature in GC serum was 0.894, with a 95% CI of 0.822-0.944. Moreover, lncRNA AC129926.1 was significantly overexpressed in GC cell lines and the serum of GC patients. Importantly, colony formation, wound healing, and transwell assays further confirmed the oncogenic role of AC129926.1 in GC. CONCLUSION In this study, a prognostic signature model consisting of five CRLs was developed to improve OS prediction accuracy in GC patients. The model also has the potential to predict immune infiltration and immunotherapy effectiveness. Furthermore, the CRLSig might serve as a novel serum biomarker to differentiate GC patients from healthy individuals.
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Affiliation(s)
- Li Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, Anhui, China
| | - Ke Xiao
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, Jinan, 250012, Shandong Province, China
| | - Zhaogang Dong
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, Jinan, 250012, Shandong Province, China
| | - Tao Meng
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, Anhui, China
| | - Xiaowen Cheng
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, Anhui, China.
| | - Yuanhong Xu
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, Anhui, China.
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3
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Buckingham L, Hao T, O’Donnell J, Zhao Z, Zhang X, Fan Y, Sun W, Zhang Y, Suo H, Secord AA, Zhou C, Bae-Jump V. Ipatasertib, an oral AKT inhibitor, inhibits cell proliferation and migration, and induces apoptosis in serous endometrial cancer. Am J Cancer Res 2022; 12:2850-2862. [PMID: 35812065 PMCID: PMC9251705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 05/27/2022] [Indexed: 01/05/2023] Open
Abstract
Ipatasertib (IPAT) is an orally administered, selective protein kinase B (AKT) inhibitor with promising data in solid tumors in both pre-clinical studies and clinical trials. Given that the PI3K/AKT/mTOR pathway is frequently dysregulated in uterine serous carcinoma (USC), we aimed to explore the functional impact of IPAT on anti-tumorigenic activity in USC cell lines and primary cultures of USC. We found that IPAT significantly inhibited cell proliferation and colony formation in a dose-dependent manner in USC cells. Induction of cell cycle arrest and apoptosis was observed in IPAT-treated ARK1 and SPEC-2 cells. Treatment with IPAT resulted in reduced adhesion and invasion of both cell lines with a concomitant decrease in the expression of Snail, Slug, and N-Cadherin. Compared with single-drug treatment, the combination of IPAT and paclitaxel synergistically reduced cell proliferation and increased the activity of cleaved caspase 3 in both cell lines. Additionally, IPAT inhibited growth in four of five primary USC cultures, and three of five primary cultures also exhibited synergistic growth inhibition when paclitaxel and IPAT were combined. These results support that IPAT appears to be a promising targeted agent in the treatment of USC.
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Affiliation(s)
- Lindsey Buckingham
- Division of Gynecologic Oncology, University of North Carolina at Chapel HillChapel Hill, NC, USA
| | - Tianran Hao
- Division of Gynecologic Oncology, University of North Carolina at Chapel HillChapel Hill, NC, USA
| | - Jillian O’Donnell
- Division of Gynecologic Oncology, University of North Carolina at Chapel HillChapel Hill, NC, USA
| | - Ziyi Zhao
- Division of Gynecologic Oncology, University of North Carolina at Chapel HillChapel Hill, NC, USA,Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care HospitalBeijing, China
| | - Xin Zhang
- Division of Gynecologic Oncology, University of North Carolina at Chapel HillChapel Hill, NC, USA,Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care HospitalBeijing, China
| | - Yali Fan
- Division of Gynecologic Oncology, University of North Carolina at Chapel HillChapel Hill, NC, USA,Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care HospitalBeijing, China
| | - Wenchuan Sun
- Division of Gynecologic Oncology, University of North Carolina at Chapel HillChapel Hill, NC, USA
| | - Yingao Zhang
- Division of Gynecologic Oncology, University of North Carolina at Chapel HillChapel Hill, NC, USA
| | - Hongyan Suo
- Division of Gynecologic Oncology, University of North Carolina at Chapel HillChapel Hill, NC, USA,Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care HospitalBeijing, China
| | - Angeles Alvarez Secord
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecologic, Duke Cancer Institute, Duke UniversityDurham, NC, USA
| | - Chunxiao Zhou
- Division of Gynecologic Oncology, University of North Carolina at Chapel HillChapel Hill, NC, USA,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel HillChapel Hill, NC, USA
| | - Victoria Bae-Jump
- Division of Gynecologic Oncology, University of North Carolina at Chapel HillChapel Hill, NC, USA,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel HillChapel Hill, NC, USA
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Baghery Saghchy Khorasani A, Pourbagheri-Sigaroodi A, Pirsalehi A, Safaroghli-Azar A, Zali MR, Bashash D. The PI3K/Akt/mTOR signaling pathway in gastric cancer; from oncogenic variations to the possibilities for pharmacologic interventions. Eur J Pharmacol 2021; 898:173983. [PMID: 33647255 DOI: 10.1016/j.ejphar.2021.173983] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 02/13/2021] [Accepted: 02/23/2021] [Indexed: 12/24/2022]
Abstract
Genetic and epigenetic alterations have been under concentrated investigations for many years in order to unearth the molecules regulating human cancer pathogenesis. However, the identification of a wide range of dysregulated genes and their protein products has raised a question regarding how the results of this large collection of alterations could converge into a formation of one malignancy. The answer may be found in the signaling cascades that regulate the survival and metabolism of the cells. Aberrancies of each participant molecule of such cascades may well result in augmented viability and unlimited proliferation of cancer cells. Among various signaling pathways, the phosphatidylinositol-3-kinase (PI3K) axis has been shown to be activated in about one-third of human cancers. One of the malignancies that is mostly affected by this axis is gastric cancer (GC), one of the most fatal cancers worldwide. In the present review, we aimed to illustrate the significance of the PI3K/Akt/mTOR axis in the pathogenesis of GC and also provided a wide perspective about the application of the inhibitors of this axis in the therapeutic strategies of this malignancy.
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Affiliation(s)
| | - Atieh Pourbagheri-Sigaroodi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Pirsalehi
- Department of Internal Medicine, School of Medicine, Ayatollah Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ava Safaroghli-Azar
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Fattahi S, Amjadi-Moheb F, Tabaripour R, Ashrafi GH, Akhavan-Niaki H. PI3K/AKT/mTOR signaling in gastric cancer: Epigenetics and beyond. Life Sci 2020; 262:118513. [PMID: 33011222 DOI: 10.1016/j.lfs.2020.118513] [Citation(s) in RCA: 238] [Impact Index Per Article: 47.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 09/22/2020] [Accepted: 09/22/2020] [Indexed: 02/07/2023]
Abstract
PI3K/AKT/mTOR pathway is one of the most important signaling pathways involved in normal cellular processes. Its aberrant activation modulates autophagy, epithelial-mesenchymal transition, apoptosis, chemoresistance, and metastasis in many human cancers. Emerging evidence demonstrates that some infections as well as epigenetic regulatory mechanisms can control PI3K/AKT/mTOR signaling pathway. In this review, we focused on the role of this pathway in gastric cancer development, prognosis, and metastasis, with an emphasis on epigenetic alterations including DNA methylation, histone modifications, and post-transcriptional modulations through non-coding RNAs fluctuations as well as H. pylori and Epstein-Barr virus infections. Finally, we reviewed different molecular targets and therapeutic agents in clinical trials as a potential strategy for gastric cancer treatment through the PI3K/AKT/mTOR pathway.
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Affiliation(s)
- Sadegh Fattahi
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran; Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran; North Research Center, Pasteur Institute, Amol, Iran
| | - Fatemeh Amjadi-Moheb
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Reza Tabaripour
- Department of Cellular and Molecular Biology, Islamic Azad University Babol-Branch, Iran
| | - Gholam Hossein Ashrafi
- Kingston University London, Cancer theme, School of Life Science, Pharmacy and Chemistry, SEC Faculty, Kingston upon Thames, KT12EE, London, UK
| | - Haleh Akhavan-Niaki
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran.
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6
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Mobasheri T, Rayzan E, Shabani M, Hosseini M, Mahmoodi Chalbatani G, Rezaei N. Neuroblastoma-targeted nanoparticles and novel nanotechnology-based treatment methods. J Cell Physiol 2020; 236:1751-1775. [PMID: 32735058 DOI: 10.1002/jcp.29979] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 07/11/2020] [Accepted: 07/16/2020] [Indexed: 12/17/2022]
Abstract
Neuroblastoma is a complicated pediatric tumor, originating from the neural crest, which is the most prevalent in adrenal glands, but may rarely be seen in some other tissues as well. Studies are focused on developing new strategies through novel chemo- and immuno-therapeutic drug targets. Different types of oncogenes such as MYCN, tumor suppressor genes such as p53, and some structural genes such as vascular endothelial growth factor are considered as targets for neuroblastoma therapy. The individual expression patterns in NB cells make them appropriate for this purpose. The combined effect of nano-drug delivery systems and specific drug targets will result in lower systemic side effects, prolonged therapeutic effects, and improvements in the pharmacokinetic properties of the drugs. Some of these novel drug delivery systems with a focus on liposomes as carriers are also discussed. In this review, genes and protein products that are beneficial as drug targets in the treatment of neuroblastoma have been discussed.
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Affiliation(s)
- Taranom Mobasheri
- International Hematology/Oncology of Pediatrics Experts (IHOPE), Universal Scientific Education and Research Network (USERN), Tehran, Iran.,School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Elham Rayzan
- International Hematology/Oncology of Pediatrics Experts (IHOPE), Universal Scientific Education and Research Network (USERN), Tehran, Iran.,Research Center for Immunodeficiencies (RCID), Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahsima Shabani
- Research Center for Immunodeficiencies (RCID), Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,International Hematology/Oncology of Pediatrics Experts (IHOPE), Universal Scientific Education and Research Network (USERN), Baltimore, Maryland
| | - Mina Hosseini
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Nima Rezaei
- Research Center for Immunodeficiencies (RCID), Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
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Ruan T, Liu W, Tao K, Wu C. A Review of Research Progress in Multidrug-Resistance Mechanisms in Gastric Cancer. Onco Targets Ther 2020; 13:1797-1807. [PMID: 32184615 PMCID: PMC7053652 DOI: 10.2147/ott.s239336] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 02/15/2020] [Indexed: 12/14/2022] Open
Abstract
Gastric cancer is one of the most common malignant tumors, and it is also one of the leading causes of cancer death worldwide. Because of its insidious symptoms and lack of early dictation screening, many cases of gastric cancer are at late stages which make it more complicated to cure. For these advanced-stage gastric cancers, combination therapy of surgery, chemotherapy, radiotherapy and target therapy would bring more benefit to the patients. However, the drug-resistance to the chemotherapy restricts its effect and might lead to treatment failure. In this review article, we discuss the mechanisms which have been found in recent years of drug resistance in gastric cancer. And we also want to find new approaches to counteract chemotherapy resistance and bring more benefits to the patients.
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Affiliation(s)
- Tuo Ruan
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Weizhen Liu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Kaixiong Tao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Chuanqing Wu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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8
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Shi N, Yu H, Chen T. Inhibition of esophageal cancer growth through the suppression of PI3K/AKT/mTOR signaling pathway. Onco Targets Ther 2019; 12:7637-7647. [PMID: 31571914 PMCID: PMC6756275 DOI: 10.2147/ott.s205457] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 06/20/2019] [Indexed: 12/11/2022] Open
Abstract
Background The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is implicated in several cancers. AKT allosteric inhibitor MK2206 and dual PI3K and mTOR inhibitor BEZ235 are promising drug candidates with potential anti-tumor effects. Purpose In this study, we aimed to detect the activation of PI3K/AKT/mTOR pathway and assess the efficacy of MK2206 and BEZ235 in inhibiting esophageal cancer growth. Materials and methods We used three different systems including carcinogen-induced animal model, human esophageal squamous cell carcinoma (SCC) cell lines, and xenograft mouse model. Results Our data indicated that components of the PI3K/AKT/mTOR pathway were overexpressed and activated in esophageal SCC. MK2206 and BEZ235 inhibited cell proliferation, enhanced apoptosis, and induced cell-cycle arrest through downstream effectors SKP2, MCL-1, and cyclin D1 in esophageal SCC cells. MK2206 and BEZ235 also inhibited tumor growth in xenograft mice through the inhibition of AKT phosphorylation. MK2206/BEZ235 combination showed greater anti-tumor effect than MK2206 or BEZ235 alone. The enhanced efficacy of the combination was associated with the inhibition of phosphorylation ATK on both Thr308 and Ser473. Conclusion The combination of MK2206 and BEZ235 exhibits potent antitumor effects and may have important clinical applications for esophageal SCC treatment.
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Affiliation(s)
- Ni Shi
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
| | - Hao Yu
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
| | - Tong Chen
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
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9
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Combination of eribulin plus AKT inhibitor evokes synergistic cytotoxicity in soft tissue sarcoma cells. Sci Rep 2019; 9:5759. [PMID: 30962488 PMCID: PMC6453888 DOI: 10.1038/s41598-019-42300-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Accepted: 03/28/2019] [Indexed: 12/13/2022] Open
Abstract
An activated AKT pathway underlies the pathogenesis of soft tissue sarcoma (STS), with over-expressed phosphorylated AKT (p-AKT) correlating with a poor prognosis in a subset of STS cases. Recently, eribulin, a microtubule dynamics inhibitor, has demonstrated efficacy and is approved in patients with advanced/metastatic liposarcoma and breast cancer. However, mechanisms of eribulin resistance and/or insensitivity remain largely unknown. In this study, we demonstrated that an increased p-AKT level was associated with eribulin resistance in STS cells. We found a combination of eribulin with the AKT inhibitor, MK-2206, synergistically inhibited STS cell growth in vivo as well as in vitro. Mechanistically, eribulin plus MK-2206 induced G1 or G2/M arrest by down-regulating cyclin-dependent kinases, cyclins and cdc2, followed by caspase-dependent apoptosis in STS cells. Our findings demonstrate the significance of p-AKT signaling for eribulin-resistance in STS cells and provide a rationale for the development of an AKT inhibitor in combination with eribulin to treat patients with STS.
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10
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Cui G, Shu B, Veeran S, Yuan H, Yi X, Zhong G. Natural β-carboline alkaloids regulate the PI3K/Akt/mTOR pathway and induce autophagy in insect Sf9 cells. PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY 2019; 154:67-77. [PMID: 30765058 DOI: 10.1016/j.pestbp.2018.12.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 11/18/2018] [Accepted: 12/17/2018] [Indexed: 06/09/2023]
Abstract
The β-carboline alkaloids are a large group of naturally occurring and synthetic indole alkaloids with remarkable pharmacological properties. Furthermore, these alkaloids have also been reported to be effective agents for controlling many pests and plant pathogenic nematodes. However, studies on these potential insecticidal components are scarce. The previous finding that these bioactive compounds can induce programmed cell death in cancer cell lines provided a new insight for exploration of their toxicological mechanisms on insects. In the present study, the cytotoxicity of five natural harmala alkaloids was measured, and the autophagy-inducing effect was confirmed in the Spodoptera frugiperda Sf9 cultured cell line. The results demonstrated that these alkaloids inhibited the proliferation of Sf9 cells in a dose- and time-dependent manner, and the unsaturated β-carboline alkaloids, harmine and harmol, exhibited stronger autophagy induction activity based on monodansylcadaverineand LysoTracker Red staining. Many autophagy-related genes were increased after β-carbolines treatment at the RNA level, and the protein expression of Sf-Atg8 was also confirmed to increase after treatment. In addition, the primary autophagic signaling pathway, the PI3K/Akt/mTOR pathway, was altered during the procedure. Furthermore, experiments with special inhibitors and activators were performed to confirm the effect of β-carbolines on this pathway. The results suggested that the PI3K/Akt/mTOR pathway primarily regulated harmine-induced autophagy in insect cells, and this finding may potentially benefit the application of these promising bioactivity components.
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Affiliation(s)
- Gaofeng Cui
- Key Laboratory of Natural Pesticide and Chemical Biology, Ministry of Education, South China Agricultural University, Guangzhou 510642, China; Key Laboratory of Integrated Pest Management on Crops in South China, Ministry of Agriculture, South China Agricultural University, Guangzhou 510642, China
| | - Benshui Shu
- Key Laboratory of Natural Pesticide and Chemical Biology, Ministry of Education, South China Agricultural University, Guangzhou 510642, China; Key Laboratory of Integrated Pest Management on Crops in South China, Ministry of Agriculture, South China Agricultural University, Guangzhou 510642, China; Guangzhou City Key Laboratory of Subtropical Fruit Trees Outbreak Control, Zhongkai University of Agriculture and Engineering, Guangzhou, 510225, China
| | - Sethuraman Veeran
- Key Laboratory of Natural Pesticide and Chemical Biology, Ministry of Education, South China Agricultural University, Guangzhou 510642, China; Key Laboratory of Integrated Pest Management on Crops in South China, Ministry of Agriculture, South China Agricultural University, Guangzhou 510642, China
| | - Haiqi Yuan
- Key Laboratory of Natural Pesticide and Chemical Biology, Ministry of Education, South China Agricultural University, Guangzhou 510642, China; Key Laboratory of Integrated Pest Management on Crops in South China, Ministry of Agriculture, South China Agricultural University, Guangzhou 510642, China
| | - Xin Yi
- Key Laboratory of Natural Pesticide and Chemical Biology, Ministry of Education, South China Agricultural University, Guangzhou 510642, China; Key Laboratory of Integrated Pest Management on Crops in South China, Ministry of Agriculture, South China Agricultural University, Guangzhou 510642, China
| | - Guohua Zhong
- Key Laboratory of Natural Pesticide and Chemical Biology, Ministry of Education, South China Agricultural University, Guangzhou 510642, China; Key Laboratory of Integrated Pest Management on Crops in South China, Ministry of Agriculture, South China Agricultural University, Guangzhou 510642, China.
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11
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Kim HJ, Byun HJ, Park MK, Kim EJ, Kang GJ, Lee CH. Novel involvement of RhebL1 in sphingosylphosphorylcholine-induced keratin phosphorylation and reorganization: Binding to and activation of AKT1. Oncotarget 2017; 8:20851-20864. [PMID: 28209923 PMCID: PMC5400551 DOI: 10.18632/oncotarget.15364] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Accepted: 02/06/2017] [Indexed: 11/25/2022] Open
Abstract
Sphingosylphosphorylcholine induces keratin phosphorylation and reorganization, and increases viscoelasticity of metastatic cancer cells such as PANC-1 cells. However, the mechanism involved in sphingosylphosphorylcholine-induced keratin phosphorylation and reorganization is largely unknown. Sphingosylphosphorylcholine dose- and time-dependently induces the expression of RhebL1. The involvement of RhebL1 in sphingosylphosphorylcholine-induced events including keratin 8 (K8) phosphorylation, reorganization, migration and invasion was examined. Gene silencing of RhebL1 suppressed the sphingosylphosphorylcholine-induced events and overexpression of RhebL1 enhanced those events even without sphingosylphosphorylcholine treatment. We examined whether the G protein function of RhebL1 induces K8 phosphorylation using constitutively active RhebL1Q64L and dominant negative RhebL1D60K. G protein activity of RhebL1 is involved in sphingosylphosphorylcholine-induced K8 phosphorylation. We found that RhebL1 binds and activates AKT1. G protein activity of RhebL1 is involved in the binding and activation of AKT1. MK2206 (AKT inhibitor) and gene silencing of AKT1 inhibited the sphingosylphosphorylcholine-induced events, whereas overexpression of activated-AKT1 induced K8 phosphorylation, reorganization, migration and invasion even without sphingosylphosphorylcholine treatment. The collective results indicate that RhebL1 is involved in sphingosylphosphorylcholine-induced events in A549 lung cancer cells via binding to AKT1 leading to activation of it. These results suggest that suppression of RhebL1 or inhibition of RhebL1′s binding to AKT1 might be a novel way that prevents changes in the physical properties of metastatic cancer cells.
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Affiliation(s)
- Hyun Ji Kim
- College of Pharmacy, Dongguk University, Seoul 100-715, Republic of Korea
| | - Hyun Jung Byun
- College of Pharmacy, Dongguk University, Seoul 100-715, Republic of Korea
| | - Mi Kyung Park
- College of Pharmacy, Dongguk University, Seoul 100-715, Republic of Korea
| | - Eun Ji Kim
- College of Pharmacy, Dongguk University, Seoul 100-715, Republic of Korea
| | - Gyeoung Jin Kang
- College of Pharmacy, Dongguk University, Seoul 100-715, Republic of Korea
| | - Chang Hoon Lee
- College of Pharmacy, Dongguk University, Seoul 100-715, Republic of Korea
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12
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Li Y, Zhou W, Tang K, Chen X, Feng Z, Chen J. Silencing Aurora A leads to re-sensitization of breast cancer cells to Taxol through downregulation of SRC-mediated ERK and mTOR pathways. Oncol Rep 2017; 38:2011-2022. [PMID: 28849180 PMCID: PMC5652950 DOI: 10.3892/or.2017.5908] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Accepted: 07/31/2017] [Indexed: 12/11/2022] Open
Abstract
While Taxol has been reported to improve the clinical survival of breast cancer patients, subsequently developed drug-resistance of the cancer cells limits its final efficacy and applications. Previous studies suggested that Aurora A is involved in the development of the Taxol-resistance of breast cancer. We established Taxol-resistant breast cancer MCF-7/T cells and xenograft models to explore the role of Aurora A in Taxol resistant ER-positive breast cancer. Compared with their parental MCF-7/C cells, the Taxol-resistant MCF-7/T cells exhibited enhanced colony formation, less cell death and higher invasive ability. The resistant cells presented overexpressed Aurora A, elevated phosphorylated SRC and upregulated Ras/Raf/ERK and Akt/mTOR pathways. Silencing of Aurora A reduced the activity of SRC and downregulated the ERK and Akt/mTOR pathways, which led to re-sensitization of the resistant MCF-7/T cells to Taxol in vitro. These results suggested that the activation of Aurora A and the subsequent upregulation of ERK and Akt through SRC induced Taxol-resistance in breast cancer cells, and inhibiting Aurora A and the related SRC/EKT/Akt pathway could restore the sensitivity of breast cancer cells to Taxol. These results might shed light on the development of strategies to circumvent Taxol-related chemoresistance in breast cancer clinical practice.
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Affiliation(s)
- Yan Li
- State Key Laboratory of Bioactive Substances and Functions of Nature Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China
| | - Wanqi Zhou
- State Key Laboratory of Bioactive Substances and Functions of Nature Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China
| | - Ke Tang
- State Key Laboratory of Bioactive Substances and Functions of Nature Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China
| | - Xiaoguang Chen
- State Key Laboratory of Bioactive Substances and Functions of Nature Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China
| | - Zhiqiang Feng
- Beijing Key Laboratory of Active Substance Discovery and Drugability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China
| | - Jindong Chen
- Department of Urology, University of Rochester Medical Center, Rochester, NY 14642, USA
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13
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Shuang W, Hou L, Zhu Y, Li Q, Hu W. Mcl-1 stabilization confers resistance to taxol in human gastric cancer. Oncotarget 2017; 8:82981-82990. [PMID: 29137317 PMCID: PMC5669943 DOI: 10.18632/oncotarget.20222] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Accepted: 07/26/2017] [Indexed: 12/11/2022] Open
Abstract
Taxol has been extensively used as an antineoplastic drug to treat human gastric cancer. However, the acquired drug resistance invariably develops and greatly limits the therapeutic efficacy of Taxol. Identification of the underlying resistance mechanisms may inform the development of new therapies of gastric cancers to Taxol treatment. Here we report that upregulation of Mcl-1 (Myeloid cell leukemia-1) confers acquired resistance to Taxol in human gastric cancer. Mcl-1 is shown to be stabilized in Taxol -resistant gastric cancer cells because of the hyper-activation of the PI3K/Akt signaling pathway. The increased Mcl-1 prevents of the permeabilization of the outer mitochondrial membrane, thereby blocking the Taxol-induced apoptosis. Furthermore, inhibition of Mcl-1 or PI3K/Akt pathway significantly reversed the resistant phenotype of Taxol-resistant human gastric cancer cells. Taken together, our findings broaden the view of PI3K/Akt pathway as an important regulator in Taxol acquired resistance, and implicate Mcl-1 as a specific therapeutic target for the treatment of Taxol-resistant human gastric cancer.
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Affiliation(s)
- Wu Shuang
- Department of Immunology, Anhui Medical University, Hefei, China
| | - Lili Hou
- Department of Clinical Nutriology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yan Zhu
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Qun Li
- Department of Immunology, Anhui Medical University, Hefei, China
| | - Wanglai Hu
- Department of Immunology, Anhui Medical University, Hefei, China
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Prêtre V, Wicki A. Inhibition of Akt and other AGC kinases: A target for clinical cancer therapy? Semin Cancer Biol 2017; 48:70-77. [PMID: 28473255 DOI: 10.1016/j.semcancer.2017.04.011] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 04/04/2017] [Accepted: 04/25/2017] [Indexed: 01/27/2023]
Abstract
AGC kinases have been identified to contribute to cancer development and progression. Currently, most AGC inhibitors in clinical development are Akt inhibitors such as MK-2206 or GDC-0068, which are known to promote cell growth arrest and to sensitize cancer cells to radiotherapy. Response rates in clinical trials with single agent Akt inhibitors are typically low. The observed adverse events are within the expected limits for compounds inhibiting the PI3K-mTOR axis. Preclinical and early clinical data for combination therapies are accumulating. Based on these data, several Akt inhibitors are about to enter phase 3 trials. Besides drugs that target Akt, p70S6K inhibitors have entered clinical development. Again, the response rates were rather low. In addition, relevant toxicities were identified, including a risk for coagulopathies with these compounds. Multi-AGC kinase inhibitors are also in early clinical development but the data is not sufficient yet to draw conclusions regarding their efficacy and side-effect profile. PKC inhibitors have been tested in the phase 3 setting but were found to lack efficacy. More trials with isoform-specific PKC inhibitors are expected. Taken together, therapies with AGC kinase inhibitors as single agents are unlikely to meet success. However, combination therapies and a precise stratification of patients according to the activation of signaling axes may increase the probability to see relevant efficacy with these compounds. The emergence of onco-immunotherapies holds some new challenges for these agents.
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Affiliation(s)
- Vincent Prêtre
- Department of Biomedicine, University of Basel, 4031 Basel, Switzerland
| | - Andreas Wicki
- Department of Biomedicine, University of Basel, 4031 Basel, Switzerland; Department of Medical Oncology, University Hospital Basel, 4031 Basel, Switzerland.
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15
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Chen X, Dai X, Zou P, Chen W, Rajamanickam V, Feng C, Zhuge W, Qiu C, Ye Q, Zhang X, Liang G. Curcuminoid EF24 enhances the anti-tumour activity of Akt inhibitor MK-2206 through ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction in gastric cancer. Br J Pharmacol 2017; 174:1131-1146. [PMID: 28255993 DOI: 10.1111/bph.13765] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Revised: 02/22/2017] [Accepted: 02/25/2017] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND AND PURPOSE Gastric cancer is one of the leading causes of morbidity and mortality worldwide. Akt is an anti-apoptotic kinase that plays a dynamic role in cell survival and is implicated in the pathogenesis of gastric cancer. MK-2206, the first allosteric inhibitor of Akt, is in clinical trials for a number of cancers. Although preclinical studies showed promise, clinical trials reported it had no effect when given alone at tolerated doses. The aim of our study was to delineate the effects of MK-2206 on gastric cancer cells and explore the ability of combination treatments to enhance the anti-tumour activity of MK-2206. EXPERIMENTAL APPROACH SGC-7901, BGC-823 cells and immunodeficient mice were chosen as a model to study the treatment effects. Changes in cell viability, apoptosis and ROS, endoplasmic reticulum stress and mitochondrial dysfunction in the cells were analysed by MTT assays, ROS imaging and FACSCalibur, electron microscopy, JC-1 staining and western blotting. KEY RESULTS MK-2206 induced apoptotic cell death through the generation of ROS. We utilized ROS production to target gastric cancer cells by combining MK-2206 and an ROS inducer EF24. Our in vitro and in vivo xenograft studies showed that combined treatment with MK-2206 and EF24 synergistically induced apoptosis in gastric cancer cells and caused cell cycle arrest. These activities were mediated through ROS generation and the induction of endoplasmic reticulum stress and mitochondrial dysfunction. CONCLUSION AND IMPLICATIONS Targeting ROS generation by using a combination of an Akt inhibitor and EF24 could have potential as a therapy for gastric cancer.
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Affiliation(s)
- Xi Chen
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Xuanxuan Dai
- Department of Surgical Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Peng Zou
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Weiqian Chen
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.,Department of Interventional Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, 323000, China
| | - Vinothkumar Rajamanickam
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Chen Feng
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Weishan Zhuge
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Chenyu Qiu
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Qingqing Ye
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Xiaohua Zhang
- Department of Surgical Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Guang Liang
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
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16
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Narayan RS, Fedrigo CA, Brands E, Dik R, Stalpers LJ, Baumert BG, Slotman BJ, Westerman BA, Peters GJ, Sminia P. The allosteric AKT inhibitor MK2206 shows a synergistic interaction with chemotherapy and radiotherapy in glioblastoma spheroid cultures. BMC Cancer 2017; 17:204. [PMID: 28320338 PMCID: PMC5359921 DOI: 10.1186/s12885-017-3193-9] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 03/11/2017] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Glioblastoma multiforme (GBM) is the most common, invasive and deadly primary type of malignant brain tumor. The Phosphatidylinositol-3-Kinase/AKT (PI3K/AKT) pathway is highly active in GBM and has been associated with increased survival and resistance to therapy. The aim of this study is to investigate the effects of AKT inhibition in combination with the current standard of care which consists of irradiation and temozolomide (TMZ) on human malignant glioma cells growing adherent and as multicellular spheroids in vitro. METHODS The effects of the allosteric inhibitor MK2206 combined with irradiation and TMZ were assessed on glioma cells growing adherent and as multicellular 3D spheroids. The interaction was studied on proliferation, clonogenic cell survival, cell invasion, -migration and on expression of key proteins in the PI3K-AKT pathway by western blot. RESULTS A differential effect was found at low- (1 μM) and high dose (10 μM) MK2206. At 1 μM, the inhibitor reduced phosphorylation of Thr308 and Ser473 residues of AKT in both adherent cells and spheroids. Low dose MK2206 delayed spheroid growth and sensitized spheroids to both irradiation and TMZ in a synergistic way (Combination index <0.35). In contrast, neither low nor high dose MK2206 did enhance therapy sensitivity in adherent growing cells. Effective inhibition of invasion and migration was observed only at higher doses of MK2206 (>5 μM). CONCLUSIONS The data show that a 3D spheroid model show different sensitivity to irradiation when combined with AKT inhibition. Thereby we show that MK2206 has potential synergistic efficacy to the current standard of care for glioma patients.
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Affiliation(s)
- Ravi S. Narayan
- Department of Radiation Oncology, VU University Medical Center/Cancer Center Amsterdam, P.O. Box 7057, Amsterdam, 1007 MB The Netherlands
| | - Carlos A. Fedrigo
- Department of Radiation Oncology, VU University Medical Center/Cancer Center Amsterdam, P.O. Box 7057, Amsterdam, 1007 MB The Netherlands
| | - Eelke Brands
- Department of Radiation Oncology, VU University Medical Center/Cancer Center Amsterdam, P.O. Box 7057, Amsterdam, 1007 MB The Netherlands
| | - Rogier Dik
- Department of Radiation Oncology, VU University Medical Center/Cancer Center Amsterdam, P.O. Box 7057, Amsterdam, 1007 MB The Netherlands
| | - Lukas J.A. Stalpers
- Department of Radiation Oncology, Academic Medical Center, Amsterdam, The Netherlands
| | - Brigitta G. Baumert
- Clinical Cooperation Unit Neurooncology, MediClin Robert Janker Klinik & University of Bonn Medical Center, Bonn, Germany
- Department of Radiation Oncology, Maastro Clinic, Maastricht, The Netherlands
| | - Ben J. Slotman
- Department of Radiation Oncology, VU University Medical Center/Cancer Center Amsterdam, P.O. Box 7057, Amsterdam, 1007 MB The Netherlands
| | - Bart A. Westerman
- Department of Neurosurgery, Neuro Oncology Research Group, VU University Medical Center, Amsterdam, The Netherlands
| | - Godefridus J. Peters
- Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
| | - Peter Sminia
- Department of Radiation Oncology, VU University Medical Center/Cancer Center Amsterdam, P.O. Box 7057, Amsterdam, 1007 MB The Netherlands
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Pragna Lakshmi T, Kumar A, Vijaykumar V, Natarajan S, Krishna R. Identification of natural allosteric inhibitor for Akt1 protein through computational approaches and in vitro evaluation. Int J Biol Macromol 2017; 96:200-213. [DOI: 10.1016/j.ijbiomac.2016.12.025] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Revised: 12/02/2016] [Accepted: 12/04/2016] [Indexed: 12/13/2022]
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Avan A, Narayan R, Giovannetti E, Peters GJ. Role of Akt signaling in resistance to DNA-targeted therapy. World J Clin Oncol 2016; 7:352-369. [PMID: 27777878 PMCID: PMC5056327 DOI: 10.5306/wjco.v7.i5.352] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Revised: 06/25/2016] [Accepted: 07/29/2016] [Indexed: 02/06/2023] Open
Abstract
The Akt signal transduction pathway controls most hallmarks of cancer. Activation of the Akt cascade promotes a malignant phenotype and is also widely implicated in drug resistance. Therefore, the modulation of Akt activity is regarded as an attractive strategy to enhance the efficacy of cancer therapy and irradiation. This pathway consists of phosphatidylinositol 3 kinase (PI3K), mammalian target of rapamycin, and the transforming serine-threonine kinase Akt protein isoforms, also known as protein kinase B. DNA-targeted agents, such as platinum agents, taxanes, and antimetabolites, as well as radiation have had a significant impact on cancer treatment by affecting DNA replication, which is aberrantly activated in malignancies. However, the caveat is that they may also trigger the activation of repairing mechanisms, such as upstream and downstream cascade of Akt survival pathway. Thus, each target can theoretically be inhibited in view of improving the potency of conventional treatment. Akt inhibitors, e.g., MK-2206 and perifosine, or PI3K modulators, e.g., LY294002 and Wortmannin, have shown some promising results in favor of sensitizing the cancer cells to the therapy in vitro and in vivo, which have provided the rationale for incorporation of these novel agents into multimodality treatment of different malignancies. Nevertheless, despite the acceptable safety profile of some of these agents in the clinical studies, with regard to the efficacy, the results are still too preliminary. Hence, we need to wait for the upcoming data from the ongoing trials before utilizing them into the standard care of cancer patients.
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Shi WJ, Gao JB. Molecular mechanisms of chemoresistance in gastric cancer. World J Gastrointest Oncol 2016; 8:673-681. [PMID: 27672425 PMCID: PMC5027022 DOI: 10.4251/wjgo.v8.i9.673] [Citation(s) in RCA: 118] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2016] [Revised: 06/07/2016] [Accepted: 06/29/2016] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer is the fourth most common cancer and the second leading cause of cancer deaths worldwide. Chemotherapy is one of the major treatments for gastric cancer, but drug resistance limits the effectiveness of chemotherapy, which results in treatment failure. Resistance to chemotherapy can be present intrinsically before the administration of chemotherapy or it can develop during chemotherapy. The mechanisms of chemotherapy resistance in gastric cancer are complex and multifactorial. A variety of factors have been demonstrated to be involved in chemoresistance, including the reduced intracellular concentrations of drugs, alterations in drug targets, the dysregulation of cell survival and death signaling pathways, and interactions between cancer cells and the tumor microenvironment. This review focuses on the molecular mechanisms of chemoresistance in gastric cancer and on recent studies that have sought to overcome the underlying mechanisms of chemoresistance.
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Wang C, Wang R, Zhou K, Wang S, Wang J, Shi H, Dou Y, Yang D, Chang L, Shi X, Liu Y, Xu X, Zhang X, Ke Y, Liu H. JD enhances the anti-tumour effects of low-dose paclitaxel on gastric cancer MKN45 cells both in vitro and in vivo. Cancer Chemother Pharmacol 2016; 78:971-982. [PMID: 27620208 DOI: 10.1007/s00280-016-3149-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2016] [Accepted: 08/26/2016] [Indexed: 10/21/2022]
Abstract
BACKGROUND Gastric cancer is the third most common cause of cancer mortality worldwide, and paclitaxel (PTX) is one of the most widely used traditional drugs in gastric cancer therapy. However, the response to traditional therapy is limited by acquired chemo-resistance and side effects. Here, we establish a newly designed combination therapy consisting of a compound that is a structural variant of oridonin, i.e. Jesridonin (JD), and low-dose PTX for gastric cancer cells (MKN45) to investigate whether the anti-tumour activity of low-dose PTX could be enhanced when combined with JD. METHODS The interaction of JD and low-dose PTX was detected in MKN45 cells using the median-effect analysis method. The synergistic effect on cell viability and apoptosis was measured by MTT assay, colony formation assay, transient transfection, flow cytometry and Western blotting. The synergistic in vivo effect of JD plus low-dose PTX was evaluated in nude mouse xenograft models using H&E and TUNEL staining and Western blotting. RESULTS JD plus low-dose PTX showed a synergistic effect, as the combination indexes were less than 1. Additionally, a synergistic anti-proliferative and pro-apoptotic effect was detected for the combination of JD and low-dose PTX. The apoptotic mechanism induced by JD plus PTX revealed that the combination therapy synergistically activated the mitochondrial pathway. CONCLUSION Our findings suggest that JD enhances the anti-tumour effect of low-dose PTX on gastric carcinoma cancer cells in both vitro and in vivo, accompanied by activation of the mitochondrial pathway, which may present a more effective therapeutic strategy in gastric cancer treatment.
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Affiliation(s)
- Cong Wang
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China
| | - Ran Wang
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China
| | - Kairui Zhou
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China
| | - Saiqi Wang
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China
| | - Junwei Wang
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China
| | - Hongge Shi
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China
| | - Yinhui Dou
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China
| | - Dongxiao Yang
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China
| | - Liming Chang
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China
| | - Xiaoli Shi
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China
| | - Ying Liu
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China
| | - Xiaowei Xu
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China
| | - Xiujuan Zhang
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China
| | - Yu Ke
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China
| | - Hongmin Liu
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China.
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Jin P, Wong CC, Mei S, He X, Qian Y, Sun L. MK-2206 co-treatment with 5-fluorouracil or doxorubicin enhances chemosensitivity and apoptosis in gastric cancer by attenuation of Akt phosphorylation. Onco Targets Ther 2016; 9:4387-96. [PMID: 27499633 PMCID: PMC4959411 DOI: 10.2147/ott.s106303] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The anticancer effect of MK-2206, an Akt inhibitor, has been explored in some types of cancers, but its effect on gastric cancer is unclear. In this study, we aimed to investigate its anticancer effect in gastric cancer cells. Cell viability and colony formation assays showed that MK-2206 effectively inhibited the proliferation of SGC-7901 and MKN45 cells. The 50% inhibitory concentration values after 24, 48, and 72 hours' treatment were 22.92, 13.68, and 8.55 μM in SGC-7901 cells and 19.21, 13.10, and 9.11 μM in MKN45 cells, respectively. Treatment with MK-2206 induced apoptosis in SGC-7901 cells as indicated by flow cytometry assay. The combination indexes of MK-2206 and doxorubicin were 0.59 in SGC-7901 cells and 0.57 in MKN45 cells, whereas for 5-fluorouracil (5-FU) the indexes were 0.17 in SGC-7901 cells and 0.73 in MKN45 cells, indicating that MK-2206 could work synergistically with doxorubicin or 5-FU to inhibit cell growth. Furthermore, a small dose (1 μM) of MK-2206 co-treatment with doxorubicin or 5-FU was sufficient for complete inhibition of chemotherapeutic alteration of phosphorylated Akt expression and significant enhancement of pro-apoptosis effect through the activation of caspase pathway. Therefore, MK-2206 effectively inhibits gastric cancer cell growth by attenuation of Akt phosphorylation and synergistically enhances the antitumor effect of doxorubicin and 5-FU via caspase-dependent apoptosis.
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Affiliation(s)
- Piaopiao Jin
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou; Department of Gastroenterology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang
| | - Chi Chun Wong
- Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong
| | - Sibin Mei
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou
| | - Xingkang He
- Institute of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Yun Qian
- Institute of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Leimin Sun
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou
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Tao K, Yin Y, Shen Q, Chen Y, Li R, Chang W, Bai J, Liu W, Shi L, Zhang P. Akt inhibitor MK-2206 enhances the effect of cisplatin in gastric cancer cells. Biomed Rep 2016; 4:365-368. [PMID: 26998277 DOI: 10.3892/br.2016.594] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Accepted: 01/27/2016] [Indexed: 01/19/2023] Open
Abstract
The phosphoinositide 3-kinase/Akt pathway activation commonly occurs in various types of human cancer and has an important role in chemoresistance. Combination of traditional chemotherapy drugs and molecular-targeted agents is a promising strategy for cancer therapy, which has shown enhanced cytotoxicity and lower drug resistance. The present study found that the Akt inhibitor, MK-2206, can increase the effect of cisplatin in the gastric cancer cell line AGS, which has higher Akt phosphorylation, but exhibited a poor combination effect in MKN-45 and MGC-803 cells, which have limited Akt activation. The MTT assay demonstrated that sequential treatment of cisplatin, followed by the Akt inhibitor, MK-2206, caused a synergistic effect of proliferation inhibition, and the apoptosis assay by propidium iodide/fluorescein isothiocyanate staining also showed that combination treatment induced more apoptosis compared to the monotherapy groups. Using western blot analysis, MK-2206 was shown to significantly suppress the phosphorylation of Akt (Ser473), however, the expression of total Akt remained the same, and the combination treatment also increased the expression of cleaved poly adenosine diphosphate ribose polymerase, which contributed to apoptosis.
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Affiliation(s)
- Kaixiong Tao
- Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Yuping Yin
- Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Qian Shen
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Ying Chen
- Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Ruidong Li
- Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Weilong Chang
- Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Jie Bai
- Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Weizhen Liu
- Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Liang Shi
- Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Peng Zhang
- Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
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23
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MK2206 overcomes the resistance of human liver cancer stem cells to sorafenib by inhibition of pAkt and upregulation of pERK. Tumour Biol 2015; 37:8047-55. [DOI: 10.1007/s13277-015-4707-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Accepted: 12/20/2015] [Indexed: 12/31/2022] Open
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24
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ROS-mediated EB1 phosphorylation through Akt/GSK3β pathway: implication in cancer cell response to microtubule-targeting agents. Oncotarget 2015; 5:3408-23. [PMID: 24930764 PMCID: PMC4102819 DOI: 10.18632/oncotarget.1982] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Microtubule-targeting agents (MTAs) are largely administered in adults and children cancers. Better deciphering their mechanism of action is of prime importance to develop more convenient therapy strategies. Here, we addressed the question of how reactive oxygen species (ROS) generation by mitochondria can be necessary for MTA efficacy. We showed for the first time that EB1 associates with microtubules in a phosphorylation-dependent manner, under control of ROS. By using phospho-defective mutants, we further characterized the Serine 155 residue as critical for EB1 accumulation at microtubule plus-ends, and both cancer cell migration and proliferation. Phosphorylation of EB1 on the Threonine 166 residue triggered opposite effects, and was identified as a requisite molecular switch in MTA activities. We then showed that GSK3β activation was responsible for MTA-triggered EB1 phosphorylation, resulting from ROS-mediated inhibition of upstream Akt. We thus disclosed here a novel pathway by which generation of mitochondrial ROS modulates microtubule dynamics through phosphorylation of EB1, improving our fundamental knowledge about this oncogenic protein, and pointing out the need to re-examine the current dogma of microtubule targeting by MTAs. The present work also provides a strong mechanistic rational to the promising therapeutic strategies that currently combine MTAs with anti-Akt targeted therapies.
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Holland WS, Chinn DC, Lara PN, Gandara DR, Mack PC. Effects of AKT inhibition on HGF-mediated erlotinib resistance in non-small cell lung cancer cell lines. J Cancer Res Clin Oncol 2014; 141:615-26. [PMID: 25323938 DOI: 10.1007/s00432-014-1855-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Accepted: 10/08/2014] [Indexed: 12/17/2022]
Abstract
PURPOSE Acquired resistance to erlotinib in patients with EGFR-mutant non-small cell lung cancer can result from aberrant activation of alternative receptor tyrosine kinases, such as the HGF-driven c-MET receptor. We sought to determine whether inhibition of AKT signaling could augment erlotinib activity and abrogate HGF-mediated resistance. METHODS The effects of MK-2206, a selective AKT inhibitor, were evaluated in combination with erlotinib on a large panel of 13 lung cancer cell lines containing different EGFR or KRAS abnormalities. The activity of the combination was assessed using proliferation assays, flow cytometry and immunoblotting. The MEK inhibitor PD0325901 was used to determine the role of the MAP kinase pathway in erlotinib resistance. RESULTS The combination of MK-2206 and erlotinib resulted in synergistic growth inhibition independent of EGFR mutation status. In cell lines where HGF blocked the anti-proliferative and cytotoxic effects of erlotinib, MK-2206 could restore cell cycle arrest, but MEK inhibition was required for erlotinib-dependent apoptosis. Both AKT and MEK inhibition contributed to cell death independent of erlotinib in the T790M-containing H1975 and the EGFR-WT cell lines tested. CONCLUSIONS These findings illustrate the potential advantages and challenges of combined signal transduction inhibition as a generalized strategy to circumvent acquired erlotinib resistance.
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Affiliation(s)
- William S Holland
- Comprehensive Cancer Center, University of California, Davis, 4501 X Street, Suite 3016, Sacramento, CA, 95817, USA
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26
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Wu G, Qin XQ, Guo JJ, Li TY, Chen JH. AKT/ERK activation is associated with gastric cancer cell resistance to paclitaxel. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2014; 7:1449-1458. [PMID: 24817940 PMCID: PMC4014224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 01/12/2014] [Accepted: 02/18/2014] [Indexed: 06/03/2023]
Abstract
Paclitaxel (PTX) has shown encouraging activity in the treatment of advanced gastric cancer (GC). However, the fact that more than half of GC patients respond poorly to PTX-based chemotherapies demonstrates the urgent need for biomarkers of PTX sensitivity in GC patients. In the present work, three GC cell lines (BGC-823, HGC-27 and NCI-N87) with different sensitivities to PTX were subjected to DNA microarray analysis. The significantly differentially expressed genes and microRNAs (miRs) were identified and pathway signatures for PTX sensitivity were proposed. Ingenuity Pathway Analysis results showed that the differentially expressed genes were mainly enriched in the ErbB signaling pathway and other pathways. Additionally, the AKT/ERK signaling pathway, which is the pathway downstream of ErbB, was predicted to be active in PTX-resistant GC cell lines. ErbB3 overexpression and AKT/ERK activation in PTX-resistant cell lines were validated, respectively, by quantitative PCR and immunoblotting. Furthermore, 10 miRs were dramatically differently expressed in the three GC cell lines, and a miR-gene network was constructed from these data. Our work uncovered a reliable signature for PTX sensitivity in GC and potential therapeutic targets for GC treatments.
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Affiliation(s)
- Gang Wu
- Department of General Surgery, Huashan Hospital, Fudan UniversityShanghai 200040, China
- Department of General Surgery, Renhe HospitalBaoshan District, Shanghai 20043, China
| | - Xue-Qian Qin
- Department of General Surgery, Renhe HospitalBaoshan District, Shanghai 20043, China
| | - Jing-Jing Guo
- Department of General Surgery, Renhe HospitalBaoshan District, Shanghai 20043, China
| | - Tian-Yi Li
- Department of General Surgery, Huashan Hospital, Fudan UniversityShanghai 200040, China
| | - Jin-Hong Chen
- Department of General Surgery, Huashan Hospital, Fudan UniversityShanghai 200040, China
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