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1
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Ye Q, Zhuang XZ, Li J, Zhou X. Targeting the inhibitors of apoptosis proteins (IAPs) to combat drug resistance in cancers. Front Pharmacol 2025; 16:1562167. [PMID: 40223934 PMCID: PMC11985858 DOI: 10.3389/fphar.2025.1562167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Accepted: 03/21/2025] [Indexed: 04/15/2025] Open
Abstract
Inhibitors of Apoptosis Proteins (IAPs) are a family of anti-apoptotic proteins that play a pivotal role in apoptosis in general but also as oncoproteins in cancer progression and, more importantly, drug resistance. IAPs enable cancer cells to evade programmed cell death and adapt to therapeutic stress by inhibiting pro-apoptotic caspase activity as well as modulating pivotal survival pathways. Recent advancements in targeting IAPs, particularly through the use of SMAC (second mitochondria-derived activator of caspase) mimetics and other small-molecule antagonists or inhibitors, have opened new avenues for overcoming drug resistance in cancers. The current review attempted to summarize the status quo of IAPs' role in promoting chemotherapeutic drug resistance in various cancer treatments and discuss the most recent development of IAP-targeting therapies, particularly small-molecule inhibitors including their combinational strategies to enhance the sensitivity or achieve synergism to existing therapeutics. Additionally, we also outline the challenges and offer future perspectives for optimizing IAP-targeted approaches to improve clinical outcomes.
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Affiliation(s)
- Qingmei Ye
- Hainan General Hospital and Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China
| | - Xiao-Zhao Zhuang
- Hainan General Hospital and Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China
| | - Juan Li
- Hubei Province Key Laboratory of Traditional Chinese Medicine Resource and Chemistry, Department of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei, China
| | - Xin Zhou
- The Fifth People’s Hospital of Hainan Province and Affiliated Dermatology Hospital of Hainan Medical University, Haikou, Hainan, China
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2
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Zhivkov AM, Hristova SH, Popov TT. Anticancer Nanoparticle Carriers of the Proapoptotic Protein Cytochrome c. Pharmaceutics 2025; 17:305. [PMID: 40142969 PMCID: PMC11945056 DOI: 10.3390/pharmaceutics17030305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 02/13/2025] [Accepted: 02/19/2025] [Indexed: 03/28/2025] Open
Abstract
This review discusses the literature data on the synthesis, physicochemical properties, and cytotoxicity of composite nanoparticles bearing the mitochondrial protein cytochrome c (cytC), which can act as a proapoptotic mediator in addition to its main function as an electron carrier in the electron transport chain. The introduction of exogenous cytC via absorption of carrier particles, the phagocytosis of colloid particles of submicrometric size, or the receptor-mediated endocytosis of nanoparticles in cancer cells, initiates the process of apoptosis-a multistage cascade of biochemical reactions leading to complete destruction of the cells. CytC-carrier composite particles have the potential for use in the treatment of neoplasms with superficial localization: skin, mouth, stomach, colon, etc. This approach can solve the two main problems of anticancer therapy: selectivity and non-toxicity. Selectivity is based on the incapability of the normal cell to absorb (nano)particles, except for the cells of the immune system. The use of cytC as a protein that normally functions in mitochondria is harmless for the macroorganism. In this review, the factors limiting cytotoxicity and the ways to increase it are discussed from the point of view of the physicochemical properties of the cytC-carrier particles. The different techniques used for the preparation of cytC-bearing colloids and nanoparticles are discussed. Articles reporting the achievement of high cytotoxicity with each of the techniques are critically analyzed.
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Affiliation(s)
- Alexandar M. Zhivkov
- Scientific Research Center, “St. Kliment Ohridski” Sofia University, 8 Dragan Tsankov Blvd., 1164 Sofia, Bulgaria
| | - Svetlana H. Hristova
- Department of Medical Physics and Biophysics, Medical Faculty, Medical University—Sofia, Zdrave Str. 2, 1431 Sofia, Bulgaria
- Faculty of Physics, Sofia University, 5 James Bourchier Blvd., 1164 Sofia, Bulgaria
| | - Trifon T. Popov
- Medical Faculty, Medical University—Sofia, Zdrave Str. 2, 1431 Sofia, Bulgaria
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3
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O'Leary B, Skinner H, Schoenfeld JD, Licitra L, Le Tourneau C, Esdar C, Schroeder A, Salmio S, Psyrri A. Evasion of apoptosis and treatment resistance in squamous cell carcinoma of the head and neck. Cancer Treat Rev 2024; 129:102773. [PMID: 38878677 DOI: 10.1016/j.ctrv.2024.102773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 05/29/2024] [Accepted: 05/30/2024] [Indexed: 08/18/2024]
Abstract
Combinations of surgery, radiotherapy and chemotherapy can eradicate tumors in patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN), but a significant proportion of tumors progress, recur, or do not respond to therapy due to treatment resistance. The prognosis for these patients is poor, thus new approaches are needed to improve outcomes. Key resistance mechanisms to chemoradiotherapy (CRT) in patients with LA SCCHN are alterations to the pathways that mediate apoptosis, a form of programmed cell death. Targeting dysregulation of apoptotic pathways represents a rational therapeutic strategy in many types of cancer, with a number of proteins, including the pro-survival B-cell lymphoma 2 family and inhibitors of apoptosis proteins (IAPs), having been identified as druggable targets. This review discusses the mechanisms by which apoptosis occurs under physiological conditions, and how this process is abnormally restrained in LA SCCHN tumor cells, with treatment strategies aimed at re-enabling apoptosis in LA SCCHN also considered. In particular, the development of, and future opportunities for, IAP inhibitors in LA SCCHN are discussed, in light of recent encouraging proof-of-concept clinical trial data.
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Affiliation(s)
| | | | | | - Lisa Licitra
- Fondazione IRCCS Istituto Nazionale dei Tumori, Milan and University of Milan, Italy
| | | | | | | | | | - Amanda Psyrri
- Attikon University Hospital, National Kapodistrian University of Athens, Greece
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4
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Lee CY, Chen PN, Kao SH, Wu HH, Hsiao YH, Huang TY, Wang PH, Yang SF. Deoxyshikonin triggers apoptosis in cervical cancer cells through p38 MAPK-mediated caspase activation. ENVIRONMENTAL TOXICOLOGY 2024; 39:4308-4317. [PMID: 38717057 DOI: 10.1002/tox.24323] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 04/10/2024] [Accepted: 04/27/2024] [Indexed: 08/09/2024]
Abstract
Deoxyshikonin (DSK) is a biological component derived from Lithospermum erythrorhizon. Although DSK possesses potential anticancer activities, whether DSK exerts anticancer effects on cervical cancer cells is incompletely explored. This study was aimed to investigate the anticancer activity of DSK against cervical cancer cells and its molecular mechanisms. Cell viability was evaluated by MTT assay. Level of phosphorylation and protein was determined using Western blot. Involvement of signaling kinases was assessed by specific inhibitors. Our results revealed that DSK reduced viability of human cervical cell in a dose-dependent fashion. Meanwhile, DSK significantly elicited apoptosis of HeLa and SiHa cells. Apoptosis microarray was used to elucidate the involved pathways, and the results showed that DSK dose-dependently diminished cellular inhibitor of apoptosis protein 1 (cIAP1), cIAP2, and XIAP, and induced cleavage of poly(ADP-ribose) polymerase (PARP) and caspase-8/9/3. Furthermore, we observed that DSK significantly triggered activation of ERK, JNK, and p38 MAPK (p38), and only inhibition of p38 diminished the DSK-mediated pro-caspases cleavage. Taken together, our results demonstrate that DSK has anti-cervical cancer effects via the apoptotic cascade elicited by downregulation of IAPs and p38-mediated caspase activation. This suggests that DSK could act as an adjuvant to facilitate cervical cancer management.
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Affiliation(s)
- Chung-Yuan Lee
- Department of Obstetrics and Gynecology, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan
- Department of Nursing, Chang Gung University of Science and Technology, Chiayi, Taiwan
| | - Pei-Ni Chen
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Shao-Hsuan Kao
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Heng-Hsiung Wu
- Program for Cancer Biology and Drug Discovery, China Medical University, Taichung, Taiwan
| | - Yi-Hsuan Hsiao
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua, Taiwan
- Women's Health Research Laboratory, Changhua Christian Hospital, Changhua, Taiwan
| | - Tzu-Yu Huang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Po-Hui Wang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
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5
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Yoo H, Kim Y, Kim J, Cho H, Kim K. Overcoming Cancer Drug Resistance with Nanoparticle Strategies for Key Protein Inhibition. Molecules 2024; 29:3994. [PMID: 39274842 PMCID: PMC11396748 DOI: 10.3390/molecules29173994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 08/06/2024] [Accepted: 08/21/2024] [Indexed: 09/16/2024] Open
Abstract
Drug resistance remains a critical barrier in cancer therapy, diminishing the effectiveness of chemotherapeutic, targeted, and immunotherapeutic agents. Overexpression of proteins such as B-cell lymphoma 2 (Bcl-2), inhibitor of apoptosis proteins (IAPs), protein kinase B (Akt), and P-glycoprotein (P-gp) in various cancers leads to resistance by inhibiting apoptosis, enhancing cell survival, and expelling drugs. Although several inhibitors targeting these proteins have been developed, their clinical use is often hampered by systemic toxicity, poor bioavailability, and resistance development. Nanoparticle-based drug delivery systems present a promising solution by improving drug solubility, stability, and targeted delivery. These systems leverage the Enhanced Permeation and Retention (EPR) effect to accumulate in tumor tissues, reducing off-target toxicity and increasing therapeutic efficacy. Co-encapsulation strategies involving anticancer drugs and resistance inhibitors within nanoparticles have shown potential in achieving coordinated pharmacokinetic and pharmacodynamic profiles. This review discusses the mechanisms of drug resistance, the limitations of current inhibitors, and the advantages of nanoparticle delivery systems in overcoming these challenges. By advancing these technologies, we can enhance treatment outcomes and move towards more effective cancer therapies.
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Affiliation(s)
- Hyeonji Yoo
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Yeonjin Kim
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Jinseong Kim
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Hanhee Cho
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Kwangmeyung Kim
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
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6
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Cao Y, Lu C, Beeraka NM, Efetov S, Enikeev M, Fu Y, Yang X, Basappa B, He M, Li Z. Exploring the relationship between anastasis and mitochondrial ROS-mediated ferroptosis in metastatic chemoresistant cancers: a call for investigation. Front Immunol 2024; 15:1428920. [PMID: 39015566 PMCID: PMC11249567 DOI: 10.3389/fimmu.2024.1428920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Accepted: 06/14/2024] [Indexed: 07/18/2024] Open
Abstract
Ferroptosis induces significant changes in mitochondrial morphology, including membrane condensation, volume reduction, cristae alteration, and outer membrane rupture, affecting mitochondrial function and cellular fate. Recent reports have described the intrinsic cellular iron metabolism and its intricate connection to ferroptosis, a significant kind of cell death characterized by iron dependence and oxidative stress regulation. Furthermore, updated molecular insights have elucidated the significance of mitochondria in ferroptosis and its implications in various cancers. In the context of cancer therapy, understanding the dual role of anastasis and ferroptosis in chemoresistance is crucial. Targeting the molecular pathways involved in anastasis may enhance the efficacy of ferroptosis inducers, providing a synergistic approach to overcome chemoresistance. Research into how DNA damage response (DDR) proteins, metabolic changes, and redox states interact during anastasis and ferroptosis can offer new insights into designing combinatorial therapeutic regimens against several cancers associated with stemness. These treatments could potentially inhibit anastasis while simultaneously inducing ferroptosis, thereby reducing the likelihood of cancer cells evading death and developing resistance to chemotherapy. The objective of this study is to explore the intricate interplay between anastasis, ferroptosis, EMT and chemoresistance, and immunotherapeutics to better understand their collective impact on cancer therapy outcomes. We searched public research databases including google scholar, PubMed, relemed, and the national library of medicine related to this topic. In this review, we discussed the interplay between the tricarboxylic acid cycle and glycolysis implicated in modulating ferroptosis, adding complexity to its regulatory mechanisms. Additionally, the regulatory role of reactive oxygen species (ROS) and the electron transport chain (ETC) in ferroptosis has garnered significant attention. Lipid metabolism, particularly involving GPX4 and System Xc- plays a significant role in both the progression of ferroptosis and cancer. There is a need to investigate the intricate interplay between anastasis, ferroptosis, and chemoresistance to better understand cancer therapy clinical outcomes. Integrating anastasis, and ferroptosis into strategies targeting chemoresistance and exploring its potential synergy with immunotherapy represent promising avenues for advancing chemoresistant cancer treatment. Understanding the intricate interplay among mitochondria, anastasis, ROS, and ferroptosis is vital in oncology, potentially revolutionizing personalized cancer treatment and drug development.
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Affiliation(s)
- Yu Cao
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation, Moscow, Russia
| | - Chang Lu
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation, Moscow, Russia
| | - Narasimha M. Beeraka
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation, Moscow, Russia
- Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, United States
- Raghavendra Institute of Pharmaceutical Education and Research (RIPER), Anantapuramu, Chiyyedu, Andhra Pradesh, India
| | - Sergey Efetov
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation, Moscow, Russia
| | - Mikhail Enikeev
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation, Moscow, Russia
| | - Yu Fu
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation, Moscow, Russia
| | - Xinyi Yang
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation, Moscow, Russia
| | - Basappa Basappa
- Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Mysore, Karnataka, India
| | - Mingze He
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation, Moscow, Russia
| | - Zhi Li
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation, Moscow, Russia
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7
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Cao Y, Lu C, Beeraka NM, Efetov S, Enikeev M, Fu Y, Yang X, Basappa B, He M, Li Z. Exploring the relationship between anastasis and mitochondrial ROS-mediated ferroptosis in metastatic chemoresistant cancers: a call for investigation. Front Immunol 2024; 15. [DOI: https:/doi.org/10.3389/fimmu.2024.1428920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/20/2024] Open
Abstract
Ferroptosis induces significant changes in mitochondrial morphology, including membrane condensation, volume reduction, cristae alteration, and outer membrane rupture, affecting mitochondrial function and cellular fate. Recent reports have described the intrinsic cellular iron metabolism and its intricate connection to ferroptosis, a significant kind of cell death characterized by iron dependence and oxidative stress regulation. Furthermore, updated molecular insights have elucidated the significance of mitochondria in ferroptosis and its implications in various cancers. In the context of cancer therapy, understanding the dual role of anastasis and ferroptosis in chemoresistance is crucial. Targeting the molecular pathways involved in anastasis may enhance the efficacy of ferroptosis inducers, providing a synergistic approach to overcome chemoresistance. Research into how DNA damage response (DDR) proteins, metabolic changes, and redox states interact during anastasis and ferroptosis can offer new insights into designing combinatorial therapeutic regimens against several cancers associated with stemness. These treatments could potentially inhibit anastasis while simultaneously inducing ferroptosis, thereby reducing the likelihood of cancer cells evading death and developing resistance to chemotherapy. The objective of this study is to explore the intricate interplay between anastasis, ferroptosis, EMT and chemoresistance, and immunotherapeutics to better understand their collective impact on cancer therapy outcomes. We searched public research databases including google scholar, PubMed, relemed, and the national library of medicine related to this topic. In this review, we discussed the interplay between the tricarboxylic acid cycle and glycolysis implicated in modulating ferroptosis, adding complexity to its regulatory mechanisms. Additionally, the regulatory role of reactive oxygen species (ROS) and the electron transport chain (ETC) in ferroptosis has garnered significant attention. Lipid metabolism, particularly involving GPX4 and System Xc- plays a significant role in both the progression of ferroptosis and cancer. There is a need to investigate the intricate interplay between anastasis, ferroptosis, and chemoresistance to better understand cancer therapy clinical outcomes. Integrating anastasis, and ferroptosis into strategies targeting chemoresistance and exploring its potential synergy with immunotherapy represent promising avenues for advancing chemoresistant cancer treatment. Understanding the intricate interplay among mitochondria, anastasis, ROS, and ferroptosis is vital in oncology, potentially revolutionizing personalized cancer treatment and drug development.
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8
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Franzese O, Ancona P, Bianchi N, Aguiari G. Apoptosis, a Metabolic "Head-to-Head" between Tumor and T Cells: Implications for Immunotherapy. Cells 2024; 13:924. [PMID: 38891056 PMCID: PMC11171541 DOI: 10.3390/cells13110924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 05/18/2024] [Accepted: 05/22/2024] [Indexed: 06/20/2024] Open
Abstract
Induction of apoptosis represents a promising therapeutic approach to drive tumor cells to death. However, this poses challenges due to the intricate nature of cancer biology and the mechanisms employed by cancer cells to survive and escape immune surveillance. Furthermore, molecules released from apoptotic cells and phagocytes in the tumor microenvironment (TME) can facilitate cancer progression and immune evasion. Apoptosis is also a pivotal mechanism in modulating the strength and duration of anti-tumor T-cell responses. Combined strategies including molecular targeting of apoptosis, promoting immunogenic cell death, modulating immunosuppressive cells, and affecting energy pathways can potentially overcome resistance and enhance therapeutic outcomes. Thus, an effective approach for targeting apoptosis within the TME should delicately balance the selective induction of apoptosis in tumor cells, while safeguarding survival, metabolic changes, and functionality of T cells targeting crucial molecular pathways involved in T-cell apoptosis regulation. Enhancing the persistence and effectiveness of T cells may bolster a more resilient and enduring anti-tumor immune response, ultimately advancing therapeutic outcomes in cancer treatment. This review delves into the pivotal topics of this multifaceted issue and suggests drugs and druggable targets for possible combined therapies.
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Affiliation(s)
- Ornella Franzese
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy;
| | - Pietro Ancona
- Department of Translational Medicine, University of Ferrara, Via Fossato di Mortara 70, 44121 Ferrara, Italy;
| | - Nicoletta Bianchi
- Department of Translational Medicine, University of Ferrara, Via Fossato di Mortara 70, 44121 Ferrara, Italy;
| | - Gianluca Aguiari
- Department of Neuroscience and Rehabilitation, University of Ferrara, Via F. Mortara 74, 44121 Ferrara, Italy;
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9
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Ferris RL, Mehanna H, Schoenfeld JD, Tahara M, Yom SS, Haddad R, König A, Witzler P, Bajars M, Tourneau CL. Xevinapant plus radiotherapy in resected, high-risk, cisplatin-ineligible LA SCCHN: the phase III XRay Vision study design. Future Oncol 2024; 20:739-748. [PMID: 38197296 DOI: 10.2217/fon-2023-0774] [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] [Indexed: 01/11/2024] Open
Abstract
There is a significant unmet need and lack of treatment options for patients with resected, high-risk, cisplatin-ineligible locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). Xevinapant, a first-in-class, potent, oral, small-molecule IAP inhibitor, is thought to restore cancer cell sensitivity to chemotherapy and radiotherapy in clinical and preclinical studies. We describe the design of XRay Vision (NCT05386550), an international, randomized, double-blind, phase III study. Approximately 700 patients with resected, high-risk, cisplatin-ineligible LA SCCHN will be randomized 1:1 to receive 6 cycles of xevinapant or placebo, in combination with radiotherapy for the first 3 cycles. The primary end point is disease-free survival, and secondary end points include overall survival, health-related quality of life, and safety.
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Affiliation(s)
- Robert L Ferris
- University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA
| | | | | | - Makoto Tahara
- National Cancer Center Hospital East, Kashiwa, Japan
| | - Sue S Yom
- University of California San Francisco, San Francisco, CA 94143, USA
| | | | | | | | | | - Christophe Le Tourneau
- Department of Drug Development and Innovation (D3i), Institut Curie, Paris-Saclay University, Paris, France
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10
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Wang R, Wang Y, Liu X, Liu M, Sun L, Pan X, Hu H, Jiang B, Zou Y, Liu Q, Gong Y, Wang M, Sun G. Anastasis enhances metastasis and chemoresistance of colorectal cancer cells through upregulating cIAP2/NFκB signaling. Cell Death Dis 2023; 14:388. [PMID: 37391410 PMCID: PMC10313691 DOI: 10.1038/s41419-023-05916-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 06/15/2023] [Accepted: 06/21/2023] [Indexed: 07/02/2023]
Abstract
Chemotherapy is a common strategy to treat cancer. However, acquired resistance and metastasis are the major obstacles to successful treatment. Anastasis is a process by which cells survive executioner caspase activation when facing apoptotic stress. Here we demonstrate that colorectal cancer cells can undergo anastasis after transient exposure to chemotherapeutic drugs. Using a lineage tracing system to label and isolate cells that have experienced executioner caspase activation in response to drug treatment, we show that anastasis grants colorectal cancer cells enhanced migration, metastasis, and chemoresistance. Mechanistically, treatment with chemotherapeutic drugs induces upregulated expression of cIAP2 and activation of NFκB, which are required for cells to survive executioner caspase activation. The elevated cIAP2/NFκB signaling persists in anastatic cancer cells to promote migration and chemoresistance. Our study unveils that cIAP2/NFκB-dependent anastasis promotes acquired resistance and metastasis after chemotherapy.
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Affiliation(s)
- Ru Wang
- Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Yuxing Wang
- Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Xiaohe Liu
- Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Menghao Liu
- Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Lili Sun
- Key Laboratory of Experimental Teratology, Ministry of Education, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Xiaohua Pan
- Department of Breast and Thyroid Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
| | - Huili Hu
- Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
- Department of Systems Biomedicine and Research Center of Stem Cell and Regenerative Medicine, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Baichun Jiang
- Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Yongxin Zou
- Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Qiao Liu
- Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Yaoqin Gong
- Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Molin Wang
- Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
| | - Gongping Sun
- Key Laboratory of Experimental Teratology, Ministry of Education, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
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11
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Singh S, Rani H, Sharma N, Behl T, Zahoor I, Makeen HA, Albratty M, Alhazm HA, Aleya L. Targeting multifunctional magnetic nanowires for drug delivery in cancer cell death: an emerging paradigm. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023; 30:57219-57235. [PMID: 37010687 DOI: 10.1007/s11356-023-26650-w] [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: 12/16/2021] [Accepted: 03/21/2023] [Indexed: 05/10/2023]
Abstract
Apoptosis, often known as programmed cell death is a mechanism used by numerous species to maintain tissue homeostasis. The process leading to cell death is complicated because it requires the stimulation of caspases. According to several studies, nanowires have important medical benefits, can kill cells by adhering to cancer cells, destroying them, and killing the entire cell using a triple attack that integrates vibration, heat, and drug delivery to trigger apoptosis. The sewage effluents and industrial, fertilizer and organic wastes decomposition can produce elevated levels of chemicals in the environment which may interrupt the cell cycle and activate apoptosis. The purpose of this review is to give a thorough summary of the evidence that is currently available on apoptosis. Current review discussed topics like the morphological and biochemical alterations that occur during apoptosis, as well as the various mechanisms that cause cell death, including the intrinsic (or mitochondrial), extrinsic (or death receptor), and intrinsic endoplasmic reticulum pathway. The apoptosis reduction in cancer development is mediated by (i) an imbalance between pro- and anti-apoptotic proteins, such as members of the B-cell lymphoma-2 (BCL2) family of proteins, tumour protein 53 and inhibitor of apoptosis proteins, (ii) a reduction in caspase activity, and (iii) impaired death receptor signalling. This review does an excellent task of outlining the function of nanowires in both apoptosis induction and targeted drug delivery for cancer cells. A comprehensive summary of the relevance of nanowires synthesised for the purpose of inducing apoptosis in cancer cells has been compiled collectively.
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Affiliation(s)
- Sukhbir Singh
- Department of Pharmaceutics, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, Haryana, 133207, India
| | - Hema Rani
- GHG Khalsa College of Pharmacy, Gurusar Sadhar, Ludhiana, 141104, India
| | - Neelam Sharma
- Department of Pharmaceutics, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, Haryana, 133207, India.
| | - Tapan Behl
- School of Health Sciences &Technology, University of Petroleum and Energy Studies, Bidholi, Uttarakhand, 248007, Dehradun, India
| | - Ishrat Zahoor
- Department of Pharmaceutics, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, Haryana, 133207, India
| | - Hafiz A Makeen
- Pharmacy Practice Research Unit, Clinical Pharmacy Department, College of Pharmacy, Jazan University, Jazan, Saudi Arabia
| | - Mohammed Albratty
- Department of Pharmaceutical Chemistry, College of Pharmacy, Jazan University, Jazan, Saudi Arabia
| | - Hassan A Alhazm
- Department of Pharmaceutical Chemistry, College of Pharmacy, Jazan University, Jazan, Saudi Arabia
- Substance Abuse and Toxicology Research Centre, Jazan University, Jazan, Saudi Arabia
| | - Lotfi Aleya
- Chrono-Environment Laboratory, UMR CNRS 6249, Bourgogne Franche-Comté University, Besançon, France
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12
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Saha G, Sarkar S, Mohanta PS, Kumar K, Chakrabarti S, Basu M, Ghosh MK. USP7 targets XIAP for cancer progression: Establishment of a p53-independent therapeutic avenue for glioma. Oncogene 2022; 41:5061-5075. [PMID: 36243803 DOI: 10.1038/s41388-022-02486-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 09/18/2022] [Accepted: 09/23/2022] [Indexed: 11/09/2022]
Abstract
Ubiquitin specific peptidase 7 (USP7) is a deubiquitinating enzyme (DUB) that removes ubiquitin tags from specific target protein substrates in order to alter their degradation rate, sub-cellular localization, interaction, and activity. The induction of apoptosis upon USP7 inhibition is well established in cancer containing wild type p53, which operates through the 'USP7-Mdm2-p53' axis. However, in cancers without functional p53, USP7-dependent apoptosis is induced through many other alternative pathways. Here, we have identified another critical p53 independent path active under USP7 to regulate apoptosis. Proteomics analysis identifies XIAP as a potential target of USP7-dependent deubiquitination. GSEA analysis revealed up-regulation of apoptosis signalling upon USP7 inhibition associated with XIAP down-regulation. Modulation of USP7 expression and activity in multiple cancer cell lines showed that USP7 deubiquitinates XIAP to inhibit apoptosis in a caspase-dependent pathway, and the combinatorial inhibition of USP7 and XIAP induces apoptosis in vitro and in vivo. Immunohistochemical staining revealed that grade-wise accumulation of USP7 correlated with an elevated level of XIAP in glioma tissue. This is the first report on the identification and validation of XIAP as a novel substrate of USP7 and together, they involve in the empowerment of the tumorigenic potential of cancer cells by inhibiting apoptosis.
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Affiliation(s)
- Gouranga Saha
- Cancer Biology & Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector-V, Salt Lake, Kolkata- 700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata, 700032, India
| | - Sibani Sarkar
- Cancer Biology & Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector-V, Salt Lake, Kolkata- 700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata, 700032, India
| | - Partha S Mohanta
- Cancer Biology & Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector-V, Salt Lake, Kolkata- 700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata, 700032, India
| | - Krishna Kumar
- Structural Biology & Bioinformatics Division, CSIR-IICB, TRUE Campus, CN-6, Sector-V, Salt Lake, Kolkata, 700091, India
| | - Saikat Chakrabarti
- Structural Biology & Bioinformatics Division, CSIR-IICB, TRUE Campus, CN-6, Sector-V, Salt Lake, Kolkata, 700091, India
| | - Malini Basu
- Department of Microbiology, Dhruba Chand Halder College, South 24 Paraganas, PIN -743372, Dakshin Barasat, West Bengal, India
| | - Mrinal K Ghosh
- Cancer Biology & Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector-V, Salt Lake, Kolkata- 700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata, 700032, India.
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13
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Tsukada R, Nomura M, Ueno T, Okuyama H. Inhibition of cIAP1 in the effective suppression of chemotherapy‑resistant hepatoblastoma. Oncol Rep 2022; 47:79. [PMID: 35211761 DOI: 10.3892/or.2022.8290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 01/19/2022] [Indexed: 11/05/2022] Open
Abstract
Cellular inhibitor of apoptosis protein‑1 (cIAP1) is a key regulator of programmed cell death and is known to be associated with chemotherapeutic resistance. The present study aimed to investigate the antitumor efficacy of birinapant, a novel selective inhibitor of cIAP1, against cisplatin (CDDP)‑resistant hepatoblastoma (HB) cells. Western blot analysis was used to investigate the antitumor effect of birinapant on cIAP1 expression in Huh6 cells at the protein level. A WST‑8 assay was performed to evaluate the tumor growth inhibitory effect of birinapant on the human HB cell lines, Huh6 and HepG2. Huh6 cells were exposed to CDDP and/or birinapant in order to confirm tumor growth inhibition. The antitumor efficacy of birinapant plus CDDP combination therapy was significantly higher than that of CDDP monotherapy in a dose‑dependent manner (P=0.035). The study also investigated the antitumor efficacy of birinapant plus CDDP combination therapy in an established xenograft model of SCID mice. Compared with CDDP monotherapy, birinapant combined with CDDP showed better inhibition of tumor growth (P=0.121). It was observed that the mRNA expression of cIAP1 in tumors was significantly enriched in the CDDP monotherapy group compared with that in the untreated group. Furthermore, immunohistochemical staining was performed to compare cIAP1 expression in pre‑ and post‑chemotherapy specimens in patients with HB, and a significant increase was observed in the post‑chemotherapy specimens (P<0.001). CDDP‑resistant Huh6 (Huh6‑CDDPR) cells were also established following repeated exposure to CDDP. Birinapant was substantially more effective against the Huh6‑CDDPR cells than against the Huh6 wild‑type cells. Taken together, these findings suggest that repeated exposure to CDDP enhances cIAP1 expression in HB cells and that birinapant is a promising therapeutic drug for CDDP‑resistant HB.
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Affiliation(s)
- Ryo Tsukada
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan
| | - Motonari Nomura
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan
| | - Takehisa Ueno
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan
| | - Hiroomi Okuyama
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan
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Kiss E, Forika G, Dank M, Krenacs T, Nemeth Z. Methyl Donors Reduce Cell Proliferation by Diminishing Erk-Signaling and NFkB Levels, While Increasing E-Cadherin Expression in Panc-1 Cell Line. Int J Mol Sci 2022; 23:2546. [PMID: 35269689 PMCID: PMC8910410 DOI: 10.3390/ijms23052546] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 02/22/2022] [Accepted: 02/24/2022] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is an aggressive malignancy with high metastatic potential. There are several lifestyle-related determinants in its etiology, including diet. Methyl donors are dietary micronutrients which play an important role in fueling vital metabolic pathways, and as bioactive food components provide methyl groups as substrates and cofactors. The imbalanced nutritional status of methyl donors has recently been linked to pathological conditions. Therefore, we hypothesized that dietary methyl donors may improve the physiology of cancer patients, including those with pancreatic cancer, and could be used for intervention therapy. In this study, methyl-donor treatment (L-methionine, choline chloride, folic acid and vitamin B12) of an aggressive pancreatic adenocarcinoma cell line (Panc-1) resulted in significantly increased p21WAF1/Cip1 cyclin-dependent kinase inhibitor levels, along with apoptotic SubG1 fractions. At the same time, phospho-Erk1/2 levels and proliferation rate were significantly reduced. Though methyl-donor treatments also increased the pro-apoptotic protein Bak, Puma and Caspase-9, it failed to elevate cleaved Caspase-3 levels. In addition, the treatment significantly reduced the production of the pro-inflammatory cytokine IL-17a and the transcription factor NFkB. Similarly, a significant decrease in VEGF and SDF-1a levels were detected, which may indicate reduced metastatic potential. As expected, E-cadherin expression was inversely associated with these changes, showing elevated expression after methyl-donor treatment. In summary, we found that methyl donors may have the potential to reduce aggressive and proliferative phenotype of Panc-1 cells. This suggests a promising role of dietary methyl donors for complementing relevant cancer therapies, even in treatment-resistant pancreatic adenocarcinomas.
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Affiliation(s)
- Eva Kiss
- 1st Department of Internal Medicine and Oncology, Oncology Profile, Semmelweis University, 1083 Budapest, Hungary; (E.K.); (M.D.)
| | - Gertrud Forika
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, Hungary; (G.F.); (T.K.)
| | - Magdolna Dank
- 1st Department of Internal Medicine and Oncology, Oncology Profile, Semmelweis University, 1083 Budapest, Hungary; (E.K.); (M.D.)
| | - Tibor Krenacs
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, Hungary; (G.F.); (T.K.)
| | - Zsuzsanna Nemeth
- 1st Department of Internal Medicine and Oncology, Semmelweis University, 1083 Budapest, Hungary
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15
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Wilczyński JR, Nowak M. Cancer Immunoediting: Elimination, Equilibrium, and Immune Escape in Solid Tumors. EXPERIENTIA SUPPLEMENTUM (2012) 2022; 113:1-57. [PMID: 35165859 DOI: 10.1007/978-3-030-91311-3_1] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Emphasizing the dynamic processes between cancer and host immune system, the initially discovered concept of cancer immunosurveillance has been replaced by the current concept of cancer immunoediting consisting of three phases: elimination, equilibrium, and escape. Solid tumors composed of both cancer and host stromal cells are an example how the three phases of cancer immunoediting functionally evolve and how tumor shaped by the host immune system gets finally resistant phenotype. The elimination, equilibrium, and escape have been described in this chapter in details, including the role of immune surveillance, cancer dormancy, disruption of the antigen-presenting machinery, tumor-infiltrating immune cells, resistance to apoptosis, as well as the function of tumor stroma, microvesicles, exosomes, and inflammation.
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Affiliation(s)
- Jacek R Wilczyński
- Department of Gynecologic Surgery and Gynecologic Oncology, Medical University of Lodz, Lodz, Poland.
| | - Marek Nowak
- Department of Operative Gynecology and Gynecologic Oncology, Polish Mother's Memorial Hospital-Research Institute, Lodz, Poland
- Department of Operative and Endoscopic Gynecology, Medical University of Lodz, Lodz, Poland
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16
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Silke J, O’Reilly LA. NF-κB and Pancreatic Cancer; Chapter and Verse. Cancers (Basel) 2021; 13:4510. [PMID: 34572737 PMCID: PMC8469693 DOI: 10.3390/cancers13184510] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 08/29/2021] [Accepted: 08/30/2021] [Indexed: 02/07/2023] Open
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is one of the world's most lethal cancers. An increase in occurrence, coupled with, presently limited treatment options, necessitates the pursuit of new therapeutic approaches. Many human cancers, including PDAC are initiated by unresolved inflammation. The transcription factor NF-κB coordinates many signals that drive cellular activation and proliferation during immunity but also those involved in inflammation and autophagy which may instigate tumorigenesis. It is not surprising therefore, that activation of canonical and non-canonical NF-κB pathways is increasingly recognized as an important driver of pancreatic injury, progression to tumorigenesis and drug resistance. Paradoxically, NF-κB dysregulation has also been shown to inhibit pancreatic inflammation and pancreatic cancer, depending on the context. A pro-oncogenic or pro-suppressive role for individual components of the NF-κB pathway appears to be cell type, microenvironment and even stage dependent. This review provides an outline of NF-κB signaling, focusing on the role of the various NF-κB family members in the evolving inflammatory PDAC microenvironment. Finally, we discuss pharmacological control of NF-κB to curb inflammation, focussing on novel anti-cancer agents which reinstate the process of cancer cell death, the Smac mimetics and their pre-clinical and early clinical trials.
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Affiliation(s)
- John Silke
- Inflammation Division, Walter and Eliza Hall Institute of Medical Research (WEHI), Parkville, VIC 3052, Australia;
- Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia
| | - Lorraine Ann O’Reilly
- Inflammation Division, Walter and Eliza Hall Institute of Medical Research (WEHI), Parkville, VIC 3052, Australia;
- Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia
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17
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Hannes S, Karlowitz R, van Wijk SJL. The Smac mimetic BV6 cooperates with STING to induce necroptosis in apoptosis-resistant pancreatic carcinoma cells. Cell Death Dis 2021; 12:816. [PMID: 34462421 PMCID: PMC8405653 DOI: 10.1038/s41419-021-04014-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 07/07/2021] [Accepted: 07/12/2021] [Indexed: 12/24/2022]
Abstract
Pancreatic cancer (PC) still remains a major cause of cancer-related death worldwide and alternative treatments are urgently required. A common problem of PC is the development of resistance against apoptosis that limits therapeutic success. Here we demonstrate that the prototypical Smac mimetic BV6 cooperates with the stimulator of interferon (IFN) genes (STING) ligand 2',3'-cyclic guanosine monophosphate-adenosine monophosphate (2'3'-cGAMP) to trigger necroptosis in apoptosis-deficient PC cells. Pharmacological inhibition of key components of necroptosis signaling, such as receptor-interacting protein 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL), significantly rescues PC cells from 2'3'-cGAMP/BV6/zVAD.fmk-mediated cell death, suggesting the induction of necroptosis. Consistently, 2'3'-cGAMP/BV6 co-treatment promotes phosphorylation of MLKL. Furthermore, we show that 2'3'-cGAMP stimulates the production of type I IFNs, which cooperate with BV6 to trigger necroptosis in apoptosis-deficient settings. STING silencing via siRNA or CRISPR/Cas9-mediated gene knockout protects PC cells from 2'3'-cGAMP/BV6/zVAD.fmk-mediated cell death. Interestingly, we demonstrate that nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNFα), and IFN-regulatory factor 1 (IRF1) signaling are involved in triggering 2'3'-cGAMP/BV6/zVAD.fmk-induced necroptosis. In conclusion, we show that activated STING and BV6 act together to exert antitumor effects on PC cells with important implications for the design of new PC treatment concepts.
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Affiliation(s)
- Sabine Hannes
- Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstrasse 3a, 60528, Frankfurt, Germany
- General and Visceral Surgery, Goethe-University, Frankfurt, Germany
| | - Rebekka Karlowitz
- Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstrasse 3a, 60528, Frankfurt, Germany
| | - Sjoerd J L van Wijk
- Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstrasse 3a, 60528, Frankfurt, Germany.
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Anson F, Thayumanavan S, Hardy JA. Exogenous Introduction of Initiator and Executioner Caspases Results in Different Apoptotic Outcomes. JACS AU 2021; 1:1240-1256. [PMID: 34467362 PMCID: PMC8385707 DOI: 10.1021/jacsau.1c00261] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Indexed: 05/06/2023]
Abstract
The balance of pro-apoptotic and pro-survival proteins defines a cell's fate. These processes are controlled through an interdependent and finely tuned protein network that enables survival or leads to apoptotic cell death. The caspase family of proteases is central to this apoptotic network, with initiator and executioner caspases, and their interaction partners, regulating and executing apoptosis. In this work, we interrogate and modulate this network by exogenously introducing specific initiator or executioner caspase proteins. Each caspase is exogenously introduced using redox-responsive polymeric nanogels. Although caspase-3 might be expected to be the most effective due to the centrality of its role in apoptosis and its heightened catalytic efficiency relative to other family members, we observed that caspase-7 and caspase-9 are the most effective at inducing apoptotic cell death. By critically analyzing the introduced activity of the delivered caspase, the pattern of substrate cleavage, as well as the ability to activate endogenous caspases, we conclude that the efficacy of each caspase correlated with the levels of pro-survival factors that both directly and indirectly impact the introduced caspase. These findings lay the groundwork for developing methods for exogenous introduction of caspases as a therapeutic option that can be tuned to the apoptotic balance in a proliferating cell.
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19
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Duan S, Pagano M. Ubiquitin ligases in cancer: Functions and clinical potentials. Cell Chem Biol 2021; 28:918-933. [PMID: 33974914 PMCID: PMC8286310 DOI: 10.1016/j.chembiol.2021.04.008] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/23/2021] [Accepted: 04/08/2021] [Indexed: 02/07/2023]
Abstract
Ubiquitylation, a highly regulated post-translational modification, controls many cellular pathways that are critical to cell homeostasis. Ubiquitin ligases recruit substrates and promote ubiquitin transfer onto targets, inducing proteasomal degradation or non-degradative signaling. Accumulating evidence highlights the critical role of dysregulated ubiquitin ligases in processes associated with the initiation and progression of cancer. Depending on the substrate specificity and biological context, a ubiquitin ligase can act either as a tumor promoter or as a tumor suppressor. In this review, we focus on the regulatory roles of ubiquitin ligases and how perturbations of their functions contribute to cancer pathogenesis. We also briefly discuss current strategies for targeting or exploiting ubiquitin ligases for cancer therapy.
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Affiliation(s)
- Shanshan Duan
- Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA; Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, USA
| | - Michele Pagano
- Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA; Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, USA; Howard Hughes Medical Institute, NYU Grossman School of Medicine, New York, NY, USA.
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20
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Kasikci E, Aydemir E, Yogurtcu BM, Sahin F, Bayrak OF. Repurposing of Alexidine Dihydrochloride as an Apoptosis Initiator and Cell Cycle Inhibitor in Human Pancreatic Cancer. Anticancer Agents Med Chem 2021; 20:1956-1965. [PMID: 32384037 DOI: 10.2174/1871520620666200508085439] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 12/30/2019] [Accepted: 01/27/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Highly aggressive and resistant to chemotherapy, pancreatic cancers are the fourth leading cause of cancer-related deaths in the western world. The absence of effective chemotherapeutics is leading researchers to develop novel drugs or repurpose existing chemicals. Alexidine Dihydrochloride (AD), an orally bioavailable bis-biguanide compound, is an apoptosis stimulating reagent. It induces mitochondrial damage by inhibiting a mitochondrial-specific protein tyrosine phosphatase, PTPMT1. The aim of this study was to test AD as a novel compound to induce apoptosis in a human pancreatic adenocarcinoma cell lines, Panc-1, MIA PaCa-2, AsPC-1, and Psn-1. METHODS After the IC50 value of the AD was determined by cytotoxicity assay, apoptosis was observed by a variety of methods, including the detection of early apoptosis marker Annexin V and the proteomic profile screening by apoptosis array. Multicaspase and mitochondrial depolarization were measured, and changes in the cell cycle were analyzed. RESULTS AD is found to initiate apoptosis by activating the intrinsic pathway and inhibit the cell cycle in pancreatic cancer cell lines. CONCLUSION In conclusion, considering its anti-cancer properties and bioavailability, Alexidine dihydrochloride can be considered as a potential candidate against pancreatic adenocarcinomas.
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Affiliation(s)
- Ezgi Kasikci
- Department of Genetics and Bioengineering, Faculty of Engineering and Architecture, Yeditepe University, Istanbul, Turkey,Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Esra Aydemir
- Department of Genetics and Bioengineering, Faculty of Engineering and Architecture, Yeditepe University, Istanbul, Turkey
| | - Bekir M Yogurtcu
- Department of Genetics and Bioengineering, Faculty of Engineering and Architecture, Yeditepe University, Istanbul, Turkey
| | - Fikrettin Sahin
- Department of Genetics and Bioengineering, Faculty of Engineering and Architecture, Yeditepe University, Istanbul, Turkey
| | - Omer F Bayrak
- Department of Medical Genetics, Yeditepe University Medical School and Yeditepe University Hospital, Istanbul 34718, Turkey
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21
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Novel therapeutic strategies and perspectives for pancreatic cancer: Autophagy and apoptosis are key mechanisms to fight pancreatic cancer. Med Oncol 2021; 38:74. [PMID: 34019188 DOI: 10.1007/s12032-021-01522-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 05/10/2021] [Indexed: 12/15/2022]
Abstract
Pancreatic cancer (PC) is the most lethal malignancy of the gastrointestinal tract. The poor prognosis of patients with PC is primarily due to lack of effective treatments against its progressive and metastatic behavior. Hence, figuring out the mechanisms underlying PC development and putting up with effective targeted therapies are of great significance to improve the prognosis of patients with PC. Apoptosis and autophagy serve to maintain tissue homoeostasis. Escaping from apoptosis or autophagy is one of the features of malignancy. PC is seriously resistant to autophagy and apoptosis, which explains its invasiveness and resistance to conventional treatment. Recently, several biological activities and pharmacological functions found in natural product extracts have been reported to inhibit PC progression. The current review focuses on understanding natural product extracts and their derivatives as one kind of novel treatments through affecting the apoptosis or autophagy in PC.
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22
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Small interfering RNA (siRNA) to target genes and molecular pathways in glioblastoma therapy: Current status with an emphasis on delivery systems. Life Sci 2021; 275:119368. [PMID: 33741417 DOI: 10.1016/j.lfs.2021.119368] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 03/11/2021] [Accepted: 03/12/2021] [Indexed: 02/08/2023]
Abstract
Glioblastoma multiforme (GBM) is one of the worst brain tumors arising from glial cells, causing many deaths annually. Surgery, chemotherapy, radiotherapy and immunotherapy are used for GBM treatment. However, GBM is still an incurable disease, and new approaches are required for its successful treatment. Because mutations and amplifications occurring in several genes are responsible for the progression and aggressive behavior of GBM cells, genetic approaches are of great importance in its treatment. Small interfering RNA (siRNA) is a new emerging tool to silence the genes responsible for disease progression, particularly cancer. SiRNA can be used for GBM treatment by down-regulating genes such as VEGF, STAT3, ELTD1 or EGFR. Furthermore, the use of siRNA can promote the chemosensitivity of GBM cells. However, the efficiency of siRNA in GBM is limited via its degradation by enzymes, and its off-targeting effects. SiRNA-loaded carriers, especially nanovehicles that are ligand-functionalized by CXCR4 or angiopep-2, can be used for the protection and targeted delivery of siRNA. Nanostructures can provide a platform for co-delivery of siRNA plus anti-tumor drugs as another benefit. The prepared nanovehicles should be stable and biocompatible in order to be tested in human studies.
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Xie X, Lee J, Liu H, Pearson T, Lu AY, Tripathy D, Devi GR, Bartholomeusz C, Ueno NT. Birinapant Enhances Gemcitabine's Antitumor Efficacy in Triple-Negative Breast Cancer by Inducing Intrinsic Pathway-Dependent Apoptosis. Mol Cancer Ther 2020; 20:296-306. [PMID: 33323457 DOI: 10.1158/1535-7163.mct-19-1160] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 09/01/2020] [Accepted: 11/30/2020] [Indexed: 11/16/2022]
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive subgroup of breast cancer, and patients with TNBC have few therapeutic options. Apoptosis resistance is a hallmark of human cancer, and apoptosis regulators have been targeted for drug development for cancer treatment. One class of apoptosis regulators is the inhibitors of apoptosis proteins (IAPs). Dysregulated IAP expression has been reported in many cancers, including breast cancer, and has been shown to be responsible for resistance to chemotherapy. Therefore, IAPs have become attractive molecular targets for cancer treatment. Here, we first investigated the antitumor efficacy of birinapant (TL32711), a biindole-based bivalent mimetic of second mitochondria-derived activator of caspases (SMACs), in TNBC. We found that birinapant as a single agent has differential antiproliferation effects in TNBC cells. We next assessed whether birinapant has a synergistic effect with commonly used anticancer drugs, including entinostat (class I histone deacetylase inhibitor), cisplatin, paclitaxel, voxtalisib (PI3K inhibitor), dasatinib (Src inhibitor), erlotinib (EGFR inhibitor), and gemcitabine, in TNBC. Among these tested drugs, gemcitabine showed a strong synergistic effect with birinapant. Birinapant significantly enhanced the antitumor activity of gemcitabine in TNBC both in vitro and in xenograft mouse models through activation of the intrinsic apoptosis pathway via degradation of cIAP2 and XIAP, leading to apoptotic cell death. Our findings demonstrate the therapeutic potential of birinapant to enhance the antitumor efficacy of gemcitabine in TNBC by targeting the IAP family of proteins.
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Affiliation(s)
- Xuemei Xie
- Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Jangsoon Lee
- Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Huey Liu
- Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Troy Pearson
- Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Alexander Y Lu
- Department of Bioengineering, Rice University, Houston, Texas
| | - Debu Tripathy
- Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Gayathri R Devi
- Department of Surgery, Division of Surgical Sciences, Duke Cancer Institute, Duke University School of Medicine, North Carolin
- Women's Cancer Program, Duke Cancer Institute, Duke University School of Medicine, North Carolina
| | - Chandra Bartholomeusz
- Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Naoto T Ueno
- Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Hydroxychavicol sensitizes imatinib-resistant chronic myelogenous leukemia cells to TRAIL-induced apoptosis by ROS-mediated IAP downregulation. Anticancer Drugs 2020; 30:167-178. [PMID: 30418193 DOI: 10.1097/cad.0000000000000710] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of cytokine superfamily, induces apoptosis in a number of tumor cells through the activation of extrinsic apoptotic pathway but shows little or no cytotoxicity toward normal cells. However some tumor cells are inherently resistant to TRAIL-mediated apoptosis, which needs to be addressed to establish TRAIL as a potential chemotherapeutic drug. In this study, our aim was to manipulate TRAIL-apoptosis pathway by hydroxychavicol (HCH), a polyphenol from Piper betel leaf, for the induction of apoptosis in TRAIL resistant chronic myeloid leukemia cell. When imatinib-resistant K562 cells were treated with HCH, it made these K562 cells sensitive to TRAIL. It was observed that HCH downregulated antiapoptotic proteins XIAP and FLIP, whereas the expression of TRAIL receptors, DR4 and DR5, remains unchanged. Moreover, we observed that reactive oxygen species or ROS played a crucial role in the downregulation of FLIP and XIAP because ROS scavenger significantly reversed the decrease of XIAP, and FLIP. Ubiquitin-proteasome pathway was observed to play a crucial role in the downregulation of XIAP and FLIP, as proteasomal inhibitor MG132 significantly reversed the downregulation of XIAP and FLIP. In conclusion, this study demonstrates the combinatorial treatment of TRAIL and HCH as promising alternative therapeutic approach to treat the imatinib-resistant leukemia, which are also resistant to TRAIL.
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25
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Kumar S, Fairmichael C, Longley DB, Turkington RC. The Multiple Roles of the IAP Super-family in cancer. Pharmacol Ther 2020; 214:107610. [PMID: 32585232 DOI: 10.1016/j.pharmthera.2020.107610] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 05/16/2020] [Accepted: 06/08/2020] [Indexed: 12/22/2022]
Abstract
The Inhibitor of Apoptosis proteins (IAPs) are a family of proteins that are mainly known for their anti-apoptotic activity and ability to directly bind and inhibit caspases. Recent research has however revealed that they have extensive roles in governing numerous other cellular processes. IAPs are known to modulate ubiquitin (Ub)-dependent signaling pathways through their E3 ligase activity and influence activation of nuclear factor κB (NF-κB). In this review, we discuss the involvement of IAPs in individual hallmarks of cancer and the current status of therapies targeting these critical proteins.
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Affiliation(s)
- Swati Kumar
- Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, United Kingdom
| | - Ciaran Fairmichael
- Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, United Kingdom
| | - Daniel B Longley
- Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, United Kingdom
| | - Richard C Turkington
- Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, United Kingdom.
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26
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Chemosensitivity to HM90822, a novel synthetic IAP antagonist, is determined by p-AKT-inducible XIAP phosphorylation in human pancreatic cancer cells. Invest New Drugs 2020; 38:1696-1706. [DOI: 10.1007/s10637-020-00956-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Accepted: 05/21/2020] [Indexed: 11/26/2022]
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27
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Schnoell J, Kadletz L, Jank BJ, Oberndorfer F, Brkic FF, Gurnhofer E, Cede J, Seemann R, Kenner L, Heiduschka G. Expression of inhibitors of apoptosis proteins in salivary gland adenoid cystic carcinoma: XIAP is an independent marker of impaired cause-specific survival. Clin Otolaryngol 2020; 45:364-369. [PMID: 31984681 PMCID: PMC7317768 DOI: 10.1111/coa.13509] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 12/28/2019] [Accepted: 01/15/2020] [Indexed: 01/17/2023]
Abstract
Objectives Inhibitors of apoptosis proteins are crucial to carcinogenesis since their expression results in evasion of apoptosis. Overexpression of inhibitors of apoptosis has repeatedly been associated with resistance to treatment and poor prognosis in various cancers. The role of inhibitors of apoptosis in adenoid cystic carcinoma of the salivary gland is still unclear. The aim of this study was to investigate the expression of inhibitors of apoptosis and their potential prognostic value in adenoid cystic carcinoma. Design, setting and participants Forty‐nine patients, diagnosed with adenoid cystic carcinoma of the salivary gland between 1996 and 2016, were retrospectively included in this study. The expression of cIAP1, cIAP2, XIAP, Birc6, Livin and Survivin was assessed using immunohistochemistry, and their association of survival and prognosis was evaluated during a median follow‐up of 6.4 years. Main outcome measure Cause‐specific survival and recurrence‐free survival rates. Results XIAP, cIAP2, Livin and nuclear Survivin showed high expression levels in adenoid cystic carcinoma in most patients. There was no significant association of cIAP1, cIAP2, Livin, Birc6 and Survivin with outcome. However, high XIAP expression was associated with worse cause‐specific survival and worse response to radiotherapy and proved to be an independent marker in multivariable analysis. Conclusion Our data indicate that high expression of XIAP may be used as a prognosticator for poor survival and poor response to radiotherapy in adenoid cystic carcinoma patients.
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Affiliation(s)
- Julia Schnoell
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University Vienna, Vienna, Austria
| | - Lorenz Kadletz
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University Vienna, Vienna, Austria
| | - Bernhard J Jank
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University Vienna, Vienna, Austria
| | | | - Faris F Brkic
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University Vienna, Vienna, Austria
| | | | - Julia Cede
- Department of Oral and Maxillofacial Surgery, Medical University of Vienna, Vienna, Austria
| | - Rudolf Seemann
- Department of Oral and Maxillofacial Surgery, Medical University of Vienna, Vienna, Austria
| | - Lukas Kenner
- Department of Pathology, Medical University of Vienna, Vienna, Austria.,Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.,Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Gregor Heiduschka
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University Vienna, Vienna, Austria
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28
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Wong SHM, Kong WY, Fang CM, Loh HS, Chuah LH, Abdullah S, Ngai SC. The TRAIL to cancer therapy: Hindrances and potential solutions. Crit Rev Oncol Hematol 2019; 143:81-94. [PMID: 31561055 DOI: 10.1016/j.critrevonc.2019.08.008] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Revised: 08/29/2019] [Accepted: 08/29/2019] [Indexed: 12/15/2022] Open
Abstract
Apoptosis is an ordered and orchestrated cellular process that occurs in physiological and pathological conditions. Resistance to apoptosis is a hallmark of virtually all malignancies. Despite being a cause of pathological conditions, apoptosis could be a promising target in cancer treatment. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), also known as Apo-2 ligand (Apo2L), is a member of TNF cytokine superfamily. It is a potent anti-cancer agent owing to its specific targeting towards cancerous cells, while sparing normal cells, to induce apoptosis. However, resistance occurs either intrinsically or after multiple treatments which may explain why cancer therapy fails. This review summarizes the apoptotic mechanisms via extrinsic and intrinsic apoptotic pathways, as well as the apoptotic resistance mechanisms. It also reviews the current clinically tested recombinant human TRAIL (rhTRAIL) and TRAIL receptor agonists (TRAs) against TRAIL-Receptors, TRAIL-R1 and TRAIL-R2, in which the outcomes of the clinical trials have not been satisfactory. Finally, this review discusses the current strategies in overcoming resistance to TRAIL-induced apoptosis in pre-clinical and clinical settings.
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Affiliation(s)
- Sonia How Ming Wong
- School of Biosciences, Faculty of Science and Engineering, University of Nottingham Malaysia, 43500, Semenyih, Selangor, Malaysia
| | - Wei Yang Kong
- School of Biosciences, Faculty of Science and Engineering, University of Nottingham Malaysia, 43500, Semenyih, Selangor, Malaysia
| | - Chee-Mun Fang
- Division of Biomedical Sciences, School of Pharmacy, University of Nottingham Malaysia, 43500, Semenyih, Selangor, Malaysia
| | - Hwei-San Loh
- School of Biosciences, Faculty of Science and Engineering, University of Nottingham Malaysia, 43500, Semenyih, Selangor, Malaysia
| | - Lay-Hong Chuah
- School of Pharmacy, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia; Advanced Engineering Platform, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia
| | - Syahril Abdullah
- Medical Genetics Laboratory, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, 43400 UPM, Malaysia; UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Selangor, 43400 UPM, Malaysia
| | - Siew Ching Ngai
- School of Biosciences, Faculty of Science and Engineering, University of Nottingham Malaysia, 43500, Semenyih, Selangor, Malaysia.
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Polykretis P, Luchinat E, Bonucci A, Giachetti A, Graewert MA, Svergun DI, Banci L. Conformational characterization of full-length X-chromosome-linked inhibitor of apoptosis protein (XIAP) through an integrated approach. IUCRJ 2019; 6:948-957. [PMID: 31576227 PMCID: PMC6760453 DOI: 10.1107/s205225251901073x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 07/31/2019] [Indexed: 06/10/2023]
Abstract
The X-chromosome-linked inhibitor of apoptosis protein (XIAP) is a multidomain protein whose main function is to block apoptosis by caspase inhibition. XIAP is also involved in other signalling pathways, including NF-κB activation and copper homeostasis. XIAP is overexpressed in tumours, potentiating cell survival and resistance to chemotherapeutics, and has therefore become an important target for the treatment of malignancy. Despite the fact that the structure of each single domain is known, the conformation of the full-length protein has never been determined. Here, the first structural model of the full-length XIAP dimer, determined by an integrated approach using nuclear magnetic resonance, small-angle X-ray scattering and electron paramagnetic resonance data, is presented. It is shown that XIAP adopts a compact and relatively rigid conformation, implying that the spatial arrangement of its domains must be taken into account when studying the interactions with its physiological partners and in developing effective inhibitors.
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Affiliation(s)
- Panagis Polykretis
- CERM – Magnetic Resonance Center, University of Florence, Via Luigi Sacconi 6, 50019 Sesto Fiorentino, Italy
| | - Enrico Luchinat
- CERM – Magnetic Resonance Center, University of Florence, Via Luigi Sacconi 6, 50019 Sesto Fiorentino, Italy
- Department of Experimental and Clinical Biomedical Sciences ‘Mario Serio’, University of Florence, Viale Morgagni 50, 50134 Florence, Italy
| | - Alessio Bonucci
- CERM – Magnetic Resonance Center, University of Florence, Via Luigi Sacconi 6, 50019 Sesto Fiorentino, Italy
| | - Andrea Giachetti
- CERM – Magnetic Resonance Center, University of Florence, Via Luigi Sacconi 6, 50019 Sesto Fiorentino, Italy
| | - Melissa A. Graewert
- EMBL, Hamburg Outstation, European Molecular Biology Laboratory, Notkestrasse 85, 22607 Hamburg, Germany
| | - Dmitri I. Svergun
- EMBL, Hamburg Outstation, European Molecular Biology Laboratory, Notkestrasse 85, 22607 Hamburg, Germany
| | - Lucia Banci
- CERM – Magnetic Resonance Center, University of Florence, Via Luigi Sacconi 6, 50019 Sesto Fiorentino, Italy
- Department of Chemistry, University of Florence, Via della Lastruccia 3, 50019 Sesto Fiorentino, Italy
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30
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Momeny M, Esmaeili F, Hamzehlou S, Yousefi H, Javadikooshesh S, Vahdatirad V, Alishahi Z, Mousavipak SH, Bashash D, Dehpour AR, Tavangar SM, Tavakkoly-Bazzaz J, Haddad P, Kordbacheh F, Alimoghaddam K, Ghavamzadeh A, Ghaffari SH. The ERBB receptor inhibitor dacomitinib suppresses proliferation and invasion of pancreatic ductal adenocarcinoma cells. Cell Oncol (Dordr) 2019; 42:491-504. [PMID: 31025257 DOI: 10.1007/s13402-019-00448-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/16/2019] [Indexed: 12/23/2022] Open
Abstract
PURPOSE Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, is the fourth most common cause of cancer-related death in the USA. Local progression, early tumor dissemination and low efficacy of current treatments are the major reasons for its high mortality rate. The ERBB family is over-expressed in PDAC and plays essential roles in its tumorigenesis; however, single-targeted ERBB inhibitors have shown limited activity in this disease. Here, we examined the anti-tumor activity of dacomitinib, a pan-ERBB receptor inhibitor, on PDAC cells. METHODS Anti-proliferative effects of dacomitinib were determined using a cell proliferation assay and crystal violet staining. Annexin V/PI staining, radiation therapy and cell migration and invasion assays were carried out to examine the effects of dacomitinib on apoptosis, radio-sensitivity and cell motility, respectively. Quantitative reverse transcription-PCR (qRT-PCR) and Western blot analyses were applied to elucidate the molecular mechanisms underlying the anti-tumor activity of dacomitinib. RESULTS We found that dacomitinib diminished PDAC cell proliferation via inhibition of FOXM1 and its targets Aurora kinase B and cyclin B1. Moreover, we found that dacomitinib induced apoptosis and potentiated radio-sensitivity via inhibition of the anti-apoptotic proteins survivin and MCL1. Treatment with dacomitinib attenuated cell migration and invasion through inhibition of the epithelial-to-mesenchymal transition (EMT) markers ZEB1, Snail and N-cadherin. In contrast, we found that the anti-tumor activity of single-targeted ERBB agents including cetuximab (anti-EGFR mAb), trastuzumab (anti-HER2 mAb), H3.105.5 (anti-HER3 mAb) and erlotinib (EGFR small molecule inhibitor) were marginal. CONCLUSIONS Our findings indicate that dacomitinib-mediated blockade of the ERBB receptors yields advantages over single-targeted ERBB inhibition and provide a rationale for further investigation of the therapeutic potential of dacomitinib in the treatment of ERBB-driven PDAC.
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Affiliation(s)
- Majid Momeny
- Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
| | - Fatemeh Esmaeili
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Sepideh Hamzehlou
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hassan Yousefi
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Sepehr Javadikooshesh
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vasimeh Vahdatirad
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Zivar Alishahi
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyedeh H Mousavipak
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ahmad R Dehpour
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyyed M Tavangar
- Department of Pathology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Javad Tavakkoly-Bazzaz
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Peiman Haddad
- Radiation Oncology Research Center, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Farzaneh Kordbacheh
- Cancer and Vascular Biology Group, ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, Australia
| | - Kamran Alimoghaddam
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ardeshir Ghavamzadeh
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed H Ghaffari
- Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran.
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31
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Jeong Y, Lim JW, Kim H. Lycopene Inhibits Reactive Oxygen Species-Mediated NF-κB Signaling and Induces Apoptosis in Pancreatic Cancer Cells. Nutrients 2019; 11:nu11040762. [PMID: 30939781 PMCID: PMC6521322 DOI: 10.3390/nu11040762] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 03/26/2019] [Accepted: 03/29/2019] [Indexed: 12/21/2022] Open
Abstract
Generation of excess quantities of reactive oxygen species (ROS) caused by mitochondrial dysfunction facilitates rapid growth of pancreatic cancer cells. Elevated ROS levels in cancer cells cause an anti-apoptotic effect by activating survival signaling pathways, such as NF-κB and its target gene expression. Lycopene, a carotenoid found in tomatoes and a potent antioxidant, displays a protective effect against pancreatic cancer. The present study was designed to determine if lycopene induces apoptosis of pancreatic cancer PANC-1 cells by decreasing intracellular and mitochondrial ROS levels, and consequently suppressing NF-κB activation and expression of NF-κB target genes including cIAP1, cIAP2, and survivin. The results show that the lycopene decreased intracellular and mitochondrial ROS levels, mitochondrial function (determined by the mitochondrial membrane potential and oxygen consumption rate), NF-κB activity, and expression of NF-κB-dependent survival genes in PANC-1 cells. Lycopene reduced cell viability with increases in active caspase-3 and the Bax to Bcl-2 ratio in PANC-1 cells. These findings suggest that supplementation of lycopene could potentially reduce the incidence of pancreatic cancer.
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Affiliation(s)
- Yoonseon Jeong
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul 03722, Korea.
| | - Joo Weon Lim
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul 03722, Korea.
| | - Hyeyoung Kim
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul 03722, Korea.
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32
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Lukosiute-Urboniene A, Jasukaitiene A, Silkuniene G, Barauskas V, Gulbinas A, Dambrauskas Z. Human antigen R mediated post-transcriptional regulation of inhibitors of apoptosis proteins in pancreatic cancer. World J Gastroenterol 2019; 25:205-219. [PMID: 30670910 PMCID: PMC6337016 DOI: 10.3748/wjg.v25.i2.205] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 11/06/2018] [Accepted: 11/16/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To determine the association of human antigen R (HuR) and inhibitors of apoptosis proteins (IAP1, IAP2) and prognosis in pancreatic cancer. METHODS Protein and mRNA expression levels of IAP1, IAP2 and HuR in pancreatic ductal adenocarcinoma (PDAC) were compared with normal pancreatic tissue. The correlations among IAP1/IAP2 and HuR as well as their respective correlations with clinicopathological parameters were analyzed. The Kaplan-Meier method and log-rank tests were used for survival analysis. Immunoprecipitation assay was performed to demonstrate HuR binding to IAP1, IAP2 mRNA. PANC1 cells were transfected with either anti-HuR siRNA or control siRNA for 72 h and quantitative reverse transcription polymerase chain reaction (RT-PCR), western blot analysis was carried out. RESULTS RT-PCR analysis revealed that HuR, IAP1, IAP2 mRNA expression were accordingly 3.3-fold, 5.5-fold and 8.4 higher in the PDAC when compared to normal pancreas (P < 0.05). Expression of IAP1 was positively strongly correlated with HuR expression (P < 0.05, r = 0.783). Western blot analysis confirmed RT-PCR results. High IAP1 expression, tumor resection status, T stage, lymph-node metastases, tumor differentiation grade, perineural and lymphatic invasion were identified as significant factors for shorter survival in PDAC patients (P < 0.05). Immunohistological analysis showed that HuR was mainly expressed in the ductal cancer cell's nucleus and less so in cytoplasm. RNA immunoprecipitation analysis confirmed IAP1 and IAP2 post-transcriptional regulation by HuR protein. Following siHuR transfection, IAP1 mRNA and protein levels were decreased, however IAP2 expression levels were increased. CONCLUSION HuR mediated overexpression of IAP1 significantly correlates with poor outcomes and early progression of pancreatic cancer. Further studies are needed to assess the underlying mechanisms.
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MESH Headings
- Aged
- Aged, 80 and over
- Baculoviral IAP Repeat-Containing 3 Protein/genetics
- Baculoviral IAP Repeat-Containing 3 Protein/metabolism
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/mortality
- Carcinoma, Pancreatic Ductal/pathology
- Cell Line, Tumor
- ELAV-Like Protein 1/genetics
- ELAV-Like Protein 1/metabolism
- Female
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- Humans
- Inhibitor of Apoptosis Proteins/genetics
- Inhibitor of Apoptosis Proteins/metabolism
- Kaplan-Meier Estimate
- Lymphatic Metastasis
- Male
- Middle Aged
- Neoplasm Grading
- Pancreas/pathology
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/mortality
- Pancreatic Neoplasms/pathology
- Prognosis
- RNA, Messenger/metabolism
- RNA, Small Interfering/metabolism
- Ubiquitin-Protein Ligases/genetics
- Ubiquitin-Protein Ligases/metabolism
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Affiliation(s)
- Ausra Lukosiute-Urboniene
- Institute for Digestive System Research, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania
- Department of Pediatric Surgery, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania
| | - Aldona Jasukaitiene
- Institute for Digestive System Research, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania
| | - Giedre Silkuniene
- Institute for Digestive System Research, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania
| | - Vidmantas Barauskas
- Department of Pediatric Surgery, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania
| | - Antanas Gulbinas
- Institute for Digestive System Research, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania
- Department of Surgery, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania
| | - Zilvinas Dambrauskas
- Institute for Digestive System Research, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania
- Department of Surgery, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania
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Zhang S, Yang Y, Weng W, Guo B, Cai G, Ma Y, Cai S. Fusobacterium nucleatum promotes chemoresistance to 5-fluorouracil by upregulation of BIRC3 expression in colorectal cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:14. [PMID: 30630498 PMCID: PMC6327560 DOI: 10.1186/s13046-018-0985-y] [Citation(s) in RCA: 186] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Accepted: 11/29/2018] [Indexed: 12/16/2022]
Abstract
Background Emerging evidence suggests a potential relationship between gut microbiota and the host response to chemotherapeutic drugs including 5-fluorouracil (5-Fu). Fusobacterium nucleatum (Fn) has been linked to the initiation and progression of colorectal cancer (CRC). Unfortunately, little was known about the relationship between Fn infection and chemotherapeutic efficacy. Here, we investigate the potential relationship between Fn infection and chemotherapeutic efficacy of 5-Fu in CRC. Methods Differentially expressed genes of CRC cell lines induced by Fn infection were analyzed based on a whole genome microarray analysis Then, we explored the relationship between upregulation of BIRC3 induced by Fn infection and chemoresistance to 5-Fu in vitro and in vivo. Furthermore, we dissected the mechanisms involved in Fn-induced BIRC3 expression. Finally, we investigated the clinical relevance of Fn infection, BIRC3 protein expression and chemoresistance to 5-Fu treatment in CRC patients. Results BIRC3 was the most upregulated gene induced by Fn infection via the TLR4/NF-κB pathway in CRC cells; Fn infection reduced the chemosensitivity of CRC cells to 5-Fu through upregulation of BIRC3 in vitro and in vivo. High Fn abundance correlated with chemoresistance in advanced CRC patients who received standard 5-Fu-based adjuvant chemotherapy after radical surgery. Conclusions Our evidence suggests that Fn and BIRC3 may serve as promising therapeutic targets for reducing chemoresistance to 5-Fu treatment in advanced CRC. Electronic supplementary material The online version of this article (10.1186/s13046-018-0985-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Sheng Zhang
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Yongzhi Yang
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Wenhao Weng
- Department of Clinical Laboratory, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China.,Center for Translational Medicine, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China
| | - Bomin Guo
- Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Guoxiang Cai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Yanlei Ma
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032, China. .,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
| | - Sanjun Cai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032, China. .,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
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Hugle M, Czaplinski S, Habermann K, Vogler M, Fulda S. Identification of Smac mimetics as novel substrates for p-glycoprotein. Cancer Lett 2019; 440-441:126-134. [DOI: 10.1016/j.canlet.2018.10.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 09/23/2018] [Accepted: 10/02/2018] [Indexed: 01/03/2023]
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35
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Chen W, Fan W, Ru G, Huang F, Lu X, Zhang X, Mou X, Wang S. Gemcitabine combined with an engineered oncolytic vaccinia virus exhibits a synergistic suppressive effect on the tumor growth of pancreatic cancer. Oncol Rep 2018; 41:67-76. [PMID: 30365143 PMCID: PMC6278373 DOI: 10.3892/or.2018.6817] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2018] [Accepted: 10/03/2018] [Indexed: 12/20/2022] Open
Abstract
Pancreatic cancer (PC) is a lethal solid malignancy with resistance to traditional chemotherapy. Recently, considerable studies have demonstrated the ubiquitous antitumor properties of gene therapy mediated by the oncolytic vaccinia virus. The second mitochondrial-derived activator of caspase (Smac) has been identified as an innovative tumor suppressor that augments the chemosensitivity of cancer cells. However, the therapeutic value of oncolytic vaccinia virus (oVV)-mediated Smac gene transfer in pancreatic cancer is yet to be elucidated. In the present study, oncolytic vaccinia virus expressing Smac (second mitochondrial-derived activator of caspase) (oVV-Smac) was used to examine its beneficial value when used alone or with gemcitabine in pancreatic cancer in vitro and in vivo. The expression of Smac was evaluated by western blot analysis and quantitative polymerase chain reaction, oVV-Smac cytotoxicity by MTT assay, and apoptosis by flow cytometry and western blot analysis. Furthermore, the inhibitory effect of oVV-Smac combined with gemcitabine was also evaluated. The results indicated that oVV-Smac achieved high levels of Smac, greater cytotoxicity, and potentiated apoptosis. Moreover, co-treatment with oVV-Smac and gemcitabine resulted in a synergistic effect in vitro and in vivo. Therefore, our findings advance oVV-Smac as a potential therapeutic candidate in pancreatic cancer and indicated the synergistic effects of co-treatment with oVV-Smac and gemcitabine.
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Affiliation(s)
- Wanyuan Chen
- Department of Pathology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Weimin Fan
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Guoqing Ru
- Department of Pathology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Fang Huang
- Department of Pathology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Xiaming Lu
- Department of Pathology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Xin Zhang
- Department of Pathology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Xiaozhou Mou
- Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Shibing Wang
- Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
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An ABCG2 non-substrate anticancer agent FL118 targets drug-resistant cancer stem-like cells and overcomes treatment resistance of human pancreatic cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:240. [PMID: 30285798 PMCID: PMC6169080 DOI: 10.1186/s13046-018-0899-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 08/31/2018] [Indexed: 01/05/2023]
Abstract
Background Pancreatic cancer is a deadly disease with a very low 5-year patient survival rate of 6–8%. The major challenges of eliminating pancreatic cancer are treatment resistance and stromal barriers to optimal drug access within the tumor. Therefore, effective molecular targeting drugs with high intra-tumor access and retention are urgently needed for managing this devastating disease in the clinic. Methods This study has used the following in vitro and in vivo techniques for the investigation of exceptional anticancer drug FL118’s efficacy in treatment of resistant pancreatic cancer: cell culture; immunoblotting analysis to test protein expression; DNA sub-G1 flow cytometry analyses to test cell death; MTT assay to test cell viability; pancreatic cancer stem cell assays (fluorescence microscopy tracing; matrigel assay; CD44-positive cell colony formation assay); human luciferase-labeled pancreatic tumor orthotopic animal model in vivo imaging; pancreatic cancer patient-derived xenograft (PDX) animal models; and toxicology studies with immune-competent BALB/cj mice and beagle dogs. Results Our studies found that FL118 alone preferentially killed cisplatin-resistant cancer cells, while a combination of FL118 with cisplatin synergistically killed resistant pancreatic cancer cells and reduced spheroid formation of treatment-resistant pancreatic cancer stem-like cells. Furthermore, using in vivo-imaging, we found that FL118 in combination with cisplatin strongly inhibited both drug-resistant pancreatic xenograft tumor growth and metastasis. In PDX model, we demonstrated that FL118 alone effectively eliminated PDX tumors, while FL118 in combination with gemcitabine eliminated PDX tumors that showed relative resistance (less sensitivity) to treatment with FL118. These FL118 efficacy results are consistent with our molecular-targeting data showing that FL118 inhibited the expression of multiple antiapoptotic proteins (survivin, Mcl-1, XIAP, cIAP2) and ERCC6, a critical regulator of DNA repair, in treatment-resistant pancreatic stem-like cancer cells. Furthermore, FL118 toxicity studies in BALB/cj mice and beagle dogs indicated that FL118 exhibits favorable hematopoietic and biochemical toxicities. Conclusion Together, our studies suggest that FL118 is a promising anticancer drug for further clinical development to effectively treat drug-resistant pancreatic cancer alone or in combination with other pancreatic cancer chemotherapeutic drugs.
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Abstract
Inhibitor of apoptosis (IAP) family comprises a group of endogenous proteins that function as main regulators of caspase activity and cell death. They are considered the main culprits in evasion of apoptosis, which is a fundamental hallmark of carcinogenesis. Overexpression of IAP proteins has been documented in various solid and hematological malignancies, rendering them resistant to standard chemotherapeutics and radiation therapy and conferring poor prognosis. This observation has urged their exploitation as therapeutic targets in cancer with promising pre-clinical outcomes. This review describes the structural and functional features of IAP proteins to elucidate the mechanism of their anti-apoptotic activity. We also provide an update on patterns of IAP expression in different tumors, their impact on treatment response and prognosis, as well as the emerging investigational drugs targeting them. This aims at shedding the light on the advances in IAP targeting achieved to date, and encourage further development of clinically applicable therapeutic approaches.
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Affiliation(s)
- Mervat S Mohamed
- Department of Biochemistry, Faculty of Science, University of Tabuk, Tabuk, Kingdom of Saudi Arabia.
- Department of Chemistry, Biochemistry Speciality, Faculty of Science, Cairo University, Giza, Egypt.
- , Tabuk, Kingdom of Saudi Arabia.
| | - Mai K Bishr
- Department of Radiotherapy, Children's Cancer Hospital Egypt (CCHE), Cairo, Egypt
| | - Fahad M Almutairi
- Department of Biochemistry, Faculty of Science, University of Tabuk, Tabuk, Kingdom of Saudi Arabia
| | - Ayat G Ali
- Department of Biochemistry, El Sahel Teaching Hospital, Cairo, Egypt
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Design of Potent pan-IAP and Lys-Covalent XIAP Selective Inhibitors Using a Thermodynamics Driven Approach. J Med Chem 2018; 61:6350-6363. [PMID: 29940121 DOI: 10.1021/acs.jmedchem.8b00810] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Recently we reported that rapid determination of enthalpy of binding can be achieved for a large number of congeneric agents or in combinatorial libraries fairly efficiently. We show that using a thermodynamic Craig plot can be very useful in dissecting the enthalpy and entropy contribution of different substituents on a common scaffold, in order to design potent, selective, or pan-active compounds. In our implementation, the approach identified a critical Lys residue in the BIR3 domain of XIAP. We report for the first time that it is possible to target such residue covalently to attain potent and selective agents. Preliminary cellular studies in various models of leukemia, multiple myeloma, and pancreatic cancers suggest that the derived agents possess a potentially intriguing pattern of activity, especially for cell lines that are resistant to the pan-IAP antagonist and clinical candidate LCL161.
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Liu S, Li X, Li Q, Liu H, Shi Y, Zhuo H, Li C, Zhu H. Silencing Livin improved the sensitivity of colon cancer cells to 5-fluorouracil by regulating crosstalk between apoptosis and autophagy. Oncol Lett 2018; 15:7707-7715. [PMID: 29740490 PMCID: PMC5934728 DOI: 10.3892/ol.2018.8282] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Accepted: 10/13/2017] [Indexed: 01/27/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common cause of cancer-associated mortality worldwide. Currently, 5-fluorouracil (5-FU) remains a widely used chemotherapeutic drug in the treatment of CRC; however, 5-FU resistance during treatment has become a common problem. Livin, a member of the inhibitor of apoptosis protein family, is considered to be associated with tumor resistance to chemotherapy. In the present study, Livin-silenced cells were generated by introducing a lentivirus into HCT116 and SW620 colon cancer cell lines. Acridine orange/ethidium bromide staining was used as an indicator of cell death. Western blot analysis was performed to detect protein expression levels, and transmission electron microscopy was used to assess autophagy. The half-maximal inhibitory concentration of 5-FU in colon cancer cells was evaluated using a Cell Counting Kit-8 assay. The results of the present study confirmed that silencing Livin significantly enhanced colon cancer cell death in the presence of 5-FU, increased expression levels of various apoptosis- and autophagy-associated proteins and augmented chemotherapeutic sensitivity to 5-FU. Furthermore, the present study demonstrated that this effect may be reversed when autophagy or apoptosis was inhibited, indicating that apoptosis and autophagy were involved in this process. The protein kinase B signaling pathway and B-cell lymphoma-2 expression levels significantly decreased following Livin knockdown, suggesting they may contribute to the regulation of apoptosis and autophagy crosstalk, which caused the Livin knockdown-induced cell death observed.
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Affiliation(s)
- Shuai Liu
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250012, P.R. China
| | - Xin Li
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250012, P.R. China
| | - Qing Li
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250012, P.R. China.,Department of Urology, Yucheng People's Hospital, Yucheng, Shandong 251200, P.R. China
| | - Hongjun Liu
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250012, P.R. China
| | - Yulong Shi
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250012, P.R. China
| | - Hongqing Zhuo
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250012, P.R. China
| | - Chensheng Li
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250012, P.R. China
| | - Huijuan Zhu
- Department of Pharmacy Intravenous Admixture Services, Kaifeng Children's Hospital of Henan Province, Kaifeng, Henan 475000, P.R. China
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Veite-Schmahl MJ, Rivers AC, Regan DP, Kennedy MA. The Mouse Model of Pancreatic Cancer Atlas (MMPCA) for classification of pancreatic cancer lesions: A large histological investigation of the Ptf1aCre/+;LSL-KrasG12D/+ transgenic mouse model of pancreatic cancer. PLoS One 2017; 12:e0187552. [PMID: 29121082 PMCID: PMC5679567 DOI: 10.1371/journal.pone.0187552] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Accepted: 10/20/2017] [Indexed: 12/18/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading forms of cancer related deaths in the United States. With limited treatment options and unreliable diagnostic methods, long-term survival rates following a diagnosis of pancreatic cancer remain poor. Pancreatic intraepithelial neoplasia (PanIN) are precancerous lesions that precede progression towards PDAC. PanIN occur in increasing complexity as the disease progresses and the description of PanIN plays a critical role in describing, staging and diagnosing PDAC. Inconsistencies in PanIN classifications exist even amongst leading pathologists. This has led to debate and confusion among researchers and pathologists involved in pancreatic cancer research, diagnosis and treatment. We have sought to initiate a discussion with leading pathologists with a goal of increasing consensus in the interpretation of PanIN and associated structures within the precancerous pancreas. Toward achieving this goal, we are in the process of conducting an extensive study of over 1000 male and female pancreata in varying stages of PanIN progression isolated from the Ptf1aCre/+;LSL-KrasG12D/+ transgenic mouse model of pancreatic cancer. Using this extensive database, we have established the Mouse Model of Pancreatic Cancer Atlas (MMPCA) to serve as a platform for meaningful and interactive discussion among researchers and pathologists who study pancreatic disease. We hope that the MMPCA will be an effective tool for promoting a more consistent and accurate consensus of PanIN classifications in the future.
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Affiliation(s)
| | - Adam C. Rivers
- Department of Chemistry & Biochemistry, Miami University, Oxford, Ohio, United States of America
| | - Daniel P. Regan
- Department of Chemistry & Biochemistry, Miami University, Oxford, Ohio, United States of America
| | - Michael A. Kennedy
- Department of Chemistry & Biochemistry, Miami University, Oxford, Ohio, United States of America
- * E-mail:
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Zhao X, Sun W, Puszyk WM, Wallet S, Hochwald S, Robertson K, Liu C. Focal adhesion kinase inhibitor PF573228 and death receptor 5 agonist lexatumumab synergistically induce apoptosis in pancreatic carcinoma. Tumour Biol 2017; 39:1010428317699120. [PMID: 28459212 DOI: 10.1177/1010428317699120] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2023] Open
Abstract
Pancreatic cancer has one of the lowest survival rates of all cancers. The mechanism underlying chemo-resistance of pancreatic cancer is not well understood. Our previous article reported that small molecule YM155 induced apoptosis in pancreatic cancer cells via activation of death receptor 5. In this study, we aim to continuously address death receptor 5-mediated apoptosis in chemo-resistant pancreatic carcinoma. We found that in comparison to paired pancreatic cancer tissues and adjacent normal tissues, five of the six cancer tissues had downregulated death receptor 5 and upregulated Bcl-xL. Mono treatment with lexatumumab was not sufficient to induce apoptosis in pancreatic cancer cells, whereas focal adhesion kinase inhibitor PF573228 significantly sensitized lexatumumab-induced apoptosis. Western blotting analysis revealed that lexatumumab and PF573228 combination treatment increased death receptor 5 but decreased Bcl-xL expression. Interestingly, pre-treatment with Bcl-xL inhibitor ABT263 reversed the insensitivity of panc-1 cells to lexatumumab or PF573228-induced apoptosis. Specific small interfering RNA-mediated gene silencing of Bcl-xL effectively sensitized pancreatic cancer cells to lexatumumab or PF573228-induced apoptosis. Furthermore, lexatumumab and PF573228 combination was shown to exhibit significant xenograft pancreatic tumor growth inhibition in SCID mice. Our data provide fundamental evidence to support the notion that lexatumumab and PF573228 co-treatment could be a potentially effective regime for patients with pancreatic cancer.
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Affiliation(s)
- Xiangxuan Zhao
- 1 Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China
- 2 Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Wei Sun
- 1 Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China
| | - William M Puszyk
- 2 Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Shannon Wallet
- 3 Department of Periodontology, College of Dentistry, University of Florida, Gainesville, FL, USA
| | - Steve Hochwald
- 4 Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Keith Robertson
- 5 Departments of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - Chen Liu
- 2 Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
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Słotwiński R, Słotwińska SM. Diagnostic value of selected markers and apoptotic pathways for pancreatic cancer. Cent Eur J Immunol 2017; 41:392-403. [PMID: 28450803 PMCID: PMC5382885 DOI: 10.5114/ceji.2016.65139] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Accepted: 09/26/2016] [Indexed: 12/19/2022] Open
Abstract
Pancreatic cancer occupies the fourth place as a cause of death from cancer, and the mortality rate is similar to the number of newly detected cases. Due to the late diagnosis, only 5-6% of patients with pancreatic cancer survive for five years. Given that early diagnosis is critical for improving patients' survival rates, there is an urgent need for the discovery and validation of new biomarkers with sufficient sensitivity and specificity to help diagnose pancreatic cancer early. Detection of serum tumor markers (CA19-9, CEA, CA125 and CA242) is conducive to the early diagnosis of pancreatic cancer. The combination of miR-16, miR-196a and CA19-9 plasma level was more effective, especially in early tumor screening. Furthermore, recent studies reported that mainly miR-21, miR-155 and miR-196 were dysregulated in IPMN (intraductal papillary mucinous neoplasms) and PanIN (pancreatic intraepithelial neoplasia) lesions, suggesting their usefulness as early biomarkers of these diseases. The reduced rate of apoptosis plays a crucial role in carcinogenesis, and it is one of the most important characteristics acquired by pancreatic cancer cells, which protects them from attack by the immune system and reduces the effectiveness of pharmacological treatment. This review summarizes the data concerning the clinical utility of selected biomarkers in pancreatic cancer patients. The review mainly focuses on the genetic aspects of signaling pathway disorders associated with apoptosis in the pathogenesis and diagnosis of pancreatic cancer.
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Affiliation(s)
- Robert Słotwiński
- Department of Surgical Research and Transplantology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Poland
- Department of Immunology, Biochemistry and Nutrition, Medical University of Warsaw, Poland
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Bhattacharyya S, Sekar V, Majumder B, Mehrotra DG, Banerjee S, Bhowmick AK, Alam N, Mandal GK, Biswas J, Majumder PK, Murmu N. CDKN2A-p53 mediated antitumor effect of Lupeol in head and neck cancer. Cell Oncol (Dordr) 2016; 40:145-155. [PMID: 28039610 DOI: 10.1007/s13402-016-0311-7] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/16/2016] [Indexed: 12/16/2022] Open
Abstract
PURPOSE The tumor suppressor protein p53 is known to control cell cycle arrest and apoptosis. Lupeol is a phytochemical that has been found to induce apoptosis in different cancer types through the extrinsic pathway. As yet, however, its role in the induction of cell cycle arrest and apoptosis through the intrinsic pathway in head and neck cancer has not been investigated. Here, we aimed at understanding the mechanism underlying the antitumor effect of Lupeol in head and neck cancer. METHODS The antitumor effect of Lupeol on oral and laryngeal carcinomas was assessed using two in vitro 2D cell line models (HEp-2, UPCI:SCC-131) and, subsequently, an ex vivo 3D tumor explant culture platform that maintains key features of the native tumor microenvironment. The mechanism underlying Lupeol-mediated antitumor responses was delineated using MTT, colony formation, flow cytometry, immunofluorescence, Western blotting and immunohistochemistry assays. RESULTS We found that Lupeol induced an enhanced expression of p53 in both cell line models tested and, subsequently, cell cycle arrest at the G1 phase. In addition we found that, following Lupeol treatment, p53 induced Bax expression and activated the intrinsic apoptotic pathway (as measured by Caspase-3 cleavage). Interestingly, Lupeol was also found to trigger G1 cell cycle arrest through up-regulation of the expression of CDKN2A, but not p21, resulting in inhibition of CyclinD1. In an ex vivo platform Lupeol was found to impart a potent antitumor response as defined by inhibition of Ki67 expression, decreased cell viability and concomitant activation (cleavage) of Caspase-3. Finally, we found that Lupeol can re-sensitize primary head and neck squamous cell carcinoma (HNSCC) tumor samples that had clinically progressed under a Cisplatin treatment regimen. CONCLUSION Together, our data indicate that Lupeol may orchestrate a bifurcated regulation of neoplastic growth and apoptosis in head and neck cancers and may serve as a promising agent for the management of tumors that have progressed on a platinum-based treatment regimen.
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Affiliation(s)
- Sayantan Bhattacharyya
- Department of Signal Transduction and Biogenic Amines, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata, 700026, India
| | - Vasanthakumar Sekar
- Department of Molecular Pathology and Cancer Biology, Mitra Biotech, 202, Narayana Nethralaya, Hosur Main Road, Bangalore, 560099, India
| | - Biswanath Majumder
- Department of Molecular Pathology and Cancer Biology, Mitra Biotech, 202, Narayana Nethralaya, Hosur Main Road, Bangalore, 560099, India
| | - Debapriya G Mehrotra
- Department of Molecular Pathology and Cancer Biology, Mitra Biotech, 202, Narayana Nethralaya, Hosur Main Road, Bangalore, 560099, India
| | - Samir Banerjee
- Department of Signal Transduction and Biogenic Amines, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata, 700026, India
| | - Anup K Bhowmick
- Department of ENT, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata, 700026, India
| | - Neyaz Alam
- Department of Surgical Oncology, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata, 700026, India
| | - Gautam K Mandal
- Department of Pathology, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata, 700026, India
| | - Jaydip Biswas
- Department of Translation Research, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata, 700026, India
| | | | - Nabendu Murmu
- Department of Signal Transduction and Biogenic Amines, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata, 700026, India.
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microRNA-137 promotes apoptosis in ovarian cancer cells via the regulation of XIAP. Br J Cancer 2016; 116:66-76. [PMID: 27875524 PMCID: PMC5220146 DOI: 10.1038/bjc.2016.379] [Citation(s) in RCA: 83] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2016] [Revised: 09/28/2016] [Accepted: 10/21/2016] [Indexed: 12/21/2022] Open
Abstract
Background: microRNAs (miRNAs) have regulatory roles in various cellular processes, including apoptosis. Recently, X-linked inhibitor of apoptosis protein (XIAP) has been reported to be dysregulated in epithelial ovarian cancer (EOC). However, the mechanism underlying this dysregulation is largely unknown. Methods: Using bioinformatics and a literature analysis, a panel of miRNAs dysregulated in EOC was chosen for further experimental confirmation from hundreds of miRNAs that were predicted to interact with the XIAP 3′UTR. A dual-luciferase reporter assay was employed to detect the interaction by cellular co-transfection of an miRNA expression vector and a reporter vector with the XIAP 3′UTR fused to a Renilla luciferase reporter. DAPI and TUNEL approaches were used to further determine the effects of an miR-137 mimic and inhibitor on cisplatin-induced apoptosis in ovarian cancer cells. Results: We identified eight miRNAs by screening a panel of dysregulated miRNAs that may target the XIAP 3′UTR. The strongest inhibitory miRNA, miR-137, suppressed the activity of a luciferase reporter gene fused with the XIAP 3′UTR and decreased the levels of XIAP protein in SKOV3 ovarian cancer cells. Furthermore, forced expression of miR-137 increased cisplatin-induced apoptosis, and the depressed expression of miR-137 decreased cisplatin-induced apoptosis in SKOV3 and primary EOC cells. Consistently, the disruption of miR-137 via CRISPR/Cas9 inhibited apoptosis and upregulated XIAP in A2780 cells. Furthermore, the effect of miR-137 on apoptosis could be rescued by XIAP in SKOV3 cells. In addition, miR-137 expression is inversely correlated with the level of XIAP protein in both ovarian cancer tissues and cell lines. Conclusions: Our data suggest that multiple miRNAs can regulate XIAP via its 3′UTR. miR-137 can sensitise ovarian cancer cells to cisplatin-induced apoptosis, providing new insight into overcoming drug resistance in ovarian cancer.
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Werner K, Lademann F, Thepkaysone ML, Jahnke B, Aust DE, Kahlert C, Weber G, Weitz J, Grützmann R, Pilarsky C. Simultaneous gene silencing of KRAS and anti-apoptotic genes as a multitarget therapy. Oncotarget 2016; 7:3984-92. [PMID: 26716649 PMCID: PMC4826184 DOI: 10.18632/oncotarget.6766] [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] [Received: 06/30/2015] [Accepted: 11/29/2015] [Indexed: 12/28/2022] Open
Abstract
Pancreatic cancer is one of the most lethal tumor types worldwide and an effective therapy is still elusive. Targeted therapy focused against a specific alteration is by definition unable to attack broad pathway signaling modification. Tumor heterogeneity will render targeted therapies ineffective based on the regrowth of cancer cell sub-clones. Therefore multimodal therapy strategies, targeting signaling pathways simultaneously should improve treatment. SiRNAs against KRAS and the apoptosis associated genes BCLXL, FLIP, MCL1L, SURVIVIN and XIAP were transfected into human and murine pancreatic cancer cell lines. Induction of apoptosis was measured by Caspase 3/7 activation, subG1 FACS analysis and PARP cleavage. The therapeutic approach was tested in a subcutaneous allograft model with a murine cancer cell line. By using siRNAs as a systematic approach to remodel signal transduction in pancreatic cancer the results showed increasing inhibition of proliferation and apoptosis induction in vitro and in vivo. Thus, siRNAs are suitable to model multimodal therapy against signaling pathways in pancreatic cancer. Improvements in in vivo delivery of siRNAs against a multitude of targets might therefore be a potential therapeutic approach.
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Affiliation(s)
- Kristin Werner
- Department of Visceral, Thoracic and Vascular Surgery, TU Dresden, 01307 Dresden, Germany
| | - Franziska Lademann
- Department of Visceral, Thoracic and Vascular Surgery, TU Dresden, 01307 Dresden, Germany
| | - May-Linn Thepkaysone
- Department of Visceral, Thoracic and Vascular Surgery, TU Dresden, 01307 Dresden, Germany
| | - Beatrix Jahnke
- Department of Visceral, Thoracic and Vascular Surgery, TU Dresden, 01307 Dresden, Germany
| | - Daniela E Aust
- Institute of Pathology, TU Dresden, 01307 Dresden, Germany
| | - Christoph Kahlert
- Department of Visceral, Thoracic and Vascular Surgery, TU Dresden, 01307 Dresden, Germany
| | - Georg Weber
- Department of Surgery, Universitätsklinikum Erlangen, 91054 Erlangen, Germany
| | - Jürgen Weitz
- Department of Visceral, Thoracic and Vascular Surgery, TU Dresden, 01307 Dresden, Germany
| | - Robert Grützmann
- Department of Surgery, Universitätsklinikum Erlangen, 91054 Erlangen, Germany
| | - Christian Pilarsky
- Department of Visceral, Thoracic and Vascular Surgery, TU Dresden, 01307 Dresden, Germany
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Modi S, Kir D, Banerjee S, Saluja A. Control of Apoptosis in Treatment and Biology of Pancreatic Cancer. J Cell Biochem 2016. [PMID: 26206252 DOI: 10.1002/jcb.25284] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Pancreatic cancer is estimated to be the 12th most common cancer in the United States in 2014 and yet this malignancy is the fourth leading cause of cancer-related death in the United States. Late detection and resistance to therapy are the major causes for its dismal prognosis. Apoptosis is an actively orchestrated cell death mechanism that serves to maintain tissue homoeostasis. Cancer develops from normal cells by accruing significant changes through one or more mechanisms, leading to DNA damage and mutations, which in a normal cell would induce this programmed cell death pathway. As a result, evasion of apoptosis is one of the hallmarks of cancer cells. PDAC is notoriously resistant to apoptosis, thereby explaining its aggressive nature and resistance to conventional treatment modalities. The current review is focus on understanding different intrinsic and extrinsic pathways in pancreatic cancer that may affect apoptosis in this disease.
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Affiliation(s)
- Shrey Modi
- Division of Basic and Translational Research, Department of Surgery, Minneapolis, Minnesota
| | - Devika Kir
- Division of Basic and Translational Research, Department of Surgery, Minneapolis, Minnesota
| | - Sulagna Banerjee
- Division of Basic and Translational Research, Department of Surgery, Minneapolis, Minnesota
| | - Ashok Saluja
- Division of Basic and Translational Research, Department of Surgery, Minneapolis, Minnesota
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A novel small-molecule IAP antagonist, AZD5582, draws Mcl-1 down-regulation for induction of apoptosis through targeting of cIAP1 and XIAP in human pancreatic cancer. Oncotarget 2016; 6:26895-908. [PMID: 26314849 PMCID: PMC4694961 DOI: 10.18632/oncotarget.4822] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Accepted: 07/24/2015] [Indexed: 12/24/2022] Open
Abstract
Inhibitor of apoptosis proteins (IAPs) plays an important role in controlling cancer cell survival. IAPs have therefore attracted considerable attention as potential targets in anticancer therapy. In this study, we investigated the anti-tumor effect of AZD5582, a novel small-molecule IAP inhibitor, in human pancreatic cancer cells. Treating human pancreatic cancer cells with AZD5582 differentially induced apoptosis, dependent on the expression of p-Akt and p-XIAP. Moreover, the knockdown of endogenous Akt or XIAP via RNA interference in pancreatic cancer cells, which are resistant to AZD5582, resulted in increased sensitivity to AZD5582, whereas ectopically expressing Akt or XIAP led to resistance to AZD5582. Additionally, AZD5582 targeted cIAP1 to induce TNF-α-induced apoptosis. More importantly, AZD5582 induced a decrease of Mcl-1 protein, a member of the Bcl-2 family, but not that of Bcl-2 and Bcl-xL. Interestingly, ectopically expressing XIAP and cIAP1 inhibited the AZD5582-induced decrease of Mcl-1 protein, which suggests that AZD5582 elicits Mcl-1 decrease for apoptosis induction by targeting of XIAP and cIAP1. Taken together, these results indicate that sensitivity to AZD5582 is determined by p-Akt-inducible XIAP phosphorylation and by targeting cIAP1. Furthermore, Mcl-1 in pancreatic cancer may act as a potent marker to analyze the therapeutic effects of AZD5582.
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Zhao X, Sun B, Zhang J, Zhang R, Zhang Q. Short-chain C6 ceramide sensitizes AT406-induced anti-pancreatic cancer cell activity. Biochem Biophys Res Commun 2016; 479:166-172. [PMID: 27562715 DOI: 10.1016/j.bbrc.2016.08.121] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 08/20/2016] [Indexed: 02/07/2023]
Abstract
Our previous study has shown that AT406, a first-in-class small molecular antagonist of IAPs (inhibitor of apoptosis proteins), inhibits pancreatic cancer cell proliferation in vitro and in vivo. The aim of this research is to increase AT406's sensitivity by adding short-chain C6 ceramide. We show that co-treatment of C6 ceramide dramatically potentiated AT406-induced caspase/apoptosis activation and cytotoxicity in established (Panc-1 and Mia-PaCa-2 lines) and primary human pancreatic cancer cells. Reversely, caspase inhibitors largely attenuated C6 ceramide plus AT406-induced above cancer cell death. Molecularly, C6 ceramide downregulated Bcl-2 to increase AT406's sensitivity in pancreatic cancer cells. Intriguingly, C6 ceramide-mediated AT406 sensitization was nullified with Bcl-2 shRNA knockdown or pretreatment of the Bcl-2 inhibitor ABT-737. In vivo, liposomal C6 ceramide plus AT406 co-administration dramatically inhibited Panc-1 xenograft tumor growth in severe combined immunodeficient (SCID) mice. The combined anti-tumor activity was significantly more potent than either single treatment. Expressions of IAPs (cIAP1/XIAP) and Bcl-2 were downregulated in Panc-1 xenografts with the co-administration. Together, we demonstrate that C6 ceramide sensitizes AT406-mediated anti-pancreatic cancer cell activity possibly via downregulating Bcl-2.
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Affiliation(s)
- Xiaoguang Zhao
- Department of Neurosurgery, CPLA Bethune International Peace Hospital, Shijiazhuang, Hebei, China.
| | - Baoyou Sun
- Department of General Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Jingjing Zhang
- Department of Thoracic Surgery III, The Chest Hospital of Hebei Province, Shijiazhuang, Hebei, China
| | - Ruishen Zhang
- Hospital of China Railway Electric Bureau Group First Engineering Company, Shijiazhuang, Hebei, China
| | - Qing Zhang
- Department of Neurology, The Chest Hospital of Hebei Province, Shijiazhuang, Hebei, China
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Zeligs KP, Neuman MK, Annunziata CM. Molecular Pathways: The Balance between Cancer and the Immune System Challenges the Therapeutic Specificity of Targeting Nuclear Factor-κB Signaling for Cancer Treatment. Clin Cancer Res 2016; 22:4302-8. [PMID: 27422962 DOI: 10.1158/1078-0432.ccr-15-1374] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Accepted: 06/29/2016] [Indexed: 12/23/2022]
Abstract
The NF-κB signaling pathway is a complex network linking extracellular stimuli to cell survival and proliferation. Cytoplasmic signaling to activate NF-κB can occur as part of the DNA damage response or in response to a large variety of activators, including viruses, inflammation, and cell death. NF-κB transcription factors play a fundamental role in tumorigenesis and are implicated in the origination and propagation of both hematologic and solid tumor types, including melanoma, breast, prostate, ovarian, pancreatic, colon, lung, and thyroid cancers. On the other hand, NF-κB signaling is key to immune function and is likely necessary for antitumor immunity. This presents a dilemma when designing therapeutic approaches to target NF-κB. There is growing interest in identifying novel modulators to inhibit NF-κB activity as impeding different steps of the NF-κB pathway has potential to slow tumor growth, progression, and resistance to chemotherapy. Despite significant advances in our understanding of this pathway, our ability to effectively clinically block key targets for cancer therapy remains limited due to on-target effects in normal tissues. Tumor specificity is critical to developing therapeutic strategies targeting this antiapoptotic signaling pathway to maintain antitumor immune surveillance when applying such therapy to patients. Clin Cancer Res; 22(17); 4302-8. ©2016 AACR.
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Affiliation(s)
- Kristen P Zeligs
- Women's Malignancies Branch, Center for Cancer Research, NCI, Bethesda, Maryland. Department of Gynecologic Oncology, Walter Reed National Military Medical Center, Bethesda, Maryland
| | - Monica K Neuman
- Women's Malignancies Branch, Center for Cancer Research, NCI, Bethesda, Maryland
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Jiang Y, Meng Q, Chen B, Shen H, Yan B, Sun B. The small-molecule IAP antagonist AT406 inhibits pancreatic cancer cells in vitro and in vivo. Biochem Biophys Res Commun 2016; 478:293-299. [PMID: 27387230 DOI: 10.1016/j.bbrc.2016.07.011] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 07/02/2016] [Indexed: 01/01/2023]
Abstract
In the present study, we tested the anti-pancreatic cancer activity by AT406, a small-molecule antagonist of IAP (inhibitor of apoptosis proteins). In established (Panc-1 and Mia-PaCa-2 lines) and primary human pancreatic cancer cells, treatment of AT406 significantly inhibited cell survival and proliferation. Yet, same AT406 treatment was non-cytotoxic to pancreatic epithelial HPDE6c7 cells. AT406 increased caspase-3/-9 activity and provoked apoptosis in the pancreatic cancer cells. Reversely, AT406' cytotoxicity in these cells was largely attenuated with pre-treatment of caspase inhibitors. AT406 treatment caused degradation of IAP family proteins (cIAP1 and XIAP) and release of cytochrome C, leaving Bcl-2 unaffected in pancreatic cancer cells. Bcl-2 inhibition (by ABT-737) or shRNA knockdown dramatically sensitized Panc-1 cells to AT406. In vivo, oral administration of AT406 at well-tolerated doses downregulated IAPs (cIAP1/XIAP) and inhibited Panc-1 xenograft tumor growth in severe combined immunodeficient (SCID) nude mice. Together, our preclinical results suggest that AT406 could be further evaluated as a promising anti-pancreatic cancer agent.
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Affiliation(s)
- Yongsheng Jiang
- Department of General Surgery, Jinan Central Hospital of Shandong University, Jinan, China
| | - Qinghua Meng
- Department of General Surgery, Jinan Central Hospital of Shandong University, Jinan, China
| | - Bo Chen
- Department of Biliary and Pancreatic Surgery, East Hospital Affiliated to Tongji University in Shanghai, Shanghai, China
| | - Haiyu Shen
- Department of General Surgery, Jinan Central Hospital of Shandong University, Jinan, China
| | - Bing Yan
- Department of General Surgery, Jinan Central Hospital of Shandong University, Jinan, China
| | - Baoyou Sun
- Department of General Surgery, Shandong Provincial Hospital Affiliated to Shandong University, No.9677 Jing-Shi Road, Jinan 250014, China.
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