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Shahrivar M, Dietrich CE, Glimelius B, Saraste D, Martling A, Buchli C, Nordenvall C. Type II diabetes and metformin use does not affect colorectal cancer prognosis. Int J Cancer 2025; 156:1736-1745. [PMID: 39600254 PMCID: PMC11887022 DOI: 10.1002/ijc.35266] [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: 08/29/2024] [Revised: 10/28/2024] [Accepted: 11/11/2024] [Indexed: 11/29/2024]
Abstract
Previous studies on the impact of metformin and colorectal cancer (CRC) outcomes have been limited by small size and confounding by indication, yielding inconsistent results. The aim of this study was to assess whether diabetes and pre-diagnostic metformin use influence CRC prognosis. The study was performed using the Colorectal Cancer Data Base Sweden, a register-linkage originating from the Swedish Colorectal Cancer Register with linkage to national health care registers and demographic registers. All adult patients diagnosed with primary non-metastatic CRC between 2007 and 2016, treated with curative surgery, were identified and followed up from 90 days post-surgery until December 31, 2022. Antidiabetic medication use was defined as dispensed prescription ≥6 months of use within 1 year of surgery. Type II diabetes mellitus (T2DM) patients were divided into three treatment groups (i) diet only, (ii) metformin user, and (iii) non-metformin user. Cox regression models estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for time to recurrence, CRC-specific, and all-cause mortality, adjusted for relevant covariates. Of 33,028 non-metastatic CRC patients, 4539 (13.7%) had T2DM, with 1745 using metformin. A T2DM diagnosis was not associated with increased recurrence rate or CRC-specific mortality; HRadj 0.97 (95% CI 0.89-1.06) and HRadj 0.95 (95% CI 0.87-1.05), respectively, compared with non-diabetic patients. Furthermore, no association between T2DM, metformin use, and recurrence or CRC-specific mortality was seen, HRadj 0.98 (95% CI 0.86-1.12) and HRadj 0.98 (95% CI 0.85-1.13), respectively. T2DM is not associated with an elevated recurrence or CRC-specific mortality. Additionally, metformin use does not impact CRC prognosis.
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Affiliation(s)
- Mehrnoosh Shahrivar
- Department of Molecular Medicine and SurgeryKarolinska InstitutetStockholmSweden
| | - Caroline E. Dietrich
- Clinical Epidemiology Division, Department of Medicine SolnaKarolinska InstitutetStockholmSweden
| | - Bengt Glimelius
- Department of Immunology, Genetics and pathologyUppsala UniversityUppsalaSweden
| | - Deborah Saraste
- Department of Clinical Science and EducationKarolinska InstitutetStockholmSweden
- Department of SurgeryStockholmSweden
| | - Anna Martling
- Department of Molecular Medicine and SurgeryKarolinska InstitutetStockholmSweden
- Department of Pelvic Cancer, GI oncology and colorectal surgery unitKarolinska University HospitalStockholmSweden
| | - Christian Buchli
- Department of Molecular Medicine and SurgeryKarolinska InstitutetStockholmSweden
- Department of Pelvic Cancer, GI oncology and colorectal surgery unitKarolinska University HospitalStockholmSweden
| | - Caroline Nordenvall
- Department of Molecular Medicine and SurgeryKarolinska InstitutetStockholmSweden
- Department of Pelvic Cancer, GI oncology and colorectal surgery unitKarolinska University HospitalStockholmSweden
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Al-Kuraishy HM, Sulaiman GM, Mohsin MH, Mohammed HA, Dawood RA, Albuhadily AK, Al-Gareeb AI, Albukhaty S, Abomughaid MM. Targeting of AMPK/MTOR signaling in the management of atherosclerosis: Outmost leveraging. Int J Biol Macromol 2025; 309:142933. [PMID: 40203916 DOI: 10.1016/j.ijbiomac.2025.142933] [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: 07/20/2024] [Revised: 04/05/2025] [Accepted: 04/06/2025] [Indexed: 04/11/2025]
Abstract
Atherosclerosis (AS) is a chronic vascular disorder that is characterized by the thickening and narrowing of arteries due to the development of atherosclerotic plaques. The traditional risk factors involved in AS are obesity, type 2 diabetes (T2D), dyslipidemia, hypertension, and smoking. Furthermore, non-traditional risk factors for AS, such as inflammation, sleep disturbances, physical inactivity, air pollution, and alterations of gut microbiota, gained attention in relation to the pathogenesis of AS. Interestingly, the pathogenesis of AS, is complex and related to different abnormalities of cellular and sub-cellular signaling pathways. It has been illustrated that AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (MTOR) pathways are involved in AS pathogenesis. Mounting evidence indicated that AMPK plays a critical role in attenuating the development of AS by activating autophagy, which is impaired during atherogenesis. AMPK has a vasculoprotective effect by reducing lipid accumulation, inflammatory cell proliferation, and the release of pro-inflammatory cytokines, as well as decreasing inflammatory cell adhesion to the vascular endothelium. AMPK activation by metformin inhibits the migration of vascular smooth muscle cells (VSMCs) and AS development. However, the MTOR pathway contributes to AS by inhibiting autophagy, highlighting autophagy as a crucial link between the AMPK and MTOR pathways in AS pathogenesis. The MTOR is a key inducer of endothelial dysfunction and is involved in the development of AS. Therefore, both the AMPK and MTOR pathways play a crucial role in the pathogenesis of AS. However, the exact role of AMPK and MTOR pathways in the pathogenesis of AS is not fully clarified. Therefore, this review aims to discuss the potential role of the AMPK/MTOR signaling pathway in AS, and how AMPK activators and MTOR inhibitors influence the development and progression of AS. In conclusion, AMPK activators and MTOR inhibitors have vasculoprotective effects against the development and progression of AS.
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Affiliation(s)
- Hayder M Al-Kuraishy
- Department of Clinical pharmacology and Medicine, College of Medicine, Mustansiriyah University, Baghdad, Iraq
| | - Ghassan M Sulaiman
- Department of Applied Sciences, University of Technology, Baghdad, Iraq.
| | - Mayyadah H Mohsin
- Department of Applied Sciences, University of Technology, Baghdad, Iraq
| | - Hamdoon A Mohammed
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Qassim 51452, Saudi Arabia
| | - Retaj A Dawood
- Department of Biology, College of Science, Al-Mustaqbal University, Hilla 51001, Iraq
| | - Ali K Albuhadily
- Department of Clinical pharmacology and Medicine, College of Medicine, Mustansiriyah University, Baghdad, Iraq
| | - Ali I Al-Gareeb
- Jabir ibn Hayyan Medical University, Al-Ameer Qu, PO.Box13 Kufa, Najaf, Iraq
| | | | - Mosleh M Abomughaid
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, 255, Bisha 67714, Saudi Arabia
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Tan JT, Mao X, Cheng HM, Seto WK, Leung WK, Cheung KS. Aspirin is associated with lower risk of pancreatic cancer and cancer-related mortality in patients with diabetes mellitus. Gut 2025; 74:603-612. [PMID: 39746785 DOI: 10.1136/gutjnl-2024-333329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 12/03/2024] [Indexed: 01/04/2025]
Abstract
BACKGROUND Patients with type 2 diabetes mellitus (T2DM) have higher pancreatic cancer (PC) risk. While aspirin has chemopreventive effects on digestive cancers, its effect on PC among patients with T2DM is unclear. METHODS This retrospective cohort study identified newly diagnosed adult patients with T2DM in Hong Kong between 2001 and 2015 from a territory-wide healthcare registry. Exclusion criteria were history of PC, pancreatic cyst, IgG4 disease, or pancreatectomy. To address reverse causality between PC and T2DM, we excluded patients with PC diagnosed within 1 year of T2DM. We also excluded patients with less than 1 year of observation. Primary outcome was PC, and secondary outcomes were PC-related and all-cause mortality. Aspirin use was treated as time-varying variable (≥180 day-use/year) to address immortal-time bias, and multivariable Cox regression model was employed to derive adjusted HR (aHR). Propensity-score (PS) matching was used as secondary analysis. RESULTS Among 343 966 newly diagnosed patients with T2DM (median follow-up: 10.5 years; IQR: 7.7-14.5 years), 1224 (0.36%) developed PC. There were 51 151 (14.9%) deaths from any cause, and 787 (0.2%) died from PC. Aspirin use was associated with lower PC risk in both time-dependent (aHR: 0.58; 95% CI 0.49 to 0.69) and PS matching analysis (aHR: 0.61; 95% CI 0.48 to 0.77). An inverse relationship was observed with increasing dose and duration of aspirin use (P trend<0.001). Aspirin was also associated with a lower risk of PC-related mortality (aHR: 0.43; 95% CI 0.34 to 0.53) and all-cause mortality (aHR: 0.78; 95% CI 0.76 to 0.80). CONCLUSION Aspirin use may be an oncopreventive strategy to reduce PC risk in patients with T2DM. Further studies are warranted to validate the study findings.
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Affiliation(s)
- Jing Tong Tan
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Xianhua Mao
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, Hong Kong
- Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Ho-Ming Cheng
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Wai-Kay Seto
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, Hong Kong
- Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Wai-K Leung
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Ka-Shing Cheung
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, Hong Kong
- Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
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Rauf A, Olatunde A, Islam MR, Ahmad Z, Hafeez N, Hemeg HA, Imran M, Mubarak MS, Ribaudo G. Acetylsalicylic acid and cancer: updates on the new potential of a nature-inspired drug. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-03959-6. [PMID: 40021514 DOI: 10.1007/s00210-025-03959-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 02/19/2025] [Indexed: 03/03/2025]
Abstract
Acetylsalicylic acid (ASA), commonly known as aspirin, is an organic compound with the formula C9H8O4 obtained from the natural compound salicylic acid, recognized for its analgesic, anti-inflammatory, antipyretic, and anticancer properties. Its role in medicine and plant biology is well-established, but its emerging potential in cancer treatment has garnered increased attention. This review aims to provide a comprehensive overview of the therapeutic applications of ASA as an anticancer agent, focusing on its mechanisms, effectiveness, and role as an adjuvant therapy, preventive compound, and radioprotective agent. Recent research papers, including mechanistic studies, preclinical investigations, and clinical trials related to the effects of ASA on various cancer types, were reviewed. The review places particular emphasis on the enhancement of traditional chemotherapy drugs by ASA and considers toxicological aspects. The analysis of recent studies highlights the potential of ASA to improve the effectiveness of chemotherapy and its role in cancer inhibition through specific molecular pathways. Mechanistic insights suggest that ASA may influence cellular processes that contribute to cancer growth suppression and increased sensitivity to conventional treatments. ASA exhibits promising potential as an adjunct therapy in cancer treatment, with evidence supporting its benefits in improving therapeutic outcomes when used alongside conventional chemotherapy. Further studies are needed to clarify its mechanisms and ensure its safe and effective application in clinical settings.
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Affiliation(s)
- Abdur Rauf
- Department of Chemistry, University of Swabi, Swabi, Pakistan.
| | - Ahmed Olatunde
- Department of Medical Biochemistry, Abubakar Tafawa Balewa University, Bauchi, 740272, Nigeria
| | - Md Rezaul Islam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka, 1216, Bangladesh
| | - Zubair Ahmad
- Department of Chemistry, University of Swabi, Swabi, Pakistan
| | - Nabia Hafeez
- Center of Biotechnology and Microbiology, University of Peshawar, Peshawar, KPK, KPK-25120, Pakistan
| | - Hassan A Hemeg
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taibah University, Al-Madinah Al-Monawra, 41411, Saudi Arabia
| | - Muhammad Imran
- Chemistry Department, Faculty of Science, King Khalid University, P.O. Box 9004, Abha, 61413, Saudi Arabia
| | - Mohammad S Mubarak
- Department of Chemistry, The University of Jordan, Amman, 11942, Jordan.
| | - Giovanni Ribaudo
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, Brescia, 25123, Italy.
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Laila UE, Zhao ZL, Liu H, Xu ZX. Aspirin in Cancer Therapy: Pharmacology and Nanotechnology Advances. Int J Nanomedicine 2025; 20:2327-2365. [PMID: 40017626 PMCID: PMC11866938 DOI: 10.2147/ijn.s505636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 02/04/2025] [Indexed: 03/01/2025] Open
Abstract
Aspirin, a non-steroidal anti-inflammatory drug (NSAID), has garnered significant attention for its anti-cancer potential. This review explores the pharmacological properties, chemical dynamics, and evolving therapeutic applications of aspirin, with an emphasis on its integration into advanced cancer therapies. Aspirin demonstrates broad-spectrum efficacy across diverse cancer types by modulating signaling pathways such as COX-dependent and COX-independent mechanisms, including Wnt, NF-κB, β-catenin/TCF, and IL-6/STAT3. Recent advancements highlight the role of nanotechnology in enhancing aspirin's targeted delivery, therapeutic effectiveness, and patient outcomes. Nanoparticle-based formulations, including liposomes, solid lipid nanoparticles, and mesoporous silica nanoparticles, offer improved solubility, stability, and bioavailability, enabling controlled drug release and tumor-specific targeting. These innovations reduce systemic toxicity and enhance therapeutic effects, paving the way for aspirin's integration into personalized cancer treatments. Ongoing clinical studies reinforce its safety profile, underscoring aspirin's role in cancer pharmacotherapy. This review calls for continued research into aspirin's repurposing in combination therapies and novel delivery systems to maximize its therapeutic potential.
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Affiliation(s)
- Umm E Laila
- School of Life Sciences, Henan University, Kaifeng, Henan Province, 475001, People’s Republic of China
| | - Zi Lon Zhao
- School of Life Sciences, Henan University, Kaifeng, Henan Province, 475001, People’s Republic of China
| | - Huai Liu
- School of Life Sciences, Henan University, Kaifeng, Henan Province, 475001, People’s Republic of China
| | - Zhi-Xiang Xu
- School of Life Sciences, Henan University, Kaifeng, Henan Province, 475001, People’s Republic of China
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Qiang M, Chen Z, Liu H, Dong J, Gong K, Zhang X, Huo P, Zhu J, Shao Y, Ma J, Zhang B, Liu W, Tang M. Targeting the PI3K/AKT/mTOR pathway in lung cancer: mechanisms and therapeutic targeting. Front Pharmacol 2025; 16:1516583. [PMID: 40041495 PMCID: PMC11877449 DOI: 10.3389/fphar.2025.1516583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 01/27/2025] [Indexed: 03/06/2025] Open
Abstract
Owing to its high mortality rate, lung cancer (LC) remains the most common cancer worldwide, with the highest malignancy diagnosis rate. The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling (PAM) pathway is a critical intracellular pathway involved in various cellular functions and regulates numerous cellular processes, including growth, survival, proliferation, metabolism, apoptosis, invasion, and angiogenesis. This review aims to highlight preclinical and clinical studies focusing on the PAM signaling pathway in LC and underscore the potential of natural products targeting it. Additionally, this review synthesizes the existing literature and discusses combination therapy and future directions for LC treatment while acknowledging the ongoing challenges in the field. Continuous development of novel therapeutic agents, technologies, and precision medicine offers an increasingly optimistic outlook for the treatment of LC.
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Affiliation(s)
- Min Qiang
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
- College of Clinical Medicine, Jilin University, Changchun, China
| | - Zhe Chen
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Hongyang Liu
- College of Clinical Medicine, Jilin University, Changchun, China
| | - Junxue Dong
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Kejian Gong
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Xinjun Zhang
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Peng Huo
- Laboratory of Infection Oncology, Institute of Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel and University Hospital Schleswig-Holstein, Kiel, Germany
| | - Jingjun Zhu
- Department of Thoracic and Cardiovascular Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yifeng Shao
- Department of General Surgery, Capital Institute of Pediatrics’ Children’s Hospital, Beijing, China
| | - Jinazun Ma
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Bowei Zhang
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Wei Liu
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Mingbo Tang
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
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7
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Matos ALSA, Ovens AJ, Jakobsen E, Iglesias-Gato D, Bech JM, Friis S, Bak LK, Madsen GI, Oakhill JS, Puustinen P, Moreira JMA. Salicylate-Elicited Activation of AMP-Activated Protein Kinase Directly Triggers Degradation of C-Myc in Colorectal Cancer Cells. Cells 2025; 14:294. [PMID: 39996767 PMCID: PMC11854256 DOI: 10.3390/cells14040294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 12/03/2024] [Accepted: 01/23/2025] [Indexed: 02/26/2025] Open
Abstract
Aspirin has consistently shown preventive effects in some solid cancers, notably colorectal cancer. However, the precise molecular mechanisms underlying this positive effect have remained elusive. In this study, we used an azoxymethane-induced mouse model of colon carcinogenesis to identify aspirin-associated molecular alterations that could account for its cancer-preventive effect. Transcriptomic analysis of aspirin-treated mice showed a strong reduction in c-Myc protein levels and effects on the Myc-dependent transcriptional program in colonic cells. Proto-oncogene c-Myc cooperates with AMP-activated protein kinase (AMPK) to control cellular energetics. Here, we show that salicylate, the active metabolite of aspirin, reduces c-Myc protein expression levels through multiple mechanisms that are both AMPK dependent and independent. This effect is cell-type dependent and occurs at both the transcriptional and post-translational levels. Salicylate-induced AMPK activation leads to the phosphorylation of c-Myc at Thr400, as well as its destabilization and degradation. Our results reveal a complex, multilayered, negative effect of salicylate on c-Myc protein abundance and suggest that chronic depletion of c-Myc can counteract the neoplastic transformation of colorectal epithelium, underpinning the preventive effect of aspirin on colorectal cancer.
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Affiliation(s)
- Ana Laura S. A. Matos
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
- CAPES Foundation, Ministry of Education of Brazil, Brasília DF 70040-020, Brazil
| | - Ashley J. Ovens
- Metabolic Signalling Laboratory, St. Vincent’s Institute of Medical Research, Fitzroy, VIC 3065, Australia (J.S.O.)
- Department of Medicine, University of Melbourne, Parkville, VIC 3010, Australia
| | - Emil Jakobsen
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Diego Iglesias-Gato
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Jacob M. Bech
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
- Sino-Danish Center for Education and Research, Aarhus University, 8000 Aarhus, Denmark
| | - Stine Friis
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Lasse Kristoffer Bak
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
- Department of Clinical Biochemistry, Copenhagen University Hospital-Rigshospitalet, 2600 Glostrup, Denmark
- Translational Research Center (TRACE), Copenhagen University Hospital-Rigshospitalet, 2600 Glostrup, Denmark
| | - Gunvor I. Madsen
- Department of Pathology, Odense University Hospital, 5000 Odense, Denmark
| | - Jonathan S. Oakhill
- Metabolic Signalling Laboratory, St. Vincent’s Institute of Medical Research, Fitzroy, VIC 3065, Australia (J.S.O.)
- Department of Medicine, University of Melbourne, Parkville, VIC 3010, Australia
| | - Pietri Puustinen
- Cell Death and Metabolism, Danish Cancer Society Research Center (DCRC), 2100 Copenhagen, Denmark
| | - José M. A. Moreira
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
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Lauri G, Mills K, Majumder S, Capurso G. The exposome as a target for primary prevention and a tool for early detection of pancreatic cancer. Best Pract Res Clin Gastroenterol 2025; 74:101991. [PMID: 40210335 DOI: 10.1016/j.bpg.2025.101991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 02/04/2025] [Accepted: 02/11/2025] [Indexed: 04/12/2025]
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is a highly aggressive malignancy with limited survival due to late stage diagnosis and scarce therapeutic options. Emerging evidence highlights the role of the "exposome," which encompasses environmental, lifestyle, and metabolic exposures, as a crucial determinant in PDAC risk and a potential avenue for early detection. This review synthesizes findings on modifiable risk factors, including smoking, obesity, diabetes, diet, and alcohol consumption, and their interplay with genetic and metabolic profiles in PDAC development. Additionally, we explore cutting-edge approaches in exposomic research, such as biobanking, electronic health record analysis, and AI-driven predictive models, to identify early biomarkers and stratify high-risk populations. This integrated framework aims to inform prevention strategies and improve early detection of PDAC.
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Affiliation(s)
- Gaetano Lauri
- Pancreatico-Biliary Endoscopy and Endosonography Division, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| | - Krystal Mills
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Shounak Majumder
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Gabriele Capurso
- Pancreatico-Biliary Endoscopy and Endosonography Division, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.
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9
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Maurya SK, Chaudhri S, Kumar S, Gupta S. Repurposing of Metabolic Drugs Metformin and Simvastatin as an Emerging Class of Cancer Therapeutics. Pharm Res 2025; 42:49-67. [PMID: 39775614 DOI: 10.1007/s11095-024-03811-1] [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: 10/18/2024] [Accepted: 12/17/2024] [Indexed: 01/11/2025]
Abstract
Metabolic alterations are commonly associated with various cancers and are recognized as contributing factors to cancer progression, invasion, and metastasis. Drug repurposing, a strategy in drug discovery, utilizes existing knowledge to recommend established drugs for new indications based on clinical data or biological evidence. This approach is considered a less risky alternative to traditional drug development. Metformin, a biguanide, is a product of Galega officinalis (French lilac) primarily prescribed for managing type 2 diabetes, is recognized for its ability to reduce hepatic glucose production and enhance insulin sensitivity, particularly in peripheral tissues such as muscle. It also improves glucose uptake and utilization while decreasing intestinal glucose absorption. Statins, first isolated from the fungus Penicillium citrinum is another class of medication mainly used to lower cholesterol levels in individuals at risk for cardiovascular diseases, work by inhibiting the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which is essential for cholesterol biosynthesis in the liver. Metformin is frequently used in conjunction with statins to investigate their potential synergistic effects. Combination of metformin and simvastatin has gathered much attention in cancer research because of its potential advantages for cancer prevention and treatment. In this review, we analyze the effects of metformin and simvastatin, both individually and in combination, on key cancer hallmarks, and how this combination affects the expression of biomolecules and associated signaling pathways. We also summarize preclinical research, including clinical trials, on the efficacy, safety, and potential applications of repurposing metformin and simvastatin for cancer therapy.
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Affiliation(s)
- Santosh Kumar Maurya
- Molecular Signaling & Drug Discovery Laboratory, Department of Biochemistry, Central University of Punjab, Bathinda, 151401, Punjab, India
| | - Smriti Chaudhri
- Molecular Signaling & Drug Discovery Laboratory, Department of Biochemistry, Central University of Punjab, Bathinda, 151401, Punjab, India
| | - Shashank Kumar
- Molecular Signaling & Drug Discovery Laboratory, Department of Biochemistry, Central University of Punjab, Bathinda, 151401, Punjab, India.
| | - Sanjay Gupta
- Department of Urology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA.
- The Urology Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, 44106, USA.
- Department of Pathology, Case Western Reserve University, Cleveland, OH, 44106, USA.
- Department of Pharmacology, Case Western Reserve University, Cleveland, OH, 44106, USA.
- Department of Nutrition, Case Western Reserve University, Cleveland, OH, 44106, USA.
- Division of General Medical Sciences, Case Comprehensive Cancer Center, Cleveland, OH, 44106, USA.
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10
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Shahrokhi Nejad S, Razi S, Rezaei N. The role of AMPK in pancreatic cancer: from carcinogenesis to treatment. Clin Transl Oncol 2025; 27:70-82. [PMID: 38926257 DOI: 10.1007/s12094-024-03572-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 06/15/2024] [Indexed: 06/28/2024]
Abstract
Pancreatic cancer has doubled over the previous two decades. Routine therapies are becoming incredibly resistant and failing to compensate for the burden caused by this aggressive neoplasm. As genetic susceptibility has always been a highlighted concern for this disease, identifying the molecular pathways involved in the survival and function of pancreatic cancer cells provides insight into its variant etiologies, one of which is the role of AMPK. This regulating factor of cell metabolism is crucial in the homeostasis and growth of the cell. Herein, we review the possible role of AMPK in pancreatic cancer while considering its leading effects on glycolysis and autophagy. Then, we assess the probable therapeutic agents that have resulted from the suggested pathways. Studying the underlying genetic changes in pancreatic cancer provides a chance to detect and treat patients suffering from advanced stages of the disease, and those who have given up their hope on conventional therapies can gain an opportunity to combat this cancer.
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Affiliation(s)
- Shahrzad Shahrokhi Nejad
- Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Sepideh Razi
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Dr Qarib St, Keshavarz Blvd, 14194, Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Dr Qarib St, Keshavarz Blvd, 14194, Tehran, Iran.
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Stockholm, Sweden.
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11
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Xu J, Xu X, Zhang H, Wu J, Pan R, Zhang B. Tumor-associated inflammation: The role and research progress in tumor therapy. J Drug Deliv Sci Technol 2024; 102:106376. [DOI: 10.1016/j.jddst.2024.106376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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12
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Li X, Xu F, Wang R, Shen L, Luo B, Zhou S, Zhang J, Zhang Z, Cao Z, Zhan K, Zhao Y, Zhao G. Aspirin enhances radio/chemo-therapy sensitivity in C. elegans by inducing germ cell apoptosis and suppresses RAS overactivated tumorigenesis via mtROS-mediated DNA damage and MAPK pathway. Biochem Biophys Res Commun 2024; 735:150828. [PMID: 39418772 DOI: 10.1016/j.bbrc.2024.150828] [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: 09/04/2024] [Revised: 10/10/2024] [Accepted: 10/11/2024] [Indexed: 10/19/2024]
Abstract
Previous studies have demonstrated that combination therapy involving radiotherapy and aspirin decreases the survival rate of cancer cells. However, the mechanism by which aspirin exerts its radiation sensitization effect at the in vivo level remains largely unclear. In this study, we employed Caenorhabditis elegans (C. elegans) as a model organism to investigate the effect of aspirin combined with radio/chemo-therapy on tumors at the individual level. Here, we illustrate that high-dose aspirin increases the expression of genes involved in core apoptosis pathways (egl-1, ced-9, ced-4 and ced-3) and induces germ cell apoptosis in C. elegans through mitochondrial outer membrane permeabilization (MOMP) and elevation of reactive oxygen species (ROS) levels. Crucially, aspirin-induces ROS upregulates the expression of genes critical for DNA damage response (hus-1, clk-2 and cep-1) and genes involved in MAPK pathways (lin-45, mek-2, mpk-1, sek-1 and pmk-1), thereby mediating the enhanced sensitivity of radio/chemo-therapy by aspirin. Notably, aspirin fails to induce germ cell apoptosis and enhance radio/chemo-therapy in C. elegans lacking the expression of each of those genes. Furthermore, in a C. elegans tumor-like symptom model, aspirin enhances radio/chemo-therapy sensitivity through ROS induction. However, low-dose aspirin can diminish the apoptotic signal of reproductive cells in C. elegans and exert anti-inflammatory effects. Our research results suggest that the tumor-suppressive and radio/chemo-therapy sensitizing effects of aspirin provide robust experimental evidence for improving the clinical efficacy of tumor radio/chemo-therapy and deepening our understanding of aspirin's mechanism of action in cancer.
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Affiliation(s)
- Xiaona Li
- Teaching and Research Section of Nuclear Medicine, School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China; High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Chinese Academy of Sciences, China; Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, China
| | - Feng Xu
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Chinese Academy of Sciences, China; Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, China; University of Science and Technology of China, Hefei, Anhui, 230026, China
| | - Ruru Wang
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Chinese Academy of Sciences, China; Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, China; University of Science and Technology of China, Hefei, Anhui, 230026, China
| | - Lili Shen
- The Second People's Hospital of Chizhou, Chizhou, Anhui, 247099, China
| | - Bowen Luo
- Teaching and Research Section of Nuclear Medicine, School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China
| | - Shenglan Zhou
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Chinese Academy of Sciences, China; Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, China; University of Science and Technology of China, Hefei, Anhui, 230026, China
| | - Jie Zhang
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Chinese Academy of Sciences, China; Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, China; University of Science and Technology of China, Hefei, Anhui, 230026, China
| | - Zhaoyang Zhang
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Chinese Academy of Sciences, China; Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, China; University of Science and Technology of China, Hefei, Anhui, 230026, China
| | - Zhizun Cao
- Teaching and Research Section of Nuclear Medicine, School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China
| | - Kangren Zhan
- Teaching and Research Section of Nuclear Medicine, School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China
| | - Ye Zhao
- Teaching and Research Section of Nuclear Medicine, School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China.
| | - Guoping Zhao
- Teaching and Research Section of Nuclear Medicine, School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China; High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Chinese Academy of Sciences, China; Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, China.
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13
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Song Y, Ke Y, Lin L, Zhao M. Comparison of in vivo glycolipid metabolism regulation pathway of lotus leaf polysaccharide and its combination with flavonoids and alkaloids: Effectiveness of high-pressure homogenization-assisted dual enzyme extraction. FOOD BIOSCI 2024; 61:104618. [DOI: 10.1016/j.fbio.2024.104618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Wang N, Wang B, Maswikiti EP, Yu Y, Song K, Ma C, Han X, Ma H, Deng X, Yu R, Chen H. AMPK-a key factor in crosstalk between tumor cell energy metabolism and immune microenvironment? Cell Death Discov 2024; 10:237. [PMID: 38762523 PMCID: PMC11102436 DOI: 10.1038/s41420-024-02011-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 04/30/2024] [Accepted: 05/07/2024] [Indexed: 05/20/2024] Open
Abstract
Immunotherapy has now garnered significant attention as an essential component in cancer therapy during this new era. However, due to immune tolerance, immunosuppressive environment, tumor heterogeneity, immune escape, and other factors, the efficacy of tumor immunotherapy has been limited with its application to very small population size. Energy metabolism not only affects tumor progression but also plays a crucial role in immune escape. Tumor cells are more metabolically active and need more energy and nutrients to maintain their growth, which causes the surrounding immune cells to lack glucose, oxygen, and other nutrients, with the result of decreased immune cell activity and increased immunosuppressive cells. On the other hand, immune cells need to utilize multiple metabolic pathways, for instance, cellular respiration, and oxidative phosphorylation pathways to maintain their activity and normal function. Studies have shown that there is a significant difference in the energy expenditure of immune cells in the resting and activated states. Notably, competitive uptake of glucose is the main cause of impaired T cell function. Conversely, glutamine competition often affects the activation of most immune cells and the transformation of CD4+T cells into inflammatory subtypes. Excessive metabolite lactate often impairs the function of NK cells. Furthermore, the metabolite PGE2 also often inhibits the immune response by inhibiting Th1 differentiation, B cell function, and T cell activation. Additionally, the transformation of tumor-suppressive M1 macrophages into cancer-promoting M2 macrophages is influenced by energy metabolism. Therefore, energy metabolism is a vital factor and component involved in the reconstruction of the tumor immune microenvironment. Noteworthy and vital is that not only does the metabolic program of tumor cells affect the antigen presentation and recognition of immune cells, but also the metabolic program of immune cells affects their own functions, ultimately leading to changes in tumor immune function. Metabolic intervention can not only improve the response of immune cells to tumors, but also increase the immunogenicity of tumors, thereby expanding the population who benefit from immunotherapy. Consequently, identifying metabolic crosstalk molecules that link tumor energy metabolism and immune microenvironment would be a promising anti-tumor immune strategy. AMPK (AMP-activated protein kinase) is a ubiquitous serine/threonine kinase in eukaryotes, serving as the central regulator of metabolic pathways. The sequential activation of AMPK and its associated signaling cascades profoundly impacts the dynamic alterations in tumor cell bioenergetics. By modulating energy metabolism and inflammatory responses, AMPK exerts significant influence on tumor cell development, while also playing a pivotal role in tumor immunotherapy by regulating immune cell activity and function. Furthermore, AMPK-mediated inflammatory response facilitates the recruitment of immune cells to the tumor microenvironment (TIME), thereby impeding tumorigenesis, progression, and metastasis. AMPK, as the link between cell energy homeostasis, tumor bioenergetics, and anti-tumor immunity, will have a significant impact on the treatment and management of oncology patients. That being summarized, the main objective of this review is to pinpoint the efficacy of tumor immunotherapy by regulating the energy metabolism of the tumor immune microenvironment and to provide guidance for the development of new immunotherapy strategies.
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Affiliation(s)
- Na Wang
- The Second Clinical Medical School, Lanzhou University, Lanzhou, Gansu, 730030, China
| | - Bofang Wang
- The Second Clinical Medical School, Lanzhou University, Lanzhou, Gansu, 730030, China
| | - Ewetse Paul Maswikiti
- The Second Clinical Medical School, Lanzhou University, Lanzhou, Gansu, 730030, China
| | - Yang Yu
- The Second Clinical Medical School, Lanzhou University, Lanzhou, Gansu, 730030, China
| | - Kewei Song
- The Second Clinical Medical School, Lanzhou University, Lanzhou, Gansu, 730030, China
| | - Chenhui Ma
- The Second Clinical Medical School, Lanzhou University, Lanzhou, Gansu, 730030, China
| | - Xiaowen Han
- The Second Clinical Medical School, Lanzhou University, Lanzhou, Gansu, 730030, China
| | - Huanhuan Ma
- The Second Clinical Medical School, Lanzhou University, Lanzhou, Gansu, 730030, China
| | - Xiaobo Deng
- The Second Clinical Medical School, Lanzhou University, Lanzhou, Gansu, 730030, China
| | - Rong Yu
- The Second Clinical Medical School, Lanzhou University, Lanzhou, Gansu, 730030, China
| | - Hao Chen
- The Department of Tumor Surgery, The Second Hospital of Lanzhou University, Lanzhou, Gansu, 730030, China.
- Key Laboratory of Environmental Oncology of Gansu Province, Lanzhou, Gansu, 730030, China.
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15
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Hashemi M, Razzazan M, Bagheri M, Asadi S, Jamali B, Khalafi M, Azimi A, Rad S, Behroozaghdam M, Nabavi N, Rashidi M, Dehkhoda F, Taheriazam A, Entezari M. Versatile function of AMPK signaling in osteosarcoma: An old player with new emerging carcinogenic functions. Pathol Res Pract 2023; 251:154849. [PMID: 37837858 DOI: 10.1016/j.prp.2023.154849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 10/01/2023] [Accepted: 10/02/2023] [Indexed: 10/16/2023]
Abstract
AMP-activated protein kinase (AMPK) signaling has a versatile role in Osteosarcoma (OS), an aggressive bone malignancy with a poor prognosis, particularly in cases that have metastasized or recurred. This review explores the regulatory mechanisms, functional roles, and therapeutic applications of AMPK signaling in OS. It focuses on the molecular activation of AMPK and its interactions with cellular processes like proliferation, apoptosis, and metabolism. The uncertain role of AMPK in cancer is also discussed, highlighting its potential as both a tumor suppressor and a contributor to carcinogenesis. The therapeutic potential of targeting AMPK signaling in OS treatment is examined, including direct and indirect activators like metformin, A-769662, resveratrol, and salicylate. Further research is needed to determine dosing, toxicities, and molecular mechanisms responsible for the anti-osteosarcoma effects of these compounds. This review underscores the complex involvement of AMPK signaling in OS and emphasizes the need for a comprehensive understanding of its molecular mechanisms. By elucidating the role of AMPK in OS, the aim is to pave the way for innovative therapeutic approaches that target this pathway, ultimately improving the prognosis and quality of life for OS patients.
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Affiliation(s)
- Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mehrnaz Razzazan
- Medical Student, Student Research Committee, Golestan University of Medical Sciences, Gorgan, Iran
| | - Maryam Bagheri
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Saba Asadi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Behdokht Jamali
- Department of Microbiology and Genetics, Kherad Institute of Higher Education, Bushehr, lran
| | - Maryam Khalafi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics,Faculty of Medicine, Islamic Azad University, Kish International Branch, Kish, Iran
| | - Abolfazl Azimi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics,Faculty of Medicine, Islamic Azad University, Kish International Branch, Kish, Iran
| | - Sepideh Rad
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics,Faculty of Medicine, Islamic Azad University, Kish International Branch, Kish, Iran
| | - Mitra Behroozaghdam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Noushin Nabavi
- Department of Urologic Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H3Z6, Canada
| | - Mohsen Rashidi
- The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran; Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Farshid Dehkhoda
- Department of Orthopedics, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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16
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Tajaldini M, Poorkhani A, Amiriani T, Amiriani A, Javid H, Aref P, Ahmadi F, Sadani S, Khori V. Strategy of targeting the tumor microenvironment via inhibition of fibroblast/fibrosis remodeling new era to cancer chemo-immunotherapy resistance. Eur J Pharmacol 2023; 957:175991. [PMID: 37619785 DOI: 10.1016/j.ejphar.2023.175991] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 08/02/2023] [Accepted: 08/10/2023] [Indexed: 08/26/2023]
Abstract
The use of repurposing drugs that may have neoplastic and anticancer effects increases the efficiency and decrease resistance to chemotherapy drugs through a biochemical and mechanical transduction mechanisms through modulation of fibroblast/fibrosis remodeling in tumor microenvironment (TME). Interestingly, fibroblast/fibrosis remodeling plays a vital role in mediating cancer metastasis and drug resistance after immune chemotherapy. The most essential hypothesis for induction of chemo-immunotherapy resistance is via activation of fibroblast/fibrosis remodeling and preventing the infiltration of T cells after is mainly due to the interference between cytoskeleton, mechanical, biochemical, metabolic, vascular, and remodeling signaling pathways in TME. The structural components of the tumor that can be targeted in the fibroblast/fibrosis remodeling include the depletion of the TME components, targeting the cancer-associated fibroblasts and tumor associated macrophages, alleviating the mechanical stress within the ECM, and normalizing the blood vessels. It has also been found that during immune-chemotherapy, TME injury and fibroblast/fibrosis remodeling causes the up-regulation of inhibitory signals and down-regulation of activated signals, which results in immune escape or chemo-resistance of the tumor. In this regard, repurposing or neo-adjuvant drugs with various transduction signaling mechanisms, including anti-fibrotic effects, are used to target the TME and fibroblast/fibrosis signaling pathway such as angiotensin 2, transforming growth factor-beta, physical barriers of the TME, cytokines and metabolic factors which finally led to the reverse of the chemo-resistance. Consistent to many repurposing drugs such as pirfenidone, metformin, losartan, tranilast, dexamethasone and pentoxifylline are used to decrease immune-suppression by abrogation of TME inhibitory signal that stimulates the immune system and increases efficiency and reduces resistance to chemotherapy drugs. To overcome immunosuppression based on fibroblast/fibrosis remodeling, in this review, we focus on inhibitory signal transduction, which is the physical barrier, alleviates mechanical stress and prevents mechano-metabolic activation.
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Affiliation(s)
- Mahboubeh Tajaldini
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Amirhoushang Poorkhani
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Taghi Amiriani
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Amirhossein Amiriani
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Hossein Javid
- Department of Medical Laboratory Sciencess, Catastega Institue of Medical Sciences, Mashhad, Iran
| | - Parham Aref
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Farahnazsadat Ahmadi
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Somayeh Sadani
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran.
| | - Vahid Khori
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran.
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17
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Ma M, Pan Y, Zhang Y, Yang M, Xi Y, Lin B, Hao W, Liu J, Wu L, Liu Y, Qin X. Metformin combined with rapamycin ameliorates podocyte injury in idiopathic membranous nephropathy through the AMPK/mTOR signaling pathway. J Cell Commun Signal 2023:10.1007/s12079-023-00781-8. [PMID: 37702819 DOI: 10.1007/s12079-023-00781-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 08/01/2023] [Indexed: 09/14/2023] Open
Abstract
Autophagy activation protects against podocyte injury in idiopathic membranous nephropathy (IMN). The AMPK/mTOR signaling pathway is a vital autophagy regulatory pathway. Metformin promotes autophagy, whereas rapamycin is an autophagy agonist. However, the therapeutic mechanisms of metformin and rapamycin in IMN remain unclear. Thus, we examined the mechanisms of action of metformin and rapamycin in IMN by regulating the AMPK/mTOR autophagy signaling pathway. Female Sprague-Dawley (SD) rats were treated with cationic bovine serum albumin (C-BSA) to establish an IMN model and were randomly divided into IMN model, metformin, rapamycin, and metformin + rapamycin groups. A control group was also established. Metformin and rapamycin were used as treatments. Renal histological changes, urinary protein excretion, the protein expression levels of key AMPK/mTOR signaling pathway proteins, renal tissue cell apoptosis, and autophagy-associated proteins (Beclin 1 and LC3) were examined. In addition, a C5b-9 sublysis model using the MPC-5 mouse podocyte cell line was established to verify the effect of metformin combined with rapamycin on podocytes. Metformin combined with rapamycin improved urinary protein excretion in IMN rats. Metformin combined with rapamycin attenuated the inflammatory response, renal fibrosis, and podocyte foot process fusion. In addition, it improved autophagy in podocytes as demonstrated by the enhanced expression of Beclin-1, p-AMPK/AMPK, LC3-II/I, and autophagosomes in podocytes and decreased p-mTOR/mTOR expression. In conclusion, metformin combined with rapamycin decreased proteinuria, improved renal fibrosis and podocyte autophagy via AMPK/mTOR pathway in IMN rats. The metformin and rapamycin decreased proteinuria and inproved renal fibrosis in IMN model rats.
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Affiliation(s)
- Meichen Ma
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, People's Republic of China
| | - Yue Pan
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, People's Republic of China
| | - Yue Zhang
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, People's Republic of China
| | - Mei Yang
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, People's Republic of China
| | - Ying Xi
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, People's Republic of China
| | - Baoxu Lin
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, People's Republic of China
| | - Wudi Hao
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, People's Republic of China
| | - Jianhua Liu
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, People's Republic of China
| | - Lina Wu
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, People's Republic of China
| | - Yong Liu
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, People's Republic of China
| | - Xiaosong Qin
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, People's Republic of China.
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18
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Shi M, Liu X, Pan W, Li N, Tang B. Anti-inflammatory strategies for photothermal therapy of cancer. J Mater Chem B 2023. [PMID: 37326239 DOI: 10.1039/d3tb00839h] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
High temperature generated by photothermal therapy (PTT) can trigger an inflammatory response at the tumor site, which not only limits the efficacy of PTT but also increases the risk of tumor metastasis and recurrence. In light of the current limitations posed by inflammation in PTT, several studies have revealed that inhibiting PTT-induced inflammation can significantly improve the efficacy of cancer treatment. In this review, we summarize the research progress made in combining anti-inflammatory strategies to enhance the effectiveness of PTT. The goal is to offer valuable insights for developing better-designed photothermal agents in clinical cancer therapy.
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Affiliation(s)
- Mingwan Shi
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, P. R. China.
| | - Xiaohan Liu
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, P. R. China.
| | - Wei Pan
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, P. R. China.
| | - Na Li
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, P. R. China.
| | - Bo Tang
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, P. R. China.
- Laoshan Laboratory, Qingdao 266237, P. R. China
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19
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Moezzi SMI, Javadi P, Mozafari N, Ashrafi H, Azadi A. Metformin-loaded nanoerythrosomes: An erythrocyte-based drug delivery system as a therapeutic tool for glioma. Heliyon 2023; 9:e17082. [PMID: 37484272 PMCID: PMC10361227 DOI: 10.1016/j.heliyon.2023.e17082] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 06/06/2023] [Accepted: 06/07/2023] [Indexed: 07/25/2023] Open
Abstract
Glioma is an intra-cranial malignancy with the origin of neural stem cells or precursor cells, the most prevalent brain tumor worldwide. Glioblastoma, the fourth-grade glioma, is a common brain tumor whose incidence rate is 5-7 people per 100,000 populations annually. Despite their high mortality rate, all efforts for treatment have yet to achieve any desirable clinical outcome. The Wnt signaling pathway is a conserved pathway among species that seems to be a candidate for cancer therapy by its inhibition. Metformin is a known inhibitor of the Wnt signaling pathway. Its effects on glioma treatment have been observed in cellular, animal, and clinical experiments. Nanoerythrosomes are drug carriers obtained from the cellular membrane of red blood cells in nano size which can offer several characteristics to deliver metformin to brain tumors. They are good at loading and carrying hydrophilic drugs, they can protect metformin from its metabolizing enzymes, which are present in the blood-brain barrier, and they can extend the period of metformin presence in circulation. In this study, nanoerythrosomes were prepared by using the hypotonic buffer. They had particle sizes in the range of 97.1 ± 34.2 nm, and their loading efficiency and loading capacity were 72.6% and 1.66%, respectively. Nanoerythrosomes could reserve metformin in their structure for a long time, and only 50% of metformin was released after 30 h. Moreover, they released metformin at a low and approximately constant rate. Besides, nanoerythrosomes could tolerate various kinds of stress and maintain most of the drug in their structure. Altogether, nanoerythrosome can be a suitable drug delivery system to deliver therapeutic amounts of metformin to various tissues.
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Affiliation(s)
- Seyed Mohammad Iman Moezzi
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmaceutics, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Parisa Javadi
- Department of Nanomedicine, School of Novel Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negin Mozafari
- Department of Pharmaceutics, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hajar Ashrafi
- Department of Pharmaceutics, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amir Azadi
- Department of Pharmaceutics, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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20
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Zhou H, Yun X, Shu Y, Xu K. Aspirin increases the efficacy of gemcitabine in pancreatic cancer by modulating the PI3K/AKT/mTOR signaling pathway and reversing epithelial‑mesenchymal transition. Oncol Lett 2023; 25:101. [PMID: 36817049 PMCID: PMC9932045 DOI: 10.3892/ol.2023.13687] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 11/15/2022] [Indexed: 02/04/2023] Open
Abstract
Gemcitabine is regarded as a standard medication for patients with pancreatic cancer. The aim of the present study was to investigate the impact of aspirin (ASA) on the efficacy of gemcitabine in pancreatic cancer and the potential mechanism. The SW1990 and BxPC-3 human pancreatic cell lines were treated with 2 mmol/l ASA and/or 1 mg/l gemcitabine. The effects of the treatments were tested on the viability, migration and invasion of the cells using MTT, wound healing and Transwell invasion assays. In addition, cell apoptosis was evaluated via flow cytometry with Annexin V-FITC/PI and the western blotting of Bax and Bcl-2. The expression of epithelial-mesenchymal transition (EMT)-associated proteins and activation of the PI3K/AKT/mTOR pathway were also assessed using western blotting. The results reveal that ASA increased the efficacy of gemcitabine in reducing the proliferation, migration and invasion of pancreatic cancer cells and increasing their apoptosis. These effects are associated with inhibition of the PI3K/AKT/mTOR pathway and the reversal of EMT. Thus, the combined use of ASA and gemcitabine is suggested to be a potential therapeutic strategy for patients with pancreatic cancer.
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Affiliation(s)
- Hanyu Zhou
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China,Department of Oncology, Gusu School, Nanjing Medical University, Suzhou, Jiangsu 215006, P.R. China,Department of Oncology, Suzhou Municipal Hospital, Suzhou, Jiangsu 215001, P.R. China,Department of Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu 215001, P.R. China
| | - Xiao Yun
- Department of General Surgery, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu 213003, P.R. China
| | - Yongqian Shu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China,Department of Oncology, Gusu School, Nanjing Medical University, Suzhou, Jiangsu 215006, P.R. China,Department of Oncology, The Affiliated Sir Run Run Hospital of Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China,Dr Yongqian Shu, Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Gulou, Nanjing, Jiangsu 210029, P.R. China, E-mail:
| | - Kequn Xu
- Department of Oncology, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu 213003, P.R. China,Correspondence to: Dr Kequn Xu, Department of Oncology, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, 29 Xinglong Lane, Tianning, Changzhou, Jiangsu 213003, P.R. China, E-mail:
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Metabolic Regulation of T cell Activity: Implications for Metabolic-Based T-cell Therapies for Cancer. IRANIAN BIOMEDICAL JOURNAL 2023; 27:1-14. [PMID: 36624636 PMCID: PMC9971708 DOI: 10.52547/ibj.3811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Immunometabolism is an emerging field in tumor immunotherapy. Understanding the metabolic competition for access to the limited nutrients between tumor cells and immune cells can reveal the complexity of the tumor microenvironment and help develop new therapeutic approaches for cancer. Recent studies have focused on modifying the function of immune cells by manipulating their metabolic pathways. Besides, identifying metabolic events, which affect the function of immune cells leads to new therapeutic opportunities for treatment of inflammatory diseases and immune-related conditions. According to the literature, metabolic pathway such as glycolysis, tricarboxylic acid cycle, and fatty acid metabolism, significantly influence the survival, proliferation, activation, and function of immune cells and thus regulate immune responses. In this paper, we reviewed the role of metabolic processes and major signaling pathways involving in T-cell regulation and T-cell responses against tumor cells. Moreover, we summarized the new therapeutics suggested to enhance anti-tumor activity of T cells through manipulating metabolic pathways.
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22
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Co-Treatments of Gardeniae Fructus and Silymarin Ameliorates Excessive Oxidative Stress-Driven Liver Fibrosis by Regulation of Hepatic Sirtuin1 Activities Using Thioacetamide-Induced Mice Model. Antioxidants (Basel) 2022; 12:antiox12010097. [PMID: 36670959 PMCID: PMC9854785 DOI: 10.3390/antiox12010097] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 12/27/2022] [Accepted: 12/28/2022] [Indexed: 01/04/2023] Open
Abstract
Gardeniae Fructus (GF, the dried ripe fruits of Gardenia jasminoides Ellis) has traditionally been used to treat various diseases in East Asian countries, such as liver disease. Silymarin is a well-known medicine used to treat numerous liver diseases globally. The present study was purposed to evaluate the synergistic effects of GF and silymarin on the thioacetamide (TAA)-induced liver fibrosis of a mouse model. Mice were orally administered with distilled water, GF (100 mg/kg, GF 100), silymarin (100 mg/kg, Sily 100), and GF and silymarin mixtures (50 and 100 mg/kg, GS 50 and 100). The GS group showed remarkable amelioration of liver injury in the serum levels and histopathology by observing the inflamed cell infiltrations and decreases in necrotic bodies through the liver tissue. TAA caused liver tissue oxidation, which was evidenced by the abnormal statuses of lipid peroxidation and deteriorations in the total glutathione in the hepatic protein levels; moreover, the immunohistochemistry supported the increases in the positive signals against 4-hydroxyneal and 8-OHdG through the liver tissue. These alterations corresponded well to hepatic inflammation by an increase in F4/80 positive cells and increases in pro-inflammatory cytokines in the hepatic protein levels; however, administration with GS, especially the high dose group, not only remarkably reduced oxidative stress and DNA damage in the liver cells but also considerably diminished pro-inflammatory cytokines, which were driven by Kupffer cell activations, as compared with each of the single treatment groups. The pharmacological properties of GS prolonged liver fibrosis by the amelioration of hepatic stellate cells’ (HSCs’) activation that is dominantly expressed by huge extracellular matrix (ECM) molecules including α-smooth muscle actin, and collagen type1 and 3, respectively. We further figured out that GS ameliorated HSCs activated by the regulation of Sirtuin 1 (Sirt1) activities in the hepatic protein levels, and this finding excellently reenacted the transforming growth factor-β-treated LX-2-cells-induced cell death signals depending on the Sirt1 activities. Future studies need to reveal the pharmacological roles of GS on the specific cell types during the liver fibrosis condition.
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23
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Du Y, Zhu YJ, Zhou YX, Ding J, Liu JY. Metformin in therapeutic applications in human diseases: its mechanism of action and clinical study. MOLECULAR BIOMEDICINE 2022; 3:41. [PMID: 36484892 PMCID: PMC9733765 DOI: 10.1186/s43556-022-00108-w] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 11/18/2022] [Indexed: 12/13/2022] Open
Abstract
Metformin, a biguanide drug, is the most commonly used first-line medication for type 2 diabetes mellites due to its outstanding glucose-lowering ability. After oral administration of 1 g, metformin peaked plasma concentration of approximately 20-30 μM in 3 h, and then it mainly accumulated in the gastrointestinal tract, liver and kidney. Substantial studies have indicated that metformin exerts its beneficial or deleterious effect by multiple mechanisms, apart from AMPK-dependent mechanism, also including several AMPK-independent mechanisms, such as restoring of redox balance, affecting mitochondrial function, modulating gut microbiome and regulating several other signals, such as FBP1, PP2A, FGF21, SIRT1 and mTOR. On the basis of these multiple mechanisms, researchers tried to repurpose this old drug and further explored the possible indications and adverse effects of metformin. Through investigating with clinical studies, researchers concluded that in addition to decreasing cardiovascular events and anti-obesity, metformin is also beneficial for neurodegenerative disease, polycystic ovary syndrome, aging, cancer and COVID-19, however, it also induces some adverse effects, such as gastrointestinal complaints, lactic acidosis, vitamin B12 deficiency, neurodegenerative disease and offspring impairment. Of note, the dose of metformin used in most studies is much higher than its clinically relevant dose, which may cast doubt on the actual effects of metformin on these disease in the clinic. This review summarizes these research developments on the mechanism of action and clinical evidence of metformin and discusses its therapeutic potential and clinical safety.
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Affiliation(s)
- Yang Du
- grid.13291.380000 0001 0807 1581Department of Biotherapy, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Ya-Juan Zhu
- grid.13291.380000 0001 0807 1581Department of Biotherapy, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Yi-Xin Zhou
- grid.13291.380000 0001 0807 1581Department of Biotherapy, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Jing Ding
- grid.54549.390000 0004 0369 4060Department of Medical Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan China
| | - Ji-Yan Liu
- grid.13291.380000 0001 0807 1581Department of Biotherapy, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
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24
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Li S, Yang Y, Wang S, Gao Y, Song Z, Chen L, Chen Z. Advances in metal graphitic nanocapsules for biomedicine. EXPLORATION (BEIJING, CHINA) 2022; 2:20210223. [PMID: 37324797 PMCID: PMC10191027 DOI: 10.1002/exp.20210223] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 02/21/2022] [Indexed: 06/16/2023]
Abstract
Metal graphitic nanocapsules have the advantages of both graphitic and metal nanomaterials, showing great promise in biomedicine. On one hand, the chemically inert graphitic shells are able to protect the metal core from external environments, quench the fluorescence signal from the biological system, offer robust platform for targeted molecules or drugs loading, and act as stable Raman labels or internal standard molecule. On the other hand, the metal cores with different compositions, sizes, and morphologies show unique physicochemical properties, and further broaden their biomedical functions. In this review, we firstly introduce the preparation, classification, and properties of metal graphitic nanocapsules, then summarize the recent progress of their applications in biodetection, bioimaging, and therapy. Challenges and their development prospects in biomedicine are eventually discussed in detail. We expect the versatile metal graphitic nanocapsules will advance the development of future clinical biomedicine.
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Affiliation(s)
- Shengkai Li
- Molecular Science and Biomedicine Laboratory (MBL)State Key Laboratory of Chemo/Bio‐Sensing and ChemometricsCollege of Chemistry and Chemical EngineeringAptamer Engineering Center of Hunan ProvinceHunan Provincial Key Laboratory of Biomacromolecular Chemical BiologyHunan UniversityChangshaChina
| | - Yanxia Yang
- Molecular Science and Biomedicine Laboratory (MBL)State Key Laboratory of Chemo/Bio‐Sensing and ChemometricsCollege of Chemistry and Chemical EngineeringAptamer Engineering Center of Hunan ProvinceHunan Provincial Key Laboratory of Biomacromolecular Chemical BiologyHunan UniversityChangshaChina
| | - Shen Wang
- Molecular Science and Biomedicine Laboratory (MBL)State Key Laboratory of Chemo/Bio‐Sensing and ChemometricsCollege of Chemistry and Chemical EngineeringAptamer Engineering Center of Hunan ProvinceHunan Provincial Key Laboratory of Biomacromolecular Chemical BiologyHunan UniversityChangshaChina
| | - Yang Gao
- College of Materials Science and EngineeringHunan Province Key Laboratory for Advanced Carbon Materials and Applied TechnologyHunan UniversityChangshaChina
| | - Zhiling Song
- Key Laboratory of Optic‐Electric Sensing and Analytical Chemistry for Life ScienceMOEShandong Key Laboratory of Biochemical AnalysisCollege of Chemistry and Molecular EngineeringQingdao University of Science and TechnologyQingdaoChina
| | - Long Chen
- Faculty of Science and TechnologyUniversity of MacauMacau SARChina
| | - Zhuo Chen
- Molecular Science and Biomedicine Laboratory (MBL)State Key Laboratory of Chemo/Bio‐Sensing and ChemometricsCollege of Chemistry and Chemical EngineeringAptamer Engineering Center of Hunan ProvinceHunan Provincial Key Laboratory of Biomacromolecular Chemical BiologyHunan UniversityChangshaChina
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25
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Ren G, Ma Y, Wang X, Zheng Z, Li G. Aspirin blocks AMPK/SIRT3-mediated glycolysis to inhibit NSCLC cell proliferation. Eur J Pharmacol 2022; 932:175208. [PMID: 35981603 DOI: 10.1016/j.ejphar.2022.175208] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 08/09/2022] [Accepted: 08/11/2022] [Indexed: 11/30/2022]
Abstract
Non-small cell lung cancer (NSCLC) has the highest incidence and mortality in the world. Aspirin has been reported to promote apoptosis, inhibit proliferation, stemness, angiogenesis, cancer-associated inflammation and migration in NSCLC. But the effect of aspirin on aerobic glycolysis in NSCLC is less reported. In the present study, we investigated whether aspirin blocked aerobic glycolysis of NSCLC cells to inhibit proliferation. Our results showed that aspirin inhibited viability, PCNA expression, ability of colony formation, dimished extracellular acidification rate (ECAR), oxygen consumption rate (OCR) and production of pyruvic acid and lactic acid, accompanied with reduced mitochondrial membrane potential (MMP), PGC-1α expression and ROS production, indicating mitochondrial dysfunction in NSCLC cells. AMPK and mitochondrial-localized deacetylase sirtuin 3 (SIRT3) were identified as the relevant molecular targets in glycolysis, but mechanism and relationship between AMPK and SIRT3 for aspirin induced glycolysis inhibition remain unknown in cancer cells. The investigation of underlying mechanism indicated that aspirin activated AMPK pathway to inhibit aerobic glycolysis and proliferation by upregulating SIRT3 after application of compound C (CC), an inhibitor of AMPK activity or SIRT3 siRNA. Upon activation of SIRT3, aspirin promoted the release of hexokinase-II (HK-II) from mitochondrial outer membrane to cytosol by deacetylating cyclophilin D (CypD). Consistently, aspirin significantly inhibited the growth of NSCLC xenografts and exhibited antitumor activity probably through AMPK/SIRT3/HK-II pathway in vivo. Collectively, AMPK/SIRT3/HK-II pathway plays a critical role in anticancer effects of aspirin, and our findings might serve as potential target for clinical practice and chemoprevention of aspirin in NSCLC.
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Affiliation(s)
- Guanghui Ren
- Shandong Provincial Key Laboratory of Animal Resistant, School of Life Sciences, Shandong Normal University, Jinan, China
| | - Yan Ma
- Shandong Provincial Key Laboratory of Animal Resistant, School of Life Sciences, Shandong Normal University, Jinan, China
| | - Xingjie Wang
- Shandong Provincial Key Laboratory of Animal Resistant, School of Life Sciences, Shandong Normal University, Jinan, China
| | - Zhaodi Zheng
- Shandong Provincial Key Laboratory of Animal Resistant, School of Life Sciences, Shandong Normal University, Jinan, China
| | - Guorong Li
- Shandong Provincial Key Laboratory of Animal Resistant, School of Life Sciences, Shandong Normal University, Jinan, China.
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Metformin Can Enhance the Inhibitory Effect of Olaparib in Bladder Cancer Cells. DISEASE MARKERS 2022; 2022:5709259. [PMID: 35783012 PMCID: PMC9249502 DOI: 10.1155/2022/5709259] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 05/26/2022] [Accepted: 05/30/2022] [Indexed: 12/24/2022]
Abstract
Background. Bladder cancer is a common urinary system tumor. In the treatment of clinical patients, it is particularly important to find an effective treatment method to inhibit tumor growth. The world’s first PARP inhibitor olaparib is mainly used for the treatment of BRCA1/BRCA2 mutated tumors. Metformin, an antidiabetic drug, has been reported to reduce cancer incidence in humans and improve survival in cancer patients. Methods. Cell viability and proliferation were detected by CCK-8 assay and colony formation assay; cell apoptosis was detected by flow cytometry; cell migration and invasion abilities were detected by scratch assay and Transwell assay; STAT3/C-MYC signaling pathway protein were detected by western blotting. Results. Olaparib combined with metformin has better effects on the proliferation, clone formation, migration, invasion, and apoptosis of bladder cancer cells than single drug, indicating that metformin can enhance the inhibitory effect of olaparib on tumor growth and regulate the expression of STAT3/C-MYC signaling pathway proteins. Conclusion. The results of this study showed that metformin could significantly enhance the antitumor effect of olaparib on bladder cancer cells, and these effects were mediated by downregulating STAT3/C-MYC signaling pathway proteins. This finding may have potential clinical application in the treatment of bladder cancer.
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27
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Miyaki C, Lynch LM. An Update on Common Pharmaceuticals in the Prevention of Pancreatic Cancer. Cureus 2022; 14:e25496. [PMID: 35800820 PMCID: PMC9246430 DOI: 10.7759/cureus.25496] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/30/2022] [Indexed: 01/03/2023] Open
Abstract
In this review, we aim to update readers about the most recent studies on common pharmaceuticals and their association with pancreatic cancer risk. The use of prophylactic aspirin, metformin, beta-blockers, and statins has been studied in the past but showed inconclusive results in the reduction of pancreatic cancer incidence. However, in recent studies, these medications along with combination therapy of aspirin and metformin were found to have a more significant association with decreasing risk. Given the poor prognosis of pancreatic cancer despite treatment, medication prophylaxis prevention should be considered. In this review, we hope to encourage future case-control or prospective studies on common medications that have shown great potential in delaying pancreatic cancer development.
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Wu J, Liu G, An K, Shi L. NPTX1 inhibits pancreatic cancer cell proliferation and migration and enhances chemotherapy sensitivity by targeting RBM10. Oncol Lett 2022; 23:154. [PMID: 35836482 PMCID: PMC9258595 DOI: 10.3892/ol.2022.13275] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 10/27/2021] [Indexed: 12/02/2022] Open
Abstract
Pancreatic cancer (PC), one of the deadliest diseases worldwide, has exhibited an increasing incidence rate in recent years. The present study aimed to explore the biological mechanism of PC. Therefore, the expression levels of neuronal pentraxin 1 (NPTX1) and RNA-binding protein 10 (RBM10) were detected in PC cell lines using reverse transcription-quantitative PCR (RT-qPCR) and western blot analyses prior to or following NPTX1 and RBM10 overexpression. Additionally, the proliferative ability of PANC-1 and BxPC-3 cells treated with or without gemcitabine (GEM) and cisplatin (DDP) was evaluated using Cell Counting Kit-8 assay. Cell apoptosis and the expression levels of apoptosis-related proteins were determined by TUNEL assay and western blot analysis, respectively. Furthermore, wound healing and Transwell assays were performed to measure the migration and invasion abilities of PANC-1 and BxPC-3 cells. The interaction between RBM10 and NPTX1 mRNA was detected by RNA binding protein immunoprecipitation (RIP) assay. Additionally, cells were treated with actinomycin D to verify the regulatory effect of RBM10 on NPTX1 expression. This effect was further confirmed by RT-qPCR analysis. The results showed that NPTX1 was downregulated in PC cell lines. In addition, NPTX1 overexpression inhibited the proliferation and promoted apoptosis in PC cells. The results from the wound healing and Transwell assays revealed that the migration and invasion abilities of PANC-1 and BxPC-3 cells were reduced following NPTX1 overexpression. However, treatment of NPTX1-overexpressing cells with GEM or DDP attenuated PC cell viability. In addition, the results of the RIP assay revealed that RBM10 could bind with NPTX1. Furthermore, RBM10 overexpression could regulate NPTX1 expression, as evidenced by actinomycin D experiments. Overall, the results of the present study suggested that NPTX1 could inhibit PC and enhance the sensitivity of PC cells to chemotherapy. Additionally, NPTX1 was found to interact with RBM10, indicating that NPTX1 could inhibit PC via targeting RBM10.
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Affiliation(s)
- Jing Wu
- Department of Digestion, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Gaifang Liu
- Department of Digestion, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Kang An
- Department of Digestion, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Linping Shi
- Department of Digestion, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
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29
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Hao W, Li N, Mi C, Wang Q, Yu Y. Salidroside attenuates cardiac dysfunction in a rat model of diabetes. Diabet Med 2022; 39:e14683. [PMID: 34467560 DOI: 10.1111/dme.14683] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 08/30/2021] [Indexed: 12/20/2022]
Abstract
AIM This study aimed to investigate the therapeutic effects of salidroside on diabetes-induced cardiovascular disease. METHODS Sprague-Dawley rats treated with 65 mg/kg of streptozotocin (STZ) on a daily basis were used to establish the diabetic rat model (blood glucose levels >13.9 mmol/L). Cardiac functions of diabetic rats were evaluated by their haemodynamic alterations. Western blot assay was performed to evaluate the protein levels of multiple signalling pathway factors. Quantitative real-time PCR assay was performed to investigate the inflammation and oxidative stress of diabetic rats. RESULTS Salidroside treatment improved the cardiac functions of diabetic rats. In addition, salidroside therapy attenuated the cardiac oxidative stress induced by diabetes. Salidroside inhibited the diabetes-induced inflammation in diabetic rat hearts. The apoptosis of cardiomyocytes was also alleviated by the treatment of salidroside. Salidroside also upregulated the phosphorylation levels of AMPK, ACC, TSC2 and RAPTOR. CONCLUSION Salidroside exerts protective effects against diabetes-induced cardiac dysfunction by modulating the mTOR and AMPK signalling pathways.
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Affiliation(s)
- Weiwei Hao
- Department of Clinical Medicine, College of Medicine, Pingdingshan University, Pingdingshan, Henan, China
| | - Na Li
- Department of Clinical Medicine, College of Medicine, Pingdingshan University, Pingdingshan, Henan, China
| | - Caifeng Mi
- Department of Gastroenterology, The First Affiliated Hospital of Pingdingshan University, Pingdingshan, Henan, China
| | - Qiang Wang
- Department of Cardiology, The First Affiliated Hospital of Pingdingshan University, Pingdingshan, Henan, China
| | - Yuanyuan Yu
- Department of Endocrinology, The First Affiliated Hospital of Pingdingshan University, Pingdingshan, Henan, China
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Huang F, Xiang Y, Li T, Huang Y, Wang J, Zhang HM, Li HH, Dai ZT, Li JP, Li H, Zhou J, Liao XH. Metformin and MiR-365 synergistically promote the apoptosis of gastric cancer cells via MiR-365-PTEN-AMPK axis. Pathol Res Pract 2022; 230:153740. [PMID: 35007850 DOI: 10.1016/j.prp.2021.153740] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 12/10/2021] [Accepted: 12/16/2021] [Indexed: 01/19/2023]
Abstract
Metformin is an oral biguanide used to treat diabetes. Recent study showed it may interfere was related to cancer progression and has a positive effect on cancer prevention and treatment, which attracts a new hot research topic. Here we show that Metformin suppressed the proliferation but induced apoptosis of gastric cells. Notably, Metformin enhanced gastriccell apoptosis via modulating AMPK signaling. Furthermore, Metformin and miR-365 synergistically promote the apoptosis of gastric cancer cells by miR-365-PTEN-AMPK axis. Our study unraveled a novel signaling axis in the regulation in gastric cancer, which could be amplified by the application of metformin. The new effect of metformin potentiates its novel therapeutic application in the future. AVAILABILITY OF DATA AND MATERIALS: The data generated during this study are included in this article and its supplementary information files are available from the corresponding author on reasonable request.
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Affiliation(s)
- Feng Huang
- Institute of Biology and Medicine, Wuhan University of Science and Technology, 430000, PR China.
| | - Yuan Xiang
- Department of Medical Laboratory, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Hubei 430014, PR China.
| | - Ting Li
- Institute of Biology and Medicine, Wuhan University of Science and Technology, 430000, PR China.
| | - You Huang
- Institute of Biology and Medicine, Wuhan University of Science and Technology, 430000, PR China.
| | - Jun Wang
- Institute of Biology and Medicine, Wuhan University of Science and Technology, 430000, PR China.
| | - Hui-Min Zhang
- Institute of Biology and Medicine, Wuhan University of Science and Technology, 430000, PR China.
| | - Han-Han Li
- Institute of Biology and Medicine, Wuhan University of Science and Technology, 430000, PR China.
| | - Zhou-Tong Dai
- Institute of Biology and Medicine, Wuhan University of Science and Technology, 430000, PR China.
| | - Jia-Peng Li
- Institute of Biology and Medicine, Wuhan University of Science and Technology, 430000, PR China.
| | - Hui Li
- Institute of Biology and Medicine, Wuhan University of Science and Technology, 430000, PR China.
| | - Jun Zhou
- Institute of Biology and Medicine, Wuhan University of Science and Technology, 430000, PR China.
| | - Xing-Hua Liao
- Institute of Biology and Medicine, Wuhan University of Science and Technology, 430000, PR China.
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Kuang X, Liu Z. Mining the Biomarkers and Associated-Drugs for Esophageal Squamous Cell Carcinoma by Bioinformatic Methods. TOHOKU J EXP MED 2022; 256:27-36. [PMID: 35067492 DOI: 10.1620/tjem.256.27] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Esophageal squamous cell carcinoma (ESCC) showed limited treatment outcome and poor prognosis. This study aimed to screen potential biomarkers and drugs in ESCC. Firstly, GSE26886, GSE111044 and GSE77861 were downloaded from the Gene Expression Omnibus (GEO) database. Next, the differentially expressed genes (DEGs) between cancer and noncancerous tissues were analyzed by the GEO2R. The Gene Ontology (GO) annotation, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation, the protein-protein interaction (PPI) analysis and hub genes screened were conducted by some bioinformatic methods, respectively. Lastly, the hub genes and potential drugs were verified by the GEPIA2 and the QuartataWeb database. The results showed that 13 up-regulated genes and 81 down-regulated genes were identified. In GO terms, DEGs were mainly associated with cell proliferation, cell migration and cell differentiation. DEGs did not cluster into the KEGG pathway. After hub genes validated, nine genes (FLG, COL1A1, COL1A2, PSCA, SCEL, PPL, ACPP, CNFN, and A2ML1) expression trends showed no change. Moreover, higher COL1A1 or COL1A2 expression for ESCC patients showed poor prognosis. Finally, five drugs used for promoting blood coagulation were identified. Probably, these drugs could show anticancer effects by promoting blood coagulation or inhibiting vascular formation in cancers, which offers a novel idea for the treatment of ESCC.
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Affiliation(s)
- Xiuying Kuang
- The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine
| | - Zhihui Liu
- The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine
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32
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Wang C, Huang B, Sun L, Wang X, Zhou B, Tang H, Geng W. MK8722, an AMPK activator, inhibiting carcinoma proliferation, invasion and migration in human pancreatic cancer cells. Biomed Pharmacother 2021; 144:112325. [PMID: 34656065 DOI: 10.1016/j.biopha.2021.112325] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 10/06/2021] [Accepted: 10/08/2021] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND MK8722 is a potent and systemic pan-AMPK activator. It is an effective, direct, allosteric activator of AMPK complex in many mammals. This study tried to explore the underlying anti-cancer molecular mechanism of MK8722 in human pancreatic cancer cells (PCCs). METHODS The anti-proliferation, invasion and migration functions of MK8722 in human pancreatic cancer analyzed by real time cellular analysis, colony formation assay, cell migration assay, transwell assay and flow cytometery analysis. Moreover, the potential targeted signaling pathway was tested via RNA-seq and pathway enrichment analysis. RESULTS In the present study, we investigated the anti-PCCs effects of MK8722 on two different human pancreatic cancer cell lines (PANC-1 and Patu8988). The results showed that MK8722 significantly inhibited human tumor cells proliferation and migration/invasion in a dose-dependent manner. Additionally, the influence of MK8722 was examined by analyzing the expression of potential key genes and pathways, which may provide novel insights to the mechanism of MK8722. CONCLUSION The inhibition of pancreatic cancer by MK8722 through a number of pathways that inhibit carcinoma proliferation, invasion and migration. The potential effect of MK8722 might be determined by regulating the expression of AL162151, IER2, REPIN1, KRT80 to inhibit cycle arrest and migration.
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Affiliation(s)
- Cheng Wang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
| | - Baojun Huang
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
| | - Linxiao Sun
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
| | - Xi Wang
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
| | - Baofeng Zhou
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
| | - Hongli Tang
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
| | - Wujun Geng
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China; Wenzhou Key Laboratory of perioperative medicine (NO. 2021HZSY0037).
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Chen Y, Zhang Y, Chen S, Liu W, Lin Y, Zhang H, Yu F. NSAIDs Sensitize Melanoma Cells to MEK Inhibition and Inhibit Metastasis and Relapse by Inducing Degradation of AXL. Pigment Cell Melanoma Res 2021; 35:238-251. [PMID: 34748282 DOI: 10.1111/pcmr.13021] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 10/12/2021] [Accepted: 11/04/2021] [Indexed: 11/29/2022]
Abstract
Melanoma is highly heterogeneous with diverse genomic alterations and partial therapeutic responses. Emergence of drug-resistant tumor cell clones accompanied with high AXL expression level is one of the major challenges for anti-tumor clinical care. Recent studies have demonstrated that high AXL expression in melanoma cells mediated drug-resistance, epithelial-mesenchymal transition (EMT) and elevated survival of cancer stem cells (CSCs). Given that we have identified several non-steroidal anti-inflammatory drugs (NSAIDs) including Aspirin potently induce the degradation of AXL, we questioned whether NSAIDs could counteract the AXL-mediated neoplastic phenotypes. Here we found NSAIDs downregulate PKA activity via the PGE2 /EP2/cAMP/PKA signaling pathway and interrupt the PKA-dependent interaction between CDC37 and HSP90, resulting in an incorrect AXL protein folding and finally AXL degradation through the ubiquitination-proteasome system (UPS) pathway. Furthermore, NSAIDs not only sensitized the MEK inhibitor treatment, but also reduced EMT and relapse mediate by AXL in tumor tissue. Our findings suggest that the combination of inhibitors and NSAIDs, especially Aspirin, could be a simple but efficient modality to treat melanoma in which AXL is a key factor for drug-resistance, metastasis, and relapse.
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Affiliation(s)
- Yingshi Chen
- Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Yiwen Zhang
- Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China
| | - Siqi Chen
- State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China
| | - Weiwei Liu
- Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China
| | - Yingtong Lin
- Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China
| | - Hui Zhang
- Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.,Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China
| | - Fei Yu
- Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
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Fan Y, Ren X, Wang Y, Xu E, Wang S, Ge R, Liu Y. Metformin inhibits the proliferation of canine mammary gland tumor cells through the AMPK/AKT/mTOR signaling pathway in vitro. Oncol Lett 2021; 22:852. [PMID: 34733370 PMCID: PMC8561621 DOI: 10.3892/ol.2021.13113] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 06/14/2021] [Indexed: 11/25/2022] Open
Abstract
As an anti-diabetic drug, metformin has been demonstrated to exhibit antitumor effects. However, the mechanisms involved in decreasing tumor formation, including canine mammary gland tumors (CMGTs), are not well elucidated. The aim of the present study was to evaluate the ability of metformin to induce apoptosis and cell cycle arrest in CMGT cells, as well as identifying the pathways underlying these effects. Cell viability was assessed by Cell Counting Kit-8 analysis following treating with metformin. Subsequently, apoptosis and cell cycle progression were assessed by flow cytometry, and the expression of associated proteins was examined. Expression levels of classical AMP-activated protein kinase (AMPK), protein kinase B (AKT), mechanistic target of rapamycin (mTOR) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) were then investigated using western blot analysis. Metformin inhibited the proliferation of CHMm cells in a concentration-dependent manner. Specifically, metformin induced cell cycle arrest in the G0/G1 phases, accompanied by increased expression of p21 and p27, and decreased expression of cyclin D1 and cyclin-dependent kinase 4. Marked levels of apoptosis were observed in CHMm cells alongside the activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase. Also, the level of Bcl-2 was decreased, and that of Bax was increased. The expression of associated signaling molecules revealed that metformin markedly increased the phosphorylation of AMPK in CHMm cells, and decreased the levels of phosphorylated (p-)AKT, p-mTOR and p-4E-BP1, while Compound C reversed these changes. These findings demonstrated that metformin may be a potential therapeutic agent for CMGTs, acting via the AMPK/AKT/mTOR signaling pathway.
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Affiliation(s)
- Yuying Fan
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang 150000, P.R. China
| | - Xiaoli Ren
- College of Veterinary Medicine, Henan University of Animal Husbandry and Economy, Zhengzhou, Henan 450046, P.R. China
| | - Yingxue Wang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang 150000, P.R. China
| | - Enshuang Xu
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163000, P.R. China
| | - Shuang Wang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang 150000, P.R. China
| | - Ruidong Ge
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang 150000, P.R. China
| | - Yun Liu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang 150000, P.R. China
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Frades I, Foguet C, Cascante M, Araúzo-Bravo MJ. Genome Scale Modeling to Study the Metabolic Competition between Cells in the Tumor Microenvironment. Cancers (Basel) 2021; 13:4609. [PMID: 34572839 PMCID: PMC8470216 DOI: 10.3390/cancers13184609] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 09/06/2021] [Accepted: 09/09/2021] [Indexed: 12/31/2022] Open
Abstract
The tumor's physiology emerges from the dynamic interplay of numerous cell types, such as cancer cells, immune cells and stromal cells, within the tumor microenvironment. Immune and cancer cells compete for nutrients within the tumor microenvironment, leading to a metabolic battle between these cell populations. Tumor cells can reprogram their metabolism to meet the high demand of building blocks and ATP for proliferation, and to gain an advantage over the action of immune cells. The study of the metabolic reprogramming mechanisms underlying cancer requires the quantification of metabolic fluxes which can be estimated at the genome-scale with constraint-based or kinetic modeling. Constraint-based models use a set of linear constraints to simulate steady-state metabolic fluxes, whereas kinetic models can simulate both the transient behavior and steady-state values of cellular fluxes and concentrations. The integration of cell- or tissue-specific data enables the construction of context-specific models that reflect cell-type- or tissue-specific metabolic properties. While the available modeling frameworks enable limited modeling of the metabolic crosstalk between tumor and immune cells in the tumor stroma, future developments will likely involve new hybrid kinetic/stoichiometric formulations.
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Affiliation(s)
- Itziar Frades
- Computational Biology and Systems Biomedicine Group, Biodonostia Health Research Institute, 20009 San Sebastian, Spain;
| | - Carles Foguet
- Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine of University of Barcelona, Faculty of Biology, Universitat de Barcelona, Av. Diagonal 643, 08028 Barcelona, Spain; (C.F.); (M.C.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD) (CB17/04/00023) and Metabolomics Node at Spanish National Bioinformatics Institute (INB-ISCIII-ES-ELIXIR), Instituto de Salud Carlos III (ISCIII), 28020 Madrid, Spain
| | - Marta Cascante
- Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine of University of Barcelona, Faculty of Biology, Universitat de Barcelona, Av. Diagonal 643, 08028 Barcelona, Spain; (C.F.); (M.C.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD) (CB17/04/00023) and Metabolomics Node at Spanish National Bioinformatics Institute (INB-ISCIII-ES-ELIXIR), Instituto de Salud Carlos III (ISCIII), 28020 Madrid, Spain
| | - Marcos J. Araúzo-Bravo
- Computational Biology and Systems Biomedicine Group, Biodonostia Health Research Institute, 20009 San Sebastian, Spain;
- Max Planck Institute of Molecular Biomedicine, 48167 Münster, Germany
- Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERfes), 28015 Madrid, Spain
- Translational Bioinformatics Network (TransBioNet), 8001 Barcelona, Spain
- Ikerbasque, Basque Foundation for Science, 48012 Bilbao, Spain
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Metformin Attenuates Hypoxia-induced Endothelial Cell Injury by Activating the AMP-Activated Protein Kinase Pathway. J Cardiovasc Pharmacol 2021; 77:862-874. [PMID: 33929389 DOI: 10.1097/fjc.0000000000001028] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 03/05/2021] [Indexed: 12/12/2022]
Abstract
ABSTRACT Metformin reduces the incidence of cardiovascular diseases, and potential underlying mechanisms of action have been suggested. Here, we investigated the role of metformin in endothelial cell injury and endothelial-mesenchymal transition (EndMT) induced by hypoxia. All experiments were performed in human cardiac microvascular endothelial cells (HCMECs). HCMECs were exposed to hypoxic conditions for 24, 48, 72, and 96 hours, and we assessed the cell viability by cell counting kit 8; metformin (2, 5, 10, and 20 mmol/L) was added to the cells after exposure to the hypoxic conditions for 48 hours. The cells were randomly divided into the control group, hypoxia group, hypoxia + metformin group, hypoxia + control small interfering RNA group, hypoxia + small interfering Prkaa1 (siPrkaa1) group, and hypoxia + siPrkaa1 + metformin group. Flow cytometry and cell counting kit 8 were used to monitor apoptosis and assess cell viability. Immunofluorescence staining was used to identify the CD31+/alpha smooth muscle actin+ double-positive cells. Quantitative real-time-PCR and Western blot were used for mRNA and protein expression analyses, respectively. Hypoxia contributed to endothelial injuries and EndMT of HCMECs in a time-dependent manner, which was mainly manifested as decreases in cell viability, increases in apoptotic rate, and changes in expression of apoptosis-related and EndMT-related mRNAs and proteins. Furthermore, metformin could attenuate the injuries and EndMT caused by hypoxia. After metformin treatment, phosphorylated-AMPK (pAMPK) and p-endothelial nitric oxide synthase expression increased, whereas p-mammalian target of rapamycin expression decreased. However, results obtained after transfection with siPrkaa1 were in contrast to the results of metformin treatment. In conclusion, metformin can attenuate endothelial injuries and suppress EndMT of HCMECs under hypoxic conditions because of its ability to activate the AMPK pathway, increase p-AMPK/AMP-activated protein kinase, and inhibit mammalian target of rapamycin.
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Nagayama D, Saiki A, Shirai K. The Anti-Cancer Effect of Pitavastatin May Be a Drug-Specific Effect: Subgroup Analysis of the TOHO-LIP Study. Vasc Health Risk Manag 2021; 17:169-173. [PMID: 33953560 PMCID: PMC8092348 DOI: 10.2147/vhrm.s306540] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Accepted: 04/09/2021] [Indexed: 12/31/2022] Open
Abstract
The significance of statin treatment for the reduction of cardiovascular (CV) disease has been reported, whereas other reports have also described anti-cancer properties associated with the class effect of statins. However, the differences in anti-cancer effect of various types of statins have rarely been examined. Pitavastatin is a statin with a different chemical structure and pharmacokinetics from other statins, and the mechanism of the specific anti-cancer effect of pitavastatin has been reported in in vivo therapeutic models. We previously revealed that pitavastatin therapy was superior to atorvastatin therapy in the prevention of CV events, despite similar LDL-cholesterol-lowering effect in the TOHO Lipid Intervention Trial Using Pitavastatin (TOHO-LIP). Furthermore, in subgroup analysis of the TOHO-LIP study, cumulative 240-week incidence of new cancer cases tended to be lower in the pitavastatin group compared to the atorvastatin group [0.32% (1/312) vs 1.94% (6/310), log-rank P=0.051]. This finding might reveal the superiority of pitavastatin to prevent carcinogenesis. The molecular mechanism by which pitavastatin suppresses the incidence of any-organ cancer is gradually elucidated, and new combination of cancer treatments with pitavastatin will be developed in the future to further enhance the anti-cancer activity and reduce the side effects.
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Affiliation(s)
- Daiji Nagayama
- Department of Internal Medicine, Nagayama Clinic, Tochigi, Japan.,Center of Diabetes, Endocrine and Metabolism, Toho University Sakura Medical Center, Chiba, Japan
| | - Atsuhito Saiki
- Center of Diabetes, Endocrine and Metabolism, Toho University Sakura Medical Center, Chiba, Japan
| | - Kohji Shirai
- Department of Internal Medicine, Mihama Hospital, Chiba, Japan
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Tian-Huang Formula, a Traditional Chinese Medicinal Prescription, Improves Hepatosteatosis and Glucose Intolerance Targeting AKT-SREBP Nexus in Diet-Induced Obese Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:6617586. [PMID: 33763145 PMCID: PMC7955866 DOI: 10.1155/2021/6617586] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 01/21/2021] [Accepted: 02/05/2021] [Indexed: 02/06/2023]
Abstract
The progressive increase of metabolic diseases underscores the necessity for developing effective therapies. Although we found Tian-Huang formula (THF) could alleviate metabolic disorders, the underlying mechanism remains to be fully understood. In the present study, firstly, male Sprague-Dawley rats were fed with high-fat diet plus high-fructose drink (HFF, the diet is about 60% of calories from fat and the drink is 12.5% fructose solution) for 14 weeks to induce hepatosteatosis and glucose intolerance and then treated with THF (200 mg/kg) for 4 weeks. Then, metabolomics analysis was performed with rat liver samples and following the clues illustrated by Ingenuity Pathway Analysis (IPA) with the metabolomics discoveries, RT-qPCR and Western blotting were carried out to validate the putative pathways. Our results showed that THF treatment reduced the body weight from 735.1 ± 81.29 to 616.3 ± 52.81 g and plasma triglyceride from 1.5 ± 0.42 to 0.88 ± 0.33 mmol/L; meanwhile, histological examinations of hepatic tissue and epididymis adipose tissue showed obvious alleviation. Compared with the HFF group, the fasting serum insulin and blood glucose level of the THF group were improved from 20.77 ± 6.58 to 9.65 ± 5.48 mIU/L and from 8.96 ± 0.56 to 7.66 ± 1.25 mmol/L, respectively, so did the serum aspartate aminotransferase, insulin resistance index, and oral glucose tolerance (p = 0.0019, 0.0053, and 0.0066, respectively). Furthermore, based on a list of 32 key differential endogenous metabolites, the molecular networks generated by IPA suggested that THF alleviated glucose intolerance and hepatosteatosis by activating phosphatidylinositol-3 kinase (PI3K) and low-density lipoprotein receptor (LDL-R) involved pathways. RT-qPCR and Western blotting results confirmed that THF alleviated hepatic steatosis and glucose intolerance partly through protein kinase B- (AKT-) sterol regulatory element-binding protein (SREBP) nexus. Our findings shed light on molecular mechanisms of THF on alleviating metabolic diseases and provided further evidence for developing its therapeutic potential.
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Yang J, Fang HJ, Cao Q, Mao ZW. The design of cyclometalated iridium(iii)-metformin complexes for hypoxic cancer treatment. Chem Commun (Camb) 2021; 57:1093-1096. [PMID: 33434260 DOI: 10.1039/d0cc07104h] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Modulating the hypoxic microenvironment is the priority for tumor treatment. Cytometalated iridium(iii)-metformin conjugates were synthesized for treating hypoxic cancer cells for the first time, which alleviate hypoxia via mitochondria respiration inhibition, thus displaying 10-fold higher cytotoxicity, emerging anti-metastasis and anti-inflammatory activities than a metformin-free Ir(iii) complex and cisplatin against hypoxic cancer cells.
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Affiliation(s)
- Jing Yang
- MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-Sen University, Guangzhou 510275, China.
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Fang L, Xu Q, Qian J, Zhou JY. Aberrant Factors of Fibrinolysis and Coagulation in Pancreatic Cancer. Onco Targets Ther 2021; 14:53-65. [PMID: 33442266 PMCID: PMC7797325 DOI: 10.2147/ott.s281251] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 12/11/2020] [Indexed: 12/13/2022] Open
Abstract
Aberrant factors associated with fibrinolysis and thrombosis are found in many cancer patients, which can promote metastasis and are associated with poor prognosis. The relationship between tumor-associated fibrinolysis and thrombosis is poorly understood in pancreatic cancer. This review provides a brief highlight of existing studies that the fibrinolysis and coagulation systems were activated in pancreatic cancer patients, along with aberrant high concentrations of tissue plasminogen activator (t-PA), urine plasminogen activator (u-PA), D-dimer, fibrinogen, or platelets. These factors cooperate with each other, propelling tumor cell shedding, localization, adhesion to distant metastasis. The relationship between thrombosis or fibrinolysis and cancer immune escape is also investigated. In addition, the potential prevention and therapy strategies of pancreatic cancer targeting factors in fibrinolysis and coagulation systems are also been discussed, in which we highlight two effective agents aspirin and low-molecular weight heparin (LMWH). Summarily, this review provides new directions for the research and treatment of pancreatic cancer.
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Affiliation(s)
- Lianghua Fang
- Department of Oncology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, People's Republic of China
| | - Qing Xu
- Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing 210029, People's Republic of China
| | - Jun Qian
- Department of Oncology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, People's Republic of China
| | - Jin-Yong Zhou
- Central Laboratory, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, People's Republic of China
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Parihar M, Dodds SG, Javors M, Strong R, Hasty P, Sharp ZD. Sex-dependent lifespan extension of Apc Min/+ FAP mice by chronic mTOR inhibition. AGING PATHOBIOLOGY AND THERAPEUTICS 2020; 2:187-194. [PMID: 33834178 PMCID: PMC8026166 DOI: 10.31491/apt.2020.12.039] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND Apc Min/+ mice model familial adenomatous polyposis (FAP), a disease that causes numerous colon polyps leading to colorectal cancer. We previously showed that chronic treatment of Apc Min/+ females with the anti-aging drug, rapamycin, restored a normal lifespan through reduced polyposis and anemia prevention. Lifespan extension by chronic rapamycin in wildtype UM-HET3 mice is sex-dependent with females gaining the most benefit. Whether Apc Min/+ mice have a similar sex-dependent response to chronic mTOR inhibition is not known. METHODS To address this knowledge gap and gain deeper insight into how chronic mTOR inhibition prevents intestinal polyposis, we compared male and female Apc Min/+ mice responses to chronic treatment with a rapamycin-containing diet. Animals were fed a diet containing either 42 ppm microencapsulate rapamycin or empty capsules, one group was used to determine lifespan and a second group with similar treatment was harvested at 16 weeks of age for cross-sectional studies. RESULTS We found that the survival of males is greater than females in this setting (P < 0.0197). To explore the potential basis for this difference we analyzed factors affected by chronic rapamycin. Immunoblot assays showed that males and females exhibited approximately the same level of mTORC1 inhibition using phosphorylation of ribosomal protein S6 (rpS6) as an indirect measure. Immunohistochemistry assays of rpS6 phosphorylation showed that rapamycin reduction of mTORC1 activity was on the same level, with the most prominent difference being in intestinal crypt Paneth cells in both sexes. Chronic rapamycin also reduced crypt depths in both male and female Apc Min/+ mice (P < 0.0001), consistent with reduced crypt epithelial cell proliferation. Finally, chronic rapamycin prevented anemia equally in males and females. CONCLUSIONS In males and females, these findings link rapamycin-mediated intestinal polyposis prevention with mTORC1 inhibition in Paneth cells and concomitant reduced epithelial cell proliferation.
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Affiliation(s)
- Manish Parihar
- Department of Molecular Medicine and Institute of
Biotechnology, University of Texas Health San Antonio, San Antonio, TX, USA
- Greehey Children's Cancer Research Institute, University of
Texas Health San Antonio, San Antonio, TX, USA
| | - Sherry G. Dodds
- Department of Molecular Medicine and Institute of
Biotechnology, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Marty Javors
- Barshop Institute for Longevity and Aging Studies,
University of Texas Health San Antonio, San Antonio, TX, USA
- Department of Pharmacology, University of Texas Health San
Antonio, San Antonio, TX, USA
- Department of Psychiatry, University of Texas Health San
Antonio, San Antonio, TX, USA
| | - Randy Strong
- Barshop Institute for Longevity and Aging Studies,
University of Texas Health San Antonio, San Antonio, TX, USA
- Department of Pharmacology, University of Texas Health San
Antonio, San Antonio, TX, USA
- South Texas Veterans Health Care System San Antonio, TX,
USA
| | - Paul Hasty
- Department of Molecular Medicine and Institute of
Biotechnology, University of Texas Health San Antonio, San Antonio, TX, USA
- Barshop Institute for Longevity and Aging Studies,
University of Texas Health San Antonio, San Antonio, TX, USA
- Mays Cancer Center, University of Texas Health San Antonio,
San Antonio, TX, USA
| | - Zelton Dave Sharp
- Department of Molecular Medicine and Institute of
Biotechnology, University of Texas Health San Antonio, San Antonio, TX, USA
- Barshop Institute for Longevity and Aging Studies,
University of Texas Health San Antonio, San Antonio, TX, USA
- Mays Cancer Center, University of Texas Health San Antonio,
San Antonio, TX, USA
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AMP-activated protein kinase regulates β-catenin protein synthesis by phosphorylating serine/arginine-rich splicing factor 9. Biochem Biophys Res Commun 2020; 534:347-352. [PMID: 33248688 DOI: 10.1016/j.bbrc.2020.11.079] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 11/17/2020] [Indexed: 12/13/2022]
Abstract
β-catenin is a multi-functional protein with a central role in regulating embryonic development and tissue homeostasis. The abnormal accumulation of β-catenin, due to disrupted β-catenin degradation or unregulated β-catenin synthesis, causes the development of cancer. A recent study showed that the overexpression of proto-oncogene serine/arginine-rich splicing factor 9 (SRSF9) promotes β-catenin accumulation via binding β-catenin mRNA and enhancing its translation in a manner that is dependent on the mechanistic target of rapamycin (mTOR). However, the regulation of the interaction between SRSF9 and mRNA of β-catenin remains unclear. Here, we show that AMP-activated protein kinase (AMPK) phosphorylates SRSF9 at the RNA-interacting SWQDLKD motif that plays a major role in determining substrate specificity. The phosphorylation by AMPK inhibits the binding of SRSF9 to β-catenin mRNA and suppresses β-catenin protein synthesis caused by SRSF9 overexpression without changing the β-catenin mRNA levels. Our findings suggest that AMPK activators are potential therapeutic targets for SRSF9-derived overproduction of β-catenin in cancer cells.
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Jin MZ, Jin WL. The updated landscape of tumor microenvironment and drug repurposing. Signal Transduct Target Ther 2020; 5:166. [PMID: 32843638 PMCID: PMC7447642 DOI: 10.1038/s41392-020-00280-x] [Citation(s) in RCA: 746] [Impact Index Per Article: 149.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 07/16/2020] [Accepted: 07/30/2020] [Indexed: 02/07/2023] Open
Abstract
Accumulating evidence shows that cellular and acellular components in tumor microenvironment (TME) can reprogram tumor initiation, growth, invasion, metastasis, and response to therapies. Cancer research and treatment have switched from a cancer-centric model to a TME-centric one, considering the increasing significance of TME in cancer biology. Nonetheless, the clinical efficacy of therapeutic strategies targeting TME, especially the specific cells or pathways of TME, remains unsatisfactory. Classifying the chemopathological characteristics of TME and crosstalk among one another can greatly benefit further studies exploring effective treating methods. Herein, we present an updated image of TME with emphasis on hypoxic niche, immune microenvironment, metabolism microenvironment, acidic niche, innervated niche, and mechanical microenvironment. We then summarize conventional drugs including aspirin, celecoxib, β-adrenergic antagonist, metformin, and statin in new antitumor application. These drugs are considered as viable candidates for combination therapy due to their antitumor activity and extensive use in clinical practice. We also provide our outlook on directions and potential applications of TME theory. This review depicts a comprehensive and vivid landscape of TME from biology to treatment.
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Affiliation(s)
- Ming-Zhu Jin
- Institute of Nano Biomedicine and Engineering, Shanghai Engineering Center for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, Key Laboratory for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electronic Engineering, Shanghai Jiao Tong University, Shanghai, 200240, P. R. China.,Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, P. R. China
| | - Wei-Lin Jin
- Institute of Nano Biomedicine and Engineering, Shanghai Engineering Center for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, Key Laboratory for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electronic Engineering, Shanghai Jiao Tong University, Shanghai, 200240, P. R. China.
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Khani M, Hosseini J, Habibi M, Mirfakhraie R, Sadeghzadeh Z, Pouresmaeili F. Investigating the relationship between ccfDNA concentration, its integrity, and some individual factors in an Iranian population. Hum Antibodies 2020; 28:319-326. [PMID: 32804121 DOI: 10.3233/hab-200419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
INTRODUCTION Circulating cell-free DNA (ccfDNA) increases in some pathologic conditions like cancer. We aimed to investigate the correlation between some individual factors and the ccfDNA level in peripheral blood of Iranian in relation to prostate cancer. MATERIAL AND METHOD 30 patients with prostate cancer (PCa), 40 with benign prostate hyperplasia (BPH), and 30 controls were studied. Personal information, ccfDNA concentration, and the integrity index were assessed for the correlation between the disease and different factors. The results were statistically analyzed using SPSS software. RESULTS In PCa group, no association was found between total ccfDNA, BMI, BPH background, non-cancerous diseases, medications, PCa length, and job (p-value > 0.05). But, total ccfDNA had statistical associations with weight, family history of cancer, and location (p-value < 0.05). No association was between the integrity of ccfDNA, weight, the background of BPH, and family history of cancer. But, the integrity of ccfDNA was significantly associated with BMI and PCa length (p-value < 0.05).In BPH group, no association between total ccfDNA or the integrity of ccfDNA and the assessed factors was obtained (p-value > 0.05). In the normal group, neither statistical association was found between total ccfDNA, weight, BMI, and job, nor between the integrity of ccfDNA, weight, BMI, non-cancerous disease, drug, job, and location (p-value > 0.05). But, a statistical association was found between the integrity of ccfDNA and family history of cancer in the recent group (Based on 95% CI and P-value less than 0.05). CONCLUSION ccfDNA and its integrity as possible prostate cancer biomarkers under the influence of individuals' physiological status are prone to the pathologic changes toward the disease. Further simultaneous study of the target groups could clarify this matter.
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Affiliation(s)
- Maryam Khani
- Medical Genetics Department, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Jalil Hosseini
- Men's Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohsen Habibi
- Medical Genetics Department, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Reza Mirfakhraie
- Medical Genetics Department, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Sadeghzadeh
- Men's Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farkhondeh Pouresmaeili
- Medical Genetics Department, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Men's Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Xu J, Kim S, Song M, Jeong M, Kim D, Kang J, Rousseau JF, Li X, Xu W, Torvik VI, Bu Y, Chen C, Ebeid IA, Li D, Ding Y. Building a PubMed knowledge graph. Sci Data 2020; 7:205. [PMID: 32591513 PMCID: PMC7320186 DOI: 10.1038/s41597-020-0543-2] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 05/26/2020] [Indexed: 01/08/2023] Open
Abstract
PubMed® is an essential resource for the medical domain, but useful concepts are either difficult to extract or are ambiguous, which has significantly hindered knowledge discovery. To address this issue, we constructed a PubMed knowledge graph (PKG) by extracting bio-entities from 29 million PubMed abstracts, disambiguating author names, integrating funding data through the National Institutes of Health (NIH) ExPORTER, collecting affiliation history and educational background of authors from ORCID®, and identifying fine-grained affiliation data from MapAffil. Through the integration of these credible multi-source data, we could create connections among the bio-entities, authors, articles, affiliations, and funding. Data validation revealed that the BioBERT deep learning method of bio-entity extraction significantly outperformed the state-of-the-art models based on the F1 score (by 0.51%), with the author name disambiguation (AND) achieving an F1 score of 98.09%. PKG can trigger broader innovations, not only enabling us to measure scholarly impact, knowledge usage, and knowledge transfer, but also assisting us in profiling authors and organizations based on their connections with bio-entities.
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Affiliation(s)
- Jian Xu
- School of Information Management, Sun Yat-sen University, Guangzhou, China
| | - Sunkyu Kim
- Department of Computer Science and Engineering, Korea University, Seoul, South Korea
| | - Min Song
- Department of Library and Information Science, Yonsei University, Seoul, South Korea
| | - Minbyul Jeong
- Department of Computer Science and Engineering, Korea University, Seoul, South Korea
| | - Donghyeon Kim
- Department of Computer Science and Engineering, Korea University, Seoul, South Korea
| | - Jaewoo Kang
- Department of Computer Science and Engineering, Korea University, Seoul, South Korea
| | | | - Xin Li
- School of Information, University of Texas at Austin, Austin, TX, USA
| | - Weijia Xu
- Texas Advanced Computing Center, Austin, TX, USA
| | - Vetle I Torvik
- School of Information Sciences, University of Illinois at Urbana-Champaign, Champaign, IL, USA
| | - Yi Bu
- Department of Information Management, Peking University, Beijing, China
| | - Chongyan Chen
- School of Information, University of Texas at Austin, Austin, TX, USA
| | - Islam Akef Ebeid
- School of Information, University of Texas at Austin, Austin, TX, USA
| | - Daifeng Li
- School of Information Management, Sun Yat-sen University, Guangzhou, China.
| | - Ying Ding
- Dell Medical School, University of Texas at Austin, Austin, TX, USA.
- School of Information, University of Texas at Austin, Austin, TX, USA.
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Yoo D, Kim N, Hwang DW, Song KB, Lee JH, Lee W, Kwon J, Park Y, Hong S, Lee JW, Hwang K, Shin D, Tak E, Kim SC. Association between Metformin Use and Clinical Outcomes Following Pancreaticoduodenectomy in Patients with Type 2 Diabetes and Pancreatic Ductal Adenocarcinoma. J Clin Med 2020; 9:1953. [PMID: 32580502 PMCID: PMC7356590 DOI: 10.3390/jcm9061953] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 06/16/2020] [Accepted: 06/18/2020] [Indexed: 12/12/2022] Open
Abstract
Retrospective studies on the association between metformin and clinical outcomes have mainly been performed on patients with non-resectable pancreatic ductal adenocarcinoma and may have been affected by time-related bias. To avoid this bias, recent studies have used time-varying analysis; however, they have only considered the start date of metformin use and not the stop date. We studied 283 patients with type 2 diabetes and pancreatic ductal adenocarcinoma following pancreaticoduodenectomy, and performed analysis using a Cox model with time-varying covariates, while considering both start and stop dates of metformin use. When start and stop dates were not considered, the metformin group showed significantly better survival. Compared with previous studies, adjusted analysis based on Cox models with time-varying covariates only considering the start date of postoperative metformin use showed no significant differences in survival. However, although adjusted analysis considering both start and stop dates showed no significant difference in recurrence-free survival, the overall survival was significantly better in the metformin group (Hazard ratio (HR), 0.747; 95% confidence interval (CI), 0.562-0.993; p = 0.045). Time-varying analysis incorporating both start and stop dates thus revealed that metformin use is associated with a higher overall survival following pancreaticoduodenectomy in patients with type 2 diabetes and pancreatic ductal adenocarcinoma.
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Affiliation(s)
- Daegwang Yoo
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (D.Y.); (D.W.H.); (K.B.S.); (J.H.L.); (W.L.); (J.K.); (Y.P.); (S.H.); (J.W.L.); (K.H.); (D.S.)
| | - Nayoung Kim
- Department of Clinical Epidemiology and Biostatistics, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea;
| | - Dae Wook Hwang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (D.Y.); (D.W.H.); (K.B.S.); (J.H.L.); (W.L.); (J.K.); (Y.P.); (S.H.); (J.W.L.); (K.H.); (D.S.)
| | - Ki Byung Song
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (D.Y.); (D.W.H.); (K.B.S.); (J.H.L.); (W.L.); (J.K.); (Y.P.); (S.H.); (J.W.L.); (K.H.); (D.S.)
| | - Jae Hoon Lee
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (D.Y.); (D.W.H.); (K.B.S.); (J.H.L.); (W.L.); (J.K.); (Y.P.); (S.H.); (J.W.L.); (K.H.); (D.S.)
| | - Woohyung Lee
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (D.Y.); (D.W.H.); (K.B.S.); (J.H.L.); (W.L.); (J.K.); (Y.P.); (S.H.); (J.W.L.); (K.H.); (D.S.)
| | - Jaewoo Kwon
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (D.Y.); (D.W.H.); (K.B.S.); (J.H.L.); (W.L.); (J.K.); (Y.P.); (S.H.); (J.W.L.); (K.H.); (D.S.)
| | - Yejong Park
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (D.Y.); (D.W.H.); (K.B.S.); (J.H.L.); (W.L.); (J.K.); (Y.P.); (S.H.); (J.W.L.); (K.H.); (D.S.)
| | - Sarang Hong
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (D.Y.); (D.W.H.); (K.B.S.); (J.H.L.); (W.L.); (J.K.); (Y.P.); (S.H.); (J.W.L.); (K.H.); (D.S.)
| | - Jong Woo Lee
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (D.Y.); (D.W.H.); (K.B.S.); (J.H.L.); (W.L.); (J.K.); (Y.P.); (S.H.); (J.W.L.); (K.H.); (D.S.)
| | - Kyungyeon Hwang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (D.Y.); (D.W.H.); (K.B.S.); (J.H.L.); (W.L.); (J.K.); (Y.P.); (S.H.); (J.W.L.); (K.H.); (D.S.)
| | - Dakyum Shin
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (D.Y.); (D.W.H.); (K.B.S.); (J.H.L.); (W.L.); (J.K.); (Y.P.); (S.H.); (J.W.L.); (K.H.); (D.S.)
| | - Eunyoung Tak
- Department of Convergence Medicine, Asan Medical Institute of Convergence Science and Technology (AMIST), Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Song Cheol Kim
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Institute of Convergence Science and Technology (AMIST), Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
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Fu X, Tan T, Liu P. Regulation of Autophagy by Non-Steroidal Anti-Inflammatory Drugs in Cancer. Cancer Manag Res 2020; 12:4595-4604. [PMID: 32606952 PMCID: PMC7305821 DOI: 10.2147/cmar.s253345] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 05/12/2020] [Indexed: 12/23/2022] Open
Abstract
Cancer is the leading cause of death, placing a substantial global health burden. The development of the most effective treatment regimen is the unmet clinical need for cancer. Inflammation plays a role in tumorigenesis and progression, and anti-inflammation may be a promising option for cancer management and prevention. Emerging studies have shown that non-steroidal anti-inflammatory drugs (NSAIDs) display anticarcinogenic and chemopreventive properties through the regulation of autophagy in certain types of cancer. In this review, we summarize the pharmacological functions and side effects of NSAIDs as chemotherapeutic agents, and focus on its mode of action on autophagy regulation, which increases our knowledge of NSAIDs and cancer-related inflammation, and contributes to a putative addition of NSAIDs in the chemoprevention and treatment of cancer.
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Affiliation(s)
- Xiangjie Fu
- Cholestatic Liver Diseases Center and Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, People’s Republic of China
| | - Tan Tan
- Translational Medicine Institute, The First Affiliated Hospital of Chenzhou, University of South China, Hunan, People’s Republic of China
| | - Peijun Liu
- Center for Translational Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Shanxi, People’s Republic of China
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Srivastava SP, Goodwin JE. Cancer Biology and Prevention in Diabetes. Cells 2020; 9:cells9061380. [PMID: 32498358 PMCID: PMC7349292 DOI: 10.3390/cells9061380] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 05/25/2020] [Accepted: 05/30/2020] [Indexed: 02/07/2023] Open
Abstract
The available evidence suggests a complex relationship between diabetes and cancer. Epidemiological data suggest a positive correlation, however, in certain types of cancer, a more complex picture emerges, such as in some site-specific cancers being specific to type I diabetes but not to type II diabetes. Reports share common and differential mechanisms which affect the relationship between diabetes and cancer. We discuss the use of antidiabetic drugs in a wide range of cancer therapy and cancer therapeutics in the development of hyperglycemia, especially antineoplastic drugs which often induce hyperglycemia by targeting insulin/IGF-1 signaling. Similarly, dipeptidyl peptidase 4 (DPP-4), a well-known target in type II diabetes mellitus, has differential effects on cancer types. Past studies suggest a protective role of DPP-4 inhibitors, but recent studies show that DPP-4 inhibition induces cancer metastasis. Moreover, molecular pathological mechanisms of cancer in diabetes are currently largely unclear. The cancer-causing mechanisms in diabetes have been shown to be complex, including excessive ROS-formation, destruction of essential biomolecules, chronic inflammation, and impaired healing phenomena, collectively leading to carcinogenesis in diabetic conditions. Diabetes-associated epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndMT) contribute to cancer-associated fibroblast (CAF) formation in tumors, allowing the epithelium and endothelium to enable tumor cell extravasation. In this review, we discuss the risk of cancer associated with anti-diabetic therapies, including DPP-4 inhibitors and SGLT2 inhibitors, and the role of catechol-o-methyltransferase (COMT), AMPK, and cell-specific glucocorticoid receptors in cancer biology. We explore possible mechanistic links between diabetes and cancer biology and discuss new therapeutic approaches.
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Affiliation(s)
- Swayam Prakash Srivastava
- Department of Pediatrics, Yale University School of Medicine, Yale University, New Haven, CT 06520-8064, USA
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520-8066, USA
- Correspondence: (S.P.S.); (J.E.G.)
| | - Julie E. Goodwin
- Department of Pediatrics, Yale University School of Medicine, Yale University, New Haven, CT 06520-8064, USA
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520-8066, USA
- Correspondence: (S.P.S.); (J.E.G.)
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Adacan K, Obakan-Yerlikaya P, Arisan ED, Coker-Gurkan A, Kaya RI, Palavan-Unsal N. Epibrassinolide-induced autophagy occurs in an Atg5-independent manner due to endoplasmic stress induction in MEF cells. Amino Acids 2020; 52:871-891. [PMID: 32449072 DOI: 10.1007/s00726-020-02857-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 05/12/2020] [Indexed: 01/10/2023]
Abstract
Epibrassinolide (EBR), a polyhydroxysteroid belongs to plant growth regulator family, brassinosteroids and has been shown to have a similar chemical structure to mammalian steroid hormones. Our findings indicated that EBR could trigger apoptosis in cancer cells via induction of endoplasmic reticulum (ER) stress, caused by protein folding disturbance in the ER. Normal cells exhibited a remarkable resistance to EBR treatment and avoid from apoptotic cell death. The unfolded protein response clears un/misfolded proteins and restore ER functions. When stress is chronic, cells tend to die due to improper cellular functions. To understand the effect of EBR in non-malign cells, mouse embryonic fibroblast (MEF) cells were investigated in detail for ER stress biomarkers, autophagy, and polyamine metabolism in this study. Evolutionary conserved autophagy mechanism is a crucial cellular process to clean damaged organelles and protein aggregates through lysosome under the control of autophagy-related genes (ATGs). Cells tend to activate autophagy to promote cell survival under stress conditions. Polyamines are polycationic molecules playing a role in the homeostasis of important cellular events such as cell survival, growth, and, proliferation. The administration of PAs has been markedly extended the lifespan of various organisms via inducing autophagy and inhibiting oxidative stress. Our data indicated that ER stress is induced following EBR treatment in MEF cells as well as MEF Atg5-/- cells. In addition, autophagy is activated following EBR treatment by targeting PI3K/Akt/mTOR in wildtype (wt) cells. However, EBR-induced autophagy targets ULK1 in MEF cells lacking Atg5 expression. Besides, EBR treatment depleted the PA pool in MEF cells through the alterations of metabolic enzymes. The administration of Spd with EBR further increased autophagic vacuole formation. In conclusion, EBR is an anticancer drug candidate with selective cytotoxicity for cancer cells, in addition the induction of autophagy and PA metabolism are critical for responses of normal cells against EBR.
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Affiliation(s)
- Kaan Adacan
- Department of Molecular Biology and Genetics, Istanbul Kultur University, Ataköy Campus, Bakirkoy, 34156, Istanbul, Turkey
| | - Pınar Obakan-Yerlikaya
- Department of Molecular Biology and Genetics, Istanbul Kultur University, Ataköy Campus, Bakirkoy, 34156, Istanbul, Turkey.
| | - Elif Damla Arisan
- Institute of Biotechnology, Gebze Technical University, 41400, Gebze, Kocaeli, Turkey
| | - Ajda Coker-Gurkan
- Department of Molecular Biology and Genetics, Istanbul Kultur University, Ataköy Campus, Bakirkoy, 34156, Istanbul, Turkey
| | - Resul Ismail Kaya
- Department of Molecular Biology and Genetics, Istanbul Kultur University, Ataköy Campus, Bakirkoy, 34156, Istanbul, Turkey
| | - Narçın Palavan-Unsal
- Department of Molecular Biology and Genetics, Istanbul Kultur University, Ataköy Campus, Bakirkoy, 34156, Istanbul, Turkey
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Sambi M, Samuel V, Qorri B, Haq S, Burov SV, Markvicheva E, Harless W, Szewczuk MR. A Triple Combination of Metformin, Acetylsalicylic Acid, and Oseltamivir Phosphate Impacts Tumour Spheroid Viability and Upends Chemoresistance in Triple-Negative Breast Cancer. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:1995-2019. [PMID: 32546966 PMCID: PMC7260544 DOI: 10.2147/dddt.s242514] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 04/27/2020] [Indexed: 12/14/2022]
Abstract
Introduction Targeted multimodal approaches need to be strategically developed to control tumour growth and prevent metastatic burden successfully. Breast cancer presents a unique clinical problem because of the variety of cellular subtypes that arise. The tumour stage and cellular subtypes often dictate the appropriate clinical treatment regimen. Also, the development of chemoresistance is a common clinical challenge with breast cancer. Higher doses and additional drug agents can produce additional adverse effects leading to a more aggressive malignancy. Acetylsalicylic acid (ASA), metformin (Met), and oseltamivir phosphate (OP) were investigated for their efficacy to sensitize MDA-MB-231 triple-negative breast cancer and its tamoxifen (Tmx) resistant variant (MDA-MB-231-TmxR) together in combination with Tmx treatment. Methods Microscopic imaging, the formation of 3D multicellular tumour spheroids, immunocytochemistry, flow cytometry, Annexin V Assay, Caspase 3/7 Apoptosis Assay, tube formation assay and analysis, and WST-1 cell viability assay evaluated the formation of MCTS, morphologic changes, cell viability, apoptosis activity and the expression levels of ALDH1A1, CD44 and CD24 on the cell surface, MDA-MB231 triple-negative breast cancer, tamoxifen (Tmx) resistant variant (MDA-MB-231-TmxR). Results The results using a triple combination of ASA, Met and OP on MDA-MB-231 and MDA-MB-231-TmxR cells and their matrix-free 3D multicellular tumour spheroids (MCTS) formed by using the cyclic Arg-Gly-Asp-D-Phe-Lys peptide modified with 4-carboxybutyl-triphenylphosphonium bromide (cyclo-RGDfK(TPP)) peptide method demonstrate a consistent and significant decrease in cell and tumour spheroid viability and volume with increased apoptotic activity, and increased sensitivity to Tmx therapy. Tmx treatment of MDA-MB-231 cells in combination with ASA, Met and OP markedly reduced the CD44/CD24 ratio by 6.5-fold compared to the untreated control group. Tmx treatment of MDA-MB-231-TmxR cells in combination with ASA, Met and OP markedly reduced the ALDH1A1 by 134-fold compared to the same treatment for the parental cell line. Also, the triple combination treatment of ASA, Met, and OP inhibited vasculogenic endothelial cell tube formation and induced endothelial cell apoptosis. Conclusion For the first time, the findings demonstrate that repurposing ASA, Met, and OP provides a novel and promising targeted multimodal approach in the treatment of triple-negative breast cancer and its chemoresistant variant.
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Affiliation(s)
- Manpreet Sambi
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada
| | - Vanessa Samuel
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.,Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Bessi Qorri
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada
| | - Sabah Haq
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
| | - Sergey V Burov
- Laboratory of Novel Peptide Therapeutics, Cytomed J.S.Co., St. Petersburg, Russia
| | - Elena Markvicheva
- Biomedical Materials Laboratory, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
| | | | - Myron R Szewczuk
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada
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