|
1
|
Hu C, Chen Y, Yin X, Xu R, Yin C, Wang C, Zhao Y. Pancreatic endocrine and exocrine signaling and crosstalk in physiological and pathological status. Signal Transduct Target Ther 2025; 10:39. [PMID: 39948335 PMCID: PMC11825823 DOI: 10.1038/s41392-024-02098-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 10/20/2024] [Accepted: 12/03/2024] [Indexed: 02/16/2025] Open
Abstract
The pancreas, an organ with dual functions, regulates blood glucose levels through the endocrine system by secreting hormones such as insulin and glucagon. It also aids digestion through the exocrine system by secreting digestive enzymes. Complex interactions and signaling mechanisms between the endocrine and exocrine functions of the pancreas play a crucial role in maintaining metabolic homeostasis and overall health. Compelling evidence indicates direct and indirect crosstalk between the endocrine and exocrine parts, influencing the development of diseases affecting both. From a developmental perspective, the exocrine and endocrine parts share the same origin-the "tip-trunk" domain. In certain circumstances, pancreatic exocrine cells may transdifferentiate into endocrine-like cells, such as insulin-secreting cells. Additionally, several pancreatic diseases, including pancreatic cancer, pancreatitis, and diabetes, exhibit potential relevance to both endocrine and exocrine functions. Endocrine cells may communicate with exocrine cells directly through cytokines or indirectly by regulating the immune microenvironment. This crosstalk affects the onset and progression of these diseases. This review summarizes the history and milestones of findings related to the exocrine and endocrine pancreas, their embryonic development, phenotypic transformations, signaling roles in health and disease, the endocrine-exocrine crosstalk from the perspective of diseases, and potential therapeutic targets. Elucidating the regulatory mechanisms of pancreatic endocrine and exocrine signaling and provide novel insights for the understanding and treatment of diseases.
Collapse
Grants
- National High Level Hospital Clinical Research Funding (2022, 2022-PUMCH-D-001, to YZ), CAMS Innovation Fund for Medical Sciences (2021, 2021-I2M-1-002, to YZ), National Nature Science Foundation of China (2021, 82102810, to CW, the Fundamental Research Funds for the Central Universities(3332023123)
- cNational High Level Hospital Clinical Research Funding (2022, 2022-PUMCH-D-001, to YZ), CAMS Innovation Fund for Medical Sciences (2021, 2021-I2M-1-002, to YZ), National Nature Science Foundation of China (2021, 82102810, to CW, the Fundamental Research Funds for the Central Universities(3332023123)
Collapse
Affiliation(s)
- Chenglin Hu
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Yuan Chen
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Xinpeng Yin
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Ruiyuan Xu
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Chenxue Yin
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Chengcheng Wang
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China.
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China.
- National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Beijing, PR China.
- Institute of Clinical Medicine, Peking Union Medical College Hospital, Beijing, PR China.
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China.
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China.
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China.
- National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Beijing, PR China.
| |
Collapse
|
|
2
|
Loos JA, Negro PS, Ortega HH, Salinas FJ, Arán M, Pellizza L, Salerno GL, Cumino AC. Anti-echinococcal effect of metformin in advanced experimental cystic echinococcosis: reprogrammed intermediary carbon metabolism in the parasite. Antimicrob Agents Chemother 2024; 68:e0094124. [PMID: 39264188 PMCID: PMC11459915 DOI: 10.1128/aac.00941-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 08/09/2024] [Indexed: 09/13/2024] Open
Abstract
Metformin, a safe biguanide derivative with antiproliferative properties, has shown antiparasitic efficacy against the Echinococcus larval stage. Hence, we assessed the efficacy of a dose of 250 mg kg-1 day-1 in experimental models of advanced CE, at 6 and 12 months post-infection with oral and intraperitoneal administration, respectively. At this high dose, metformin reached intracystic concentrations between 0.7 and 1.7 mM and triggered Eg-TOR inhibition through AMPK activation by AMP-independent and -dependent mechanisms, which are dependent on drug dose. Cystic metformin uptake was controlled by increased expression of organic cation transporters in the presence of the drug. In both experimental models, metformin reduced the weight of parasite cysts, altered the ultrastructural integrity of their germinal layers, and reduced the intracystic availability of glucose, limiting the cellular carbon and energy charge and the proliferative capacity of metacestodes. This glucose depletion in the parasite was associated with a slight increase in cystic uptake of 2-deoxiglucose and the transcriptional induction of GLUT genes in metacestodes. In this context, drastic glycogen consumption led to increased lactate production and altered intermediary metabolism in treated metacestodes. Specifically, the fraction of reducing soluble sugars decreased twofold, and the levels of non-reducing soluble sugars, such as sucrose and trehalose, were modified in both cystic fluid and germinal cells. Taken together, our findings highlight the relevance of metformin as a promising candidate for CE treatment and warrant further research to improve the therapeutic conditions of this chronic zoonosis in humans.
Collapse
Affiliation(s)
- Julia A. Loos
- IIPROSAM, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata (UNMdP), Mar del Plata, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Mar del Plata, Argentina
| | - Perla S. Negro
- Parasitología y Enfermedades Parasitarias, Facultad de Ciencias Veterinarias, Universidad Nacional de Rosario, Casilda, Santa Fe, Argentina
| | - Hugo H. Ortega
- Centro de Medicina Comparada, ICiVet-Litoral, Universidad Nacional del Litoral-CONICET, Esperanza, Santa Fe, Argentina
| | - Facundo J. Salinas
- Centro de Medicina Comparada, ICiVet-Litoral, Universidad Nacional del Litoral-CONICET, Esperanza, Santa Fe, Argentina
| | - Martín Arán
- Fundación Instituto Leloir e Instituto de Investigaciones Bioquímicas de Buenos Aires (IIBBA)—CONICET, Buenos Aires, Argentina
| | - Leonardo Pellizza
- Fundación Instituto Leloir e Instituto de Investigaciones Bioquímicas de Buenos Aires (IIBBA)—CONICET, Buenos Aires, Argentina
| | - Graciela L. Salerno
- Fundación Para Investigaciones Biológicas Aplicadas (FIBA), Mar del Plata, Argentina
| | - Andrea C. Cumino
- IIPROSAM, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata (UNMdP), Mar del Plata, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Mar del Plata, Argentina
- Departamento de Química, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata (UNMdP), Mar del Plata, Argentina
| |
Collapse
|
|
3
|
Catalano L, Aminzadeh-Gohari S, Weber DD, Poupardin R, Stefan VE, Smiles WJ, Tevini J, Feichtinger RG, Derdak S, Bilban M, Bareswill S, Heimesaat MM, Kofler B. Triple Therapy with Metformin, Ketogenic Diet, and Metronomic Cyclophosphamide Reduced Tumor Growth in MYCN-Amplified Neuroblastoma Xenografts. Metabolites 2023; 13:910. [PMID: 37623854 PMCID: PMC10456943 DOI: 10.3390/metabo13080910] [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: 07/07/2023] [Revised: 07/28/2023] [Accepted: 07/29/2023] [Indexed: 08/26/2023] Open
Abstract
Neuroblastoma (NB) is a childhood cancer in which amplification of the MYCN gene is the most acknowledged marker of poor prognosis. MYCN-amplified NB cells rely on both glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) for energy production. Previously, we demonstrated that a ketogenic diet (KD) combined with metronomic cyclophosphamide (CP) delayed tumor growth in MYCN-amplified NB xenografts. The anti-diabetic drug metformin (MET) also targets complex I of the OXPHOS system. Therefore, MET-induced disruptions of mitochondrial respiration may enhance the anti-tumor effect of CP when combined with a KD. In this study, we found that MET decreased cell proliferation and mitochondrial respiration in MYCN-amplified NB cell lines, while the combination of KD, MET, and low-dose CP (triple therapy) also reduced tumor growth and improved survival in vivo in MYCN-amplified NB xenografts. Gene ontology enrichment analysis revealed that this triple therapy had the greatest effect on the transcription of genes involved in fatty acid ß-oxidation, which was supported by the increased protein expression of CPT1A, a key mitochondrial fatty acid transporter. We suspect that alterations to ß-oxidation alongside the inhibition of complex I may hamper mitochondrial energy production, thus explaining these augmented anti-tumor effects, suggesting that the combination of MET and KD is an effective adjuvant therapy to CP in MYCN-amplified NB xenografts.
Collapse
Affiliation(s)
- Luca Catalano
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria; (L.C.)
| | - Sepideh Aminzadeh-Gohari
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria; (L.C.)
| | - Daniela D. Weber
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria; (L.C.)
| | - Rodolphe Poupardin
- Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Cell Therapy Institute, Paracelsus Medical University, 5020 Salzburg, Austria
| | - Victoria E. Stefan
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria; (L.C.)
| | - William J. Smiles
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria; (L.C.)
| | - Julia Tevini
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria; (L.C.)
| | - René G. Feichtinger
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria; (L.C.)
| | - Sophia Derdak
- Core Facilities, Medical University of Vienna, 1090 Vienna, Austria
| | - Martin Bilban
- Core Facilities, Medical University of Vienna, 1090 Vienna, Austria
- Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria
| | - Stefan Bareswill
- Gastrointestinal Microbiology Research Group, Institute of Microbiology, Infectious Diseases and Immunology, Charité-University Medicine Berlin, Corporate Member of Free University Berlin, Humboldt University Berlin and Berlin Institute of Health, 12203 Berlin, Germany
| | - Markus M. Heimesaat
- Gastrointestinal Microbiology Research Group, Institute of Microbiology, Infectious Diseases and Immunology, Charité-University Medicine Berlin, Corporate Member of Free University Berlin, Humboldt University Berlin and Berlin Institute of Health, 12203 Berlin, Germany
| | - Barbara Kofler
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria; (L.C.)
| |
Collapse
|
|
4
|
Zhang J, Brown R, Hogan MV, Onishi K, Wang JHC. Metformin improves tendon degeneration by blocking translocation of HMGB1 and suppressing tendon inflammation and senescence in aging mice. J Orthop Res 2023; 41:1162-1176. [PMID: 36262012 PMCID: PMC10113400 DOI: 10.1002/jor.25470] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 08/29/2022] [Accepted: 10/18/2022] [Indexed: 02/04/2023]
Abstract
This study aimed to characterize aging-induced tendinopathy in mouse Achilles tendon and also to assess the treatment effects of metformin (Met) on aging tendon. We showed that compared to young tendon, aging tendon was in an inflammatory and senescent state as shown by increased expression of inflammatory disulfide HMGB1 (dsHMGB1), inflammatory macrophage marker CD68, and senescent cell markers SA-β-gal, p53, and p16. Moreover, aging tendon was degenerated marked by accumulation of proteoglycans and lipids in its interior. However, treatment of aging tendon by intraperitoneal (IP) injection of Met, a specific inhibitor of HMGB1, reduced dsHMGB1 levels, decreased the expression of CD68, SA-β-gal, CCN1, and p16 in vitro and in vivo. Furthermore, Met treatment also increased the number of NS, SSEA-1, and CD73 positive stem cells in culture and improved the tendon structure in aging mouse. These findings of this study indicate that Met exerts anti-inflammatory and anti-senescent effects on aging tendon.
Collapse
Affiliation(s)
- Jianying Zhang
- MechanoBiology Laboratory, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Roshawn Brown
- MechanoBiology Laboratory, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - MaCalus V. Hogan
- MechanoBiology Laboratory, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Kentaro Onishi
- MechanoBiology Laboratory, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - James H-C. Wang
- MechanoBiology Laboratory, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA 15213, USA
| |
Collapse
|
|
5
|
Kumar V, Sharma K, Sachan R, Alhayyani S, Al-Abbasi FA, Singh R, Anwar F. Co-drug development of gallic acid and metformin targeting the pro-inflammatory cytokines for the treatment of breast cancer. J Biochem Mol Toxicol 2023; 37:e23300. [PMID: 36703564 DOI: 10.1002/jbt.23300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 11/09/2022] [Accepted: 01/05/2023] [Indexed: 01/28/2023]
Abstract
It is well-documented that pro-inflammatory cytokines and inflammation play a significant role in the expansion of cancer disease. Gallic acid (GA), a natural compound, and metformin (Met), a synthetic drug exhibit potent anticancer potential via the distinct molecular mechanism. However, whether both these compounds can act synergistically to preclude and treat cancer is still unknown. This prompted us to scrutinize, the synergism between GA and Met, and that of a new co-drug synthesizing of GA and Met (GA-Met) and investigated the chemo-protective effect against breast cancer with possible intervention of cytokines. In vivo studies were based on chemical carcinogenesis, challenging breast tissue by dimethylbenz[α]anthracene (DMBA). Tumour incidence, tumour burden, pro-inflammatory cytokines in serum, breast, hepatic tissue, macroscopically and histological analysis of mammary tumours were carried out and estimated. GA, Met and GA-Met co-drug exhibited the inhibition of cell proliferation; higher reduction of cell proliferation was observed by GA-Met. The inhibitory effect of GA-Met was linked to cell cycle arrest at G0/G1 phase, along with induction of apoptosis and accumulation in the sub-G1 phase. GA-Met significantly inhibited the cytokines production along with protection against DMBA-induced hyperplasia. Taken altogether, the current result suggests that GA-Met co-drug endows a safe and protective effect against cancer metastasis and can possibly use for the treatment of human breast cancer.
Collapse
Affiliation(s)
- Vikas Kumar
- Natural Product Drug Discovery Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology & Sciences, Faculty of Health Sciences, Prayagraj, Uttar Pradesh, India
| | | | - Richa Sachan
- School of Pharmacy, Sungkyunkwan University, Jangan-gu, Suwon, Republic of Korea
| | - Sultan Alhayyani
- Department of Chemistry, College of Sciences & Arts, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Fahd A Al-Abbasi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Richa Singh
- Natural Product Drug Discovery Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology & Sciences, Faculty of Health Sciences, Prayagraj, Uttar Pradesh, India
| | - Firoz Anwar
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| |
Collapse
|
|
6
|
The NAMPT Inhibitor FK866 Increases Metformin Sensitivity in Pancreatic Cancer Cells. Cancers (Basel) 2022; 14:cancers14225597. [PMID: 36428689 PMCID: PMC9688551 DOI: 10.3390/cancers14225597] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 11/07/2022] [Accepted: 11/11/2022] [Indexed: 11/16/2022] Open
Abstract
Pancreatic cancer (pancreatic ductal adenocarcinoma: PDAC) is one of the most aggressive neoplastic diseases. Metformin use has been associated with reduced pancreatic cancer incidence and better survival in diabetics. Metformin has been shown to inhibit PDAC cells growth and survival, both in vitro and in vivo. However, clinical trials using metformin have failed to reduce pancreatic cancer progression in patients, raising important questions about molecular mechanisms that protect tumor cells from the antineoplastic activities of metformin. We confirmed that metformin acts through inhibition of mitochondrial complex I, decreasing the NAD+/NADH ratio, and that NAD+/NADH homeostasis determines metformin sensitivity in several cancer cell lines. Metabolites that can restore the NAD+/NADH ratio caused PDAC cells to be resistant to metformin. In addition, metformin treatment of PDAC cell lines induced a compensatory NAMPT expression, increasing the pool of cellular NAD+. The NAMPT inhibitor FK866 sensitized PDAC cells to the antiproliferative effects of metformin in vitro and decreased the cellular NAD+ pool. Intriguingly, FK866 combined with metformin increased survival in mice bearing KP4 cell line xenografts, but not in mice with PANC-1 cell line xenografts. Transcriptome analysis revealed that the drug combination reactivated genes in the p53 pathway and oxidative stress, providing new insights about the mechanisms leading to cancer cell death.
Collapse
|
|
7
|
Haddad M, Eid S, Harb F, Massry MEL, Azar S, Sauleau EA, Eid AA. Activation of 20-HETE Synthase Triggers Oxidative Injury and Peripheral Nerve Damage in Type 2 Diabetic Mice. THE JOURNAL OF PAIN 2022; 23:1371-1388. [PMID: 35339661 DOI: 10.1016/j.jpain.2022.02.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 01/26/2022] [Accepted: 02/24/2022] [Indexed: 12/13/2022]
Abstract
Diabetic Peripheral Neuropathy (DPN), highly prevalent among patients with diabetes, is characterized by peripheral nerve dysfunction. Reactive Oxygen Species (ROS) overproduction has been suggested to orchestrate diabetic complications including DPN. Untargeted antioxidant therapy has exhibited limited efficacy, highlighting a critical need to explore ROS sources altered in a cell-specific manner in DPN. Cytochromes P450 (CYP) enzymes are prominent sources of ROS. Particularly, the 20-HETE synthase, CYP4A, is reported to mediate diabetes-induced renal, retinal, and cardiovascular injuries. This work investigates the role of CYP4A/20-HETE in DPN and their mechanisms of action. Non-obese type 2 Diabetic mice (MKR) were used and treated with a CYP4A-inhibitor (HET0016) or AMPK-activator (Metformin). Peripheral nerves of MKR mice reflect increased CYP4A and 20-HETE levels, concurrent with altered myelin proteins and sensorimotor deficits. This was associated with increased ROS production and altered Beclin-1 and LC3 protein levels, indicative of disrupted autophagic responses in tandem with AMPK inactivation. AMPK activation via Metformin restored nerve integrity, reduced ROS production, and regulated autophagy. Interestingly, similar outcomes were revealed upon HET0016 treatment whereby ROS production, autophagic responses, and AMPK signaling were normalized in diabetic mice. Altogether, the results highlight hyperglycemia-mediated oxidative injury in DPN through a novel CYP4A/20-HETE/AMPK pathological axis. PERSPECTIVE: To our knowledge, this is the first study to highlight the role of CYPs/20-HETE-induced oxidative injury in the pathogenesis of diabetic peripheral neuropathy. Targeting the identified pathological axis CYP4A/20-HETE/AMPK may be of clinical potential in predicting and alleviating peripheral nerve injury in patients with Type 2 Diabetes Mellitus.
Collapse
Affiliation(s)
- Mary Haddad
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon; Department of Biostatistics, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 7357 ICube, University of Strasbourg, Strasbourg, France
| | - Stéphanie Eid
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon
| | - Frederic Harb
- Department of Life and Earth Sciences, Faculty of Sciences, Lebanese University, Fanar, Lebanon
| | - Mohamed E L Massry
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon
| | - Sami Azar
- Department of Internal Medicine, Division of Diabetes and Endocrinology, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon; AUB Diabetes, American University of Beirut, Beirut, Lebanon
| | - Erik-Andre Sauleau
- Department of Biostatistics, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 7357 ICube, University of Strasbourg, Strasbourg, France
| | - Assaad A Eid
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon; AUB Diabetes, American University of Beirut, Beirut, Lebanon.
| |
Collapse
|
|
8
|
Pretta A, Ziranu P, Puzzoni M, Lai E, Orsi G, Liscia N, Molinaro E, Mariani S, Riggi L, Rovesti G, Dubois M, Migliari M, Persano M, Saba G, Impera V, Musio F, Batzella E, Demurtas L, Pusceddu V, Astara G, Faloppi L, Casadei Gardini A, Andrikou K, Cascinu S, Scartozzi M. Retrospective survival analysis in patients with metastatic pancreatic ductal adenocarcinoma with insulin-treated type 2 diabetes mellitus. TUMORI JOURNAL 2021; 107:550-555. [PMID: 33243068 DOI: 10.1177/0300891620976945] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION The association between pancreatic ductal adenocarcinoma (PDAC) and type 2 diabetes mellitus (DM2) has long been evaluated and the role of antidiabetic medications such as metformin has also been investigated. The objective of this study was to examine the association between insulin use and overall survival (OS) in patients with advanced PDAC and DM2. METHODS We retrospectively collected data from 164 patients, including an exploratory cohort of 96 patients from Medical Oncology Unit, University Hospital and University of Cagliari, Italy, and a validation cohort of 68 patients from Medical Oncology of Modena University Hospital. Patients had metastatic disease and received a first-line gemcitabine-based chemotherapy and, subsequently, a second-line fluoropyrimidines-based chemotherapy. We performed univariate analysis to evaluate correlation between long-term diabetes and overall survival. Then we performed multivariate analysis, adjusting for sex, metastatic sites, Eastern Cooperative Oncology Group Performance Status, Ca19.9 levels, N/L ratio, and lactate dehydrogenase levels at diagnosis, to confirm the independence of the variable. RESULTS In the exploratory cohort, DM2 was significantly associated with higher median OS at univariate analysis (16 vs 10 months; p = 0.004). This result was confirmed by validation cohort (11 months vs 6 months; p = 0.01). In multivariate analysis, insulin-treated patients compared with non diabetic patients showed a significantly increased survival of 4.6 months (p = 0.03). CONCLUSIONS Patients with insulin-treated metastatic PDAC showed better OS than non diabetic patients, as demonstrated by both cohorts. The correlation between OS and insulin-treated DM2 should be investigated further through a prospective clinical trial.
Collapse
Affiliation(s)
- Andrea Pretta
- Medical Oncology Unit, Sapienza University of Rome, Roma, Italy
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Pina Ziranu
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Marco Puzzoni
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Eleonora Lai
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Giulia Orsi
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Nicole Liscia
- Medical Oncology Unit, Sapienza University of Rome, Roma, Italy
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Eleonora Molinaro
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Stefano Mariani
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Laura Riggi
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Giulia Rovesti
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Marco Dubois
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Marco Migliari
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Mara Persano
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Giorgio Saba
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Valentino Impera
- Medical Oncology Unit, Sapienza University of Rome, Roma, Italy
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Francesca Musio
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Erich Batzella
- Department of Statistical Science, University of Padova, Padova, Veneto, Italy
| | - Laura Demurtas
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Valeria Pusceddu
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Giorgio Astara
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Luca Faloppi
- Department of Medical Oncology, Macerata General Hospital, Macerata, Italy
| | - Andrea Casadei Gardini
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Kalliopi Andrikou
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Stefano Cascinu
- IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Mario Scartozzi
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| |
Collapse
|
|
9
|
Eibl G, Rozengurt E. Metformin: review of epidemiology and mechanisms of action in pancreatic cancer. Cancer Metastasis Rev 2021; 40:865-878. [PMID: 34142285 DOI: 10.1007/s10555-021-09977-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 05/27/2021] [Indexed: 12/15/2022]
Abstract
Pancreatic ductal adenocarcinoma continues to be a lethal disease, for which efficient treatment options are very limited. Increasing efforts have been taken to understand how to prevent or intercept this disease at an early stage. There is convincing evidence from epidemiologic and preclinical studies that the antidiabetic drug metformin possesses beneficial effects in pancreatic cancer, including reducing the risk of developing the disease and improving survival in patients with early-stage disease. This review will summarize the current literature about the epidemiological data on metformin and pancreatic cancer as well as describe the preclinical evidence illustrating the anticancer effects of metformin in pancreatic cancer. Underlying mechanisms and targets of metformin will also be discussed. These include direct effects on transformed pancreatic epithelial cells and indirect, systemic effects on extra-pancreatic tissues.
Collapse
Affiliation(s)
- Guido Eibl
- Department of Surgery, David Geffen School of Medicine At UCLA, Los Angeles, CA, USA.
| | - Enrique Rozengurt
- Department of Medicine, David Geffen School of Medicine At UCLA, Los Angeles, CA, USA
| |
Collapse
|
|
10
|
Keihanian T, Barkin JA, Souto EO. Early Detection of Pancreatic Cancer: Risk Factors and the Current State of Screening Modalities. Gastroenterol Hepatol (N Y) 2021; 17:254-262. [PMID: 34776799 PMCID: PMC8576846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Pancreatic cancer (PC) is expected to become the second leading cause of cancer-related mortality in the United States within the next decade. Patients often present at late stages of the disease, when they become symptomatic; in many cases, these patients have unresectable disease that is associated with a poor prognosis. Considering the low incidence of PC in the general population, routine screening of average-risk individuals is not feasible and not recommended. Individuals with familial germline mutations or familial PC are at higher risk of developing PC. Improving detection of PC at an earlier stage entails the recognition of high-risk individuals who may benefit from a long-term screening program. This article identifies patients who may be at increased risk of developing PC, discusses PC screening recommendations, and compares imaging-based modalities and biomarkers for early detection of PC.
Collapse
Affiliation(s)
- Tara Keihanian
- Department of Medicine, Division of Gastroenterology, University of Miami Miller School of Medicine, Miami, Florida
| | - Jodie A Barkin
- Department of Medicine, Division of Gastroenterology, University of Miami Miller School of Medicine, Miami, Florida
| | - Enrico O Souto
- Department of Medicine, Division of Gastroenterology, University of Miami Miller School of Medicine, Miami, Florida
| |
Collapse
|
|
11
|
Masoud R, Reyes-Castellanos G, Lac S, Garcia J, Dou S, Shintu L, Abdel Hadi N, Gicquel T, El Kaoutari A, Diémé B, Tranchida F, Cormareche L, Borge L, Gayet O, Pasquier E, Dusetti N, Iovanna J, Carrier A. Targeting Mitochondrial Complex I Overcomes Chemoresistance in High OXPHOS Pancreatic Cancer. Cell Rep Med 2020; 1:100143. [PMID: 33294863 PMCID: PMC7691450 DOI: 10.1016/j.xcrm.2020.100143] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Revised: 08/28/2020] [Accepted: 10/22/2020] [Indexed: 02/07/2023]
Abstract
Mitochondrial respiration (oxidative phosphorylation, OXPHOS) is an emerging target in currently refractory cancers such as pancreatic ductal adenocarcinoma (PDAC). However, the variability of energetic metabolic adaptations between PDAC patients has not been assessed in functional investigations. In this work, we demonstrate that OXPHOS rates are highly heterogeneous between patient tumors, and that high OXPHOS tumors are enriched in mitochondrial respiratory complex I at protein and mRNA levels. Therefore, we treated PDAC cells with phenformin (complex I inhibitor) in combination with standard chemotherapy (gemcitabine), showing that this treatment is synergistic specifically in high OXPHOS cells. Furthermore, phenformin cooperates with gemcitabine in high OXPHOS tumors in two orthotopic mouse models (xenografts and syngeneic allografts). In conclusion, this work proposes a strategy to identify PDAC patients likely to respond to the targeting of mitochondrial energetic metabolism in combination with chemotherapy, and that phenformin should be clinically tested in appropriate PDAC patient subpopulations.
Collapse
Affiliation(s)
- Rawand Masoud
- Aix Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), F-13009 Marseille, France
| | - Gabriela Reyes-Castellanos
- Aix Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), F-13009 Marseille, France
| | - Sophie Lac
- Aix Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), F-13009 Marseille, France
| | - Julie Garcia
- Aix Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), F-13009 Marseille, France
| | - Samir Dou
- Aix Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), F-13009 Marseille, France
| | - Laetitia Shintu
- Aix Marseille Université, CNRS, Centrale Marseille, ISM2, F-13013 Marseille, France
| | - Nadine Abdel Hadi
- Aix Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), F-13009 Marseille, France
| | - Tristan Gicquel
- Aix Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), F-13009 Marseille, France
| | - Abdessamad El Kaoutari
- Aix Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), F-13009 Marseille, France
| | - Binta Diémé
- Aix Marseille Université, CNRS, Centrale Marseille, ISM2, F-13013 Marseille, France
| | - Fabrice Tranchida
- Aix Marseille Université, CNRS, Centrale Marseille, ISM2, F-13013 Marseille, France
| | - Laurie Cormareche
- Aix Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), F-13009 Marseille, France
| | - Laurence Borge
- Aix Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), F-13009 Marseille, France
| | - Odile Gayet
- Aix Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), F-13009 Marseille, France
| | - Eddy Pasquier
- Aix Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), F-13009 Marseille, France
| | - Nelson Dusetti
- Aix Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), F-13009 Marseille, France
| | - Juan Iovanna
- Aix Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), F-13009 Marseille, France
| | - Alice Carrier
- Aix Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), F-13009 Marseille, France
| |
Collapse
|
|
12
|
Soliman GA, Shukla SK, Etekpo A, Gunda V, Steenson SM, Gautam N, Alnouti Y, Singh PK. The Synergistic Effect of an ATP-Competitive Inhibitor of mTOR and Metformin on Pancreatic Tumor Growth. Curr Dev Nutr 2020; 4:nzaa131. [PMID: 32908958 PMCID: PMC7467276 DOI: 10.1093/cdn/nzaa131] [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: 05/06/2020] [Revised: 07/11/2020] [Accepted: 07/27/2020] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND The mechanistic target of rapamycin complex 1 (mTORC1) is a nutrient-sensing pathway and a key regulator of amino acid and glucose metabolism. Dysregulation of the mTOR pathways is implicated in the pathogenesis of metabolic syndrome, obesity, type 2 diabetes, and pancreatic cancer. OBJECTIVES We investigated the impact of inhibition of mTORC1/mTORC2 and synergism with metformin on pancreatic tumor growth and metabolomics. METHODS Cell lines derived from pancreatic tumors of the KPC (KrasG12D/+; p53R172H/+; Pdx1-Cre) transgenic mice model were implanted into the pancreas of C57BL/6 albino mice (n = 10/group). Two weeks later, the mice were injected intraperitoneally with daily doses of 1) Torin 2 (mTORC1/mTORC2 inhibitor) at a high concentration (TH), 2) Torin 2 at a low concentration (TL), 3) metformin at a low concentration (ML), 4) a combination of Torin 2 and metformin at low concentrations (TLML), or 5) DMSO vehicle (control) for 12 d. Tissues and blood samples were collected for targeted xenometabolomics analysis, drug concentration, and cell signaling. RESULTS Metabolomic analysis of the control and treated plasma samples showed differential metabolite profiles. Phenylalanine was significantly elevated in the TLML group compared with the control (+426%, P = 0.0004), whereas uracil was significantly lower (-38%, P = 0.009). The combination treatment reduced tumor growth in the orthotopic mouse model. TLML significantly decreased pancreatic tumor volume (498 ± 104 mm3; 37%; P < 0.0004) compared with control (1326 ± 134 mm3; 100%), ML (853 ± 67 mm3; 64%), TL (745 ± 167 mm3; 54%), and TH (665 ± 182 mm3; 50%) (ANOVA and post hoc tests). TLML significantly decreased tumor weights (0.66 ± 0.08 g; 52%) compared with the control (1.28 ± 0.19 g; 100%) (P < 0.002). CONCLUSIONS The combination of mTOR dual inhibition by Torin 2 and metformin is associated with an altered metabolomic profile and a significant reduction in pancreatic tumor burden compared with single-agent therapy, and it is better tolerated.
Collapse
Affiliation(s)
- Ghada A Soliman
- Department of Environmental, Occupational, and Geospatial Health Sciences, CUNY Graduate School of Public Health and Health Policy, City University of New York, New York, NY, USA
| | - Surendra K Shukla
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | | | - Venugopal Gunda
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sharalyn M Steenson
- Department of Health Promotion, College of Public Health, University of Nebraska Medical Center, Omaha, NE, USA
| | - Nagsen Gautam
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA
| | - Yazen Alnouti
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA
| | - Pankaj K Singh
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| |
Collapse
|
|
13
|
Grzmil M, Qin Y, Schleuniger C, Frank S, Imobersteg S, Blanc A, Spillmann M, Berger P, Schibli R, Behe M. Pharmacological inhibition of mTORC1 increases CCKBR-specific tumor uptake of radiolabeled minigastrin analogue [ 177Lu]Lu-PP-F11N. Am J Cancer Res 2020; 10:10861-10873. [PMID: 33042258 PMCID: PMC7532663 DOI: 10.7150/thno.45440] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 08/14/2020] [Indexed: 12/13/2022] Open
Abstract
Rationale: A high tumor-to-healthy-tissue uptake ratio of radiolabeled ligands is an essential prerequisite for safe and effective peptide receptor radionuclide therapy (PRRT). In the present study, we searched for novel opportunities to increase tumor-specific uptake of the radiolabeled minigastrin analogue [177Lu]Lu-DOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH2 ([177Lu]Lu-PP-F11N), that targets the cholecystokinin B receptor (CCKBR) in human cancers. Methods: A kinase inhibitor library screen followed by proliferation and internalization assays were employed to identify compounds which can increase uptake of [177Lu]Lu-PP-F11N in CCKBR-transfected human epidermoid carcinoma A431 cells and natural CCKBR-expressing rat pancreatic acinar AR42J cells. Western blot (WB) analysis verified the inhibition of the signaling pathways and the CCKBR level, whereas the cell-based assay analyzed arrestin recruitment. Biodistribution and SPECT imaging of the A431/CCKBR xenograft mouse model as well as histological analysis of the dissected tumors were used for in vivo validation. Results: Our screen identified the inhibitors of mammalian target of rapamycin complex 1 (mTORC1), which increased cell uptake of [177Lu]Lu-PP-F11N. Pharmacological mTORC1 inhibition by RAD001 and metformin increased internalization of [177Lu]Lu-PP-F11N in A431/CCKBR and in AR42J cells. Analysis of protein lysates from RAD001-treated cells revealed increased levels of CCKBR (2.2-fold) and inhibition of S6 phosphorylation. PP-F11N induced recruitment of β-arrestin1/2 and ERK1/2 phosphorylation. In A431/CCKBR-tumor bearing nude mice, 3 or 5 days of RAD001 pretreatment significantly enhanced tumor-specific uptake of [177Lu]Lu-PP-F11N (ratio [RAD001/Control] of 1.56 or 1.79, respectively), whereas metformin treatment did not show a significant difference. Quantification of SPECT/CT images confirmed higher uptake of [177Lu]Lu-PP-F11N in RAD001-treated tumors with ratios [RAD001/Control] of average and maximum concentration reaching 3.11 and 3.17, respectively. HE staining and IHC of RAD001-treated tumors showed a significant increase in necrosis (1.4% control vs.10.6% of necrotic area) and the reduction of proliferative (80% control vs. 61% of Ki67 positive cells) and mitotically active cells (1.08% control vs. 0.75% of mitotic figures). No significant difference in the tumor vascularization was observed after five-day RAD001 or metformin treatment. Conclusions: Our data demonstrates, that increased CCKBR protein level by RAD001 pretreatment has the potential to improve tumor uptake of [177Lu]Lu-PP-F11N and provides proof-of-concept for the development of molecular strategies aimed at enhancing the level of the targeted receptor, to increase the efficacy of PRRT and nuclear imaging.
Collapse
|
|
14
|
Liu SH, Yu J, Creeden JF, Sutton JM, Markowiak S, Sanchez R, Nemunaitis J, Kalinoski A, Zhang JT, Damoiseaux R, Erhardt P, Brunicardi FC. Repurposing metformin, simvastatin and digoxin as a combination for targeted therapy for pancreatic ductal adenocarcinoma. Cancer Lett 2020; 491:97-107. [PMID: 32829010 DOI: 10.1016/j.canlet.2020.08.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 07/23/2020] [Accepted: 08/01/2020] [Indexed: 12/12/2022]
Abstract
Patients with pancreatic adenocarcinoma (PDAC) have a 5-year survival rate of 8%, the lowest of any cancer in the United States. Traditional chemotherapeutic regimens, such as gemcitabine- and fluorouracil-based regimens, often only prolong survival by months. Effective precision targeted therapy is therefore urgently needed to substantially improve survival. In an effort to expedite approval and delivery of targeted therapy to patients, we utilized a platform to develop a novel combination of FDA approved drugs that would target pancreaticoduodenal homeobox1 (PDX1) and baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5) utilizing super-promoters of the target genes to interrogate an FDA approved drug library. We identified and selected metformin, simvastatin and digoxin (C3) as a novel combination of FDA approved drugs, which were shown to effectively target PDX1 and BIRC5 in human PDAC tumors in mice with no toxicity.
Collapse
Affiliation(s)
- Shi-He Liu
- Department of Surgery, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA; Department of Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.
| | - Juehua Yu
- Department of Surgery, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Justin F Creeden
- Department of Surgery, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA; Department of Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA
| | - Jeffrey M Sutton
- Department of Surgery, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA
| | - Stephen Markowiak
- Department of Surgery, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA
| | - Robbi Sanchez
- Department of Surgery, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - John Nemunaitis
- Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA
| | - Andrea Kalinoski
- Department of Surgery, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA
| | - Jian-Ting Zhang
- Department of Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA
| | - Robert Damoiseaux
- Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Paul Erhardt
- Department of Medicinal and Biological Chemistry, University of Toledo College of Pharmacy and Pharmaceutical Sciences, Toledo, OH, 43614, USA
| | - F Charles Brunicardi
- Department of Surgery, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA; Department of Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA
| |
Collapse
|
|
15
|
Dulskas A, Patasius A, Linkeviciute-Ulinskiene D, Zabuliene L, Smailyte G. Cohort Study of Antihyperglycemic Medication and Pancreatic Cancer Patients Survival. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17176016. [PMID: 32824907 PMCID: PMC7503289 DOI: 10.3390/ijerph17176016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 08/06/2020] [Accepted: 08/11/2020] [Indexed: 12/14/2022]
Abstract
Background: We assessed the association between the use of metformin and other antihyperglycemic medications on overall survival in diabetic patients with pancreatic cancer. Methods: Patients with pancreatic cancer and diabetes between 2000 and 2015 were identified from the Lithuanian Cancer Registry and the National Health Insurance Fund database. Cohort members were classified into six groups according to type 2 diabetes mellitus treatment: sulfonylurea monotherapy; metformin monotherapy; insulin monotherapy; metformin and sulfonylurea combination; metformin and other antihyperglycemic medications; all other combinations of oral antihyperglycemic medications. Survival was calculated from the date of cancer diagnosis to the date of death or the end of follow-up (31 December 2018). Results: Study group included 454 diabetic patients with pancreatic cancer. We found no statistically significant differences in overall survival between patients by glucose-lowering therapy. However, highest mortality risk was observed in patients on insulin monotherapy, and better survival was observed in the groups of patients using antihyperglycemic medication combinations, metformin alone, and metformin in combination with sulfonylurea. Analysis by cumulative dose of metformin showed significantly lower mortality risk in the highest cumulative dose category (HR 0.76, 95% CI 0.58–0.99). Conclusions: Our study showed that metformin might have a survival benefit for pancreatic cancer patients, suggesting a potentially available option for the treatment.
Collapse
Affiliation(s)
- Audrius Dulskas
- Department of Abdominal and General Surgery and Oncology, National Cancer Institute, 1 Santariskiu Str., LT-08406 Vilnius, Lithuania
- Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, 1 Santariskiu Str., LT-08406 Vilnius, Lithuania;
- Correspondence: ; Tel.: +37-067-520-094
| | - Ausvydas Patasius
- Laboratory of Cancer Epidemiology, National Cancer Institute, LT-08406 Vilnius, Lithuania; (A.P.); (G.S.)
- Institute of Health Sciences, Faculty of Medicine, Vilnius University, LT-03101 Vilnius, Lithuania
| | | | - Lina Zabuliene
- Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, 1 Santariskiu Str., LT-08406 Vilnius, Lithuania;
| | - Giedre Smailyte
- Laboratory of Cancer Epidemiology, National Cancer Institute, LT-08406 Vilnius, Lithuania; (A.P.); (G.S.)
- Institute of Health Sciences, Faculty of Medicine, Vilnius University, LT-03101 Vilnius, Lithuania
| |
Collapse
|
|
16
|
Reyes-Castellanos G, Masoud R, Carrier A. Mitochondrial Metabolism in PDAC: From Better Knowledge to New Targeting Strategies. Biomedicines 2020; 8:biomedicines8080270. [PMID: 32756381 PMCID: PMC7460249 DOI: 10.3390/biomedicines8080270] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 07/24/2020] [Accepted: 07/28/2020] [Indexed: 02/07/2023] Open
Abstract
Cancer cells reprogram their metabolism to meet bioenergetics and biosynthetic demands. The first observation of metabolic reprogramming in cancer cells was made a century ago (“Warburg effect” or aerobic glycolysis), leading to the classical view that cancer metabolism relies on a glycolytic phenotype. There is now accumulating evidence that most cancers also rely on mitochondria to satisfy their metabolic needs. Indeed, the current view of cancer metabolism places mitochondria as key actors in all facets of cancer progression. Importantly, mitochondrial metabolism has become a very promising target in cancer therapy, including for refractory cancers such as Pancreatic Ductal AdenoCarcinoma (PDAC). In particular, mitochondrial oxidative phosphorylation (OXPHOS) is an important target in cancer therapy. Other therapeutic strategies include the targeting of glutamine and fatty acids metabolism, as well as the inhibition of the TriCarboxylic Acid (TCA) cycle intermediates. A better knowledge of how pancreatic cancer cells regulate mitochondrial metabolism will allow the identification of metabolic vulnerabilities and thus novel and more efficient therapeutic options for the benefit of each patient.
Collapse
Affiliation(s)
| | | | - Alice Carrier
- Correspondence: ; Tel.: +33-491828829; Fax: +33-491826083
| |
Collapse
|
|
17
|
Jin K, Ma Y, Manrique-Caballero CL, Li H, Emlet DR, Li S, Baty CJ, Wen X, Kim-Campbell N, Frank A, Menchikova EV, Pastor-Soler NM, Hallows KR, Jackson EK, Shiva S, Pinsky MR, Zuckerbraun BS, Kellum JA, Gómez H. Activation of AMP-activated protein kinase during sepsis/inflammation improves survival by preserving cellular metabolic fitness. FASEB J 2020; 34:7036-7057. [PMID: 32246808 PMCID: PMC11956121 DOI: 10.1096/fj.201901900r] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 01/24/2020] [Accepted: 03/18/2020] [Indexed: 01/08/2023]
Abstract
The purpose was to determine the role of AMPK activation in the renal metabolic response to sepsis, the development of sepsis-induced acute kidney injury (AKI) and on survival. In a prospective experimental study, 167 10- to 12-week-old C57BL/6 mice underwent cecal ligation and puncture (CLP) and human proximal tubule epithelial cells (TEC; HK2) were exposed to inflammatory mix (IM), a combination of lipopolysaccharide (LPS) and high mobility group box 1 (HMGB1). Renal/TEC metabolic fitness was assessed by monitoring the expression of drivers of oxidative phosphorylation (OXPHOS), the rates of utilization of OXPHOS/glycolysis in response to metabolic stress, and mitochondrial function by measuring O2 consumption rates (OCR) and the membrane potential (Δψm ). Sepsis/IM resulted in AKI, increased mortality, and in renal AMPK activation 6-24 hours after CLP/IM. Pharmacologic activation of AMPK with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) or metformin during sepsis improved the survival, while AMPK inhibition with Compound C increased mortality, impaired mitochondrial respiration, decreased OCR, and disrupted TEC metabolic fitness. AMPK-driven protection was associated with increased Sirt 3 expression and restoration of metabolic fitness. Renal AMPK activation in response to sepsis/IM is an adaptive mechanism that protects TEC, organs, and the host by preserving mitochondrial function and metabolic fitness likely through Sirt3 signaling.
Collapse
Affiliation(s)
- Kui Jin
- Department of Critical Care, Anhui Provincial Hospital, He Fei, China
| | - Yujie Ma
- Department of Critical Care Medicine, Air Force Medical Center, Beijing, China
| | - Carlos L Manrique-Caballero
- Center for Critical Care Nephrology, Department of Critical Care Medicine, The CRISMA Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Hui Li
- Division of Nephrology and Hypertension and USC/UKRO Kidney Research Center, Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
| | - David R Emlet
- Center for Critical Care Nephrology, Department of Critical Care Medicine, The CRISMA Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Shengnan Li
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Catherine J Baty
- Renal Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Xiaoyan Wen
- Center for Critical Care Nephrology, Department of Critical Care Medicine, The CRISMA Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Nahmah Kim-Campbell
- Center for Critical Care Nephrology, Department of Critical Care Medicine, The CRISMA Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Alicia Frank
- Center for Critical Care Nephrology, Department of Critical Care Medicine, The CRISMA Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Elizabeth V Menchikova
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Nuria M Pastor-Soler
- Center for Critical Care Nephrology, Department of Critical Care Medicine, The CRISMA Center, University of Pittsburgh, Pittsburgh, PA, USA
- Division of Nephrology and Hypertension and USC/UKRO Kidney Research Center, Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
| | - Kenneth R Hallows
- Center for Critical Care Nephrology, Department of Critical Care Medicine, The CRISMA Center, University of Pittsburgh, Pittsburgh, PA, USA
- Division of Nephrology and Hypertension and USC/UKRO Kidney Research Center, Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
| | - Edwin K Jackson
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Sruti Shiva
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA
- Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Michael R Pinsky
- Center for Critical Care Nephrology, Department of Critical Care Medicine, The CRISMA Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Brian S Zuckerbraun
- Center for Critical Care Nephrology, Department of Critical Care Medicine, The CRISMA Center, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - John A Kellum
- Center for Critical Care Nephrology, Department of Critical Care Medicine, The CRISMA Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Hernando Gómez
- Center for Critical Care Nephrology, Department of Critical Care Medicine, The CRISMA Center, University of Pittsburgh, Pittsburgh, PA, USA
- Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA
| |
Collapse
|
|
18
|
|
|
19
|
Dong TS, Chang HH, Hauer M, Lagishetty V, Katzka W, Rozengurt E, Jacobs JP, Eibl G. Metformin alters the duodenal microbiome and decreases the incidence of pancreatic ductal adenocarcinoma promoted by diet-induced obesity. Am J Physiol Gastrointest Liver Physiol 2019; 317:G763-G772. [PMID: 31545922 PMCID: PMC6962494 DOI: 10.1152/ajpgi.00170.2019] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Revised: 09/11/2019] [Accepted: 09/15/2019] [Indexed: 01/31/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC)'s growing incidence has been linked to the rise in obesity and type 2 diabetes mellitus. In previous work, we have shown that metformin can prevent the increased incidence of PDAC in a KrasG12D mouse model subjected to a diet high in fat and calories (HFCD). One potential way that metformin can affect the host is through alterations in the gut microbiome. Therefore, we investigated microbial associations with PDAC development and metformin use in the same mouse model. Lox-Stop-Lox Kras G12D/+ (LSL-Kras G12D/+); p48-Cre (KC) mice were given control diet, HFCD, or HFCD with 5 mg/mL metformin in drinking water for 3 mo. At the end of the 3 mo, 16S rRNA sequencing was performed to characterize microbiome composition of duodenal mucosal, duodenal luminal, and cecal luminal samples. KC mice on an HFCD demonstrated depletion of intact acini and formation of advanced pancreatic intraepithelial neoplasia. This effect was completely abrogated by metformin treatment. HFCD was associated with significant changes in microbial composition and diversity in the duodenal mucosa and lumen, much of which was prevented by metformin. In particular, Clostridium sensu stricto was negatively correlated with percent intact acini and seemed to be inhibited by the addition of metformin while on an HFCD. Administration of metformin eliminated PDAC formation in KC mice. This change was associated with significant microbial changes in both the mucosal and luminal microbiome of the duodenum. This suggests that the microbiome may be a potential mediator of the chemopreventive effects of metformin.NEW & NOTEWORTHY Pancreatic ductal adenocarcinoma (PDAC)'s growing incidence has been linked to the rise in obesity and type 2 diabetes mellitus. Administration of metformin eliminated PDAC formation in KC mice with diet-induced obesity. This change was associated with significant microbial changes in both the mucosal and luminal microbiome of the duodenum. This suggests that the microbiome may be a potential mediator of the chemopreventive effects of metformin.
Collapse
Affiliation(s)
- Tien S Dong
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, California
| | - Hui-Hua Chang
- CURE: Digestive Diseases Research Center, David Geffen School of Medicine at the University of California, Los Angeles, California
- Department of Surgery, David Geffen School of Medicine at the University of California, Los Angeles, California
| | - Meg Hauer
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, California
- CURE: Digestive Diseases Research Center, David Geffen School of Medicine at the University of California, Los Angeles, California
- University of California Los Angeles Microbiome Center, David Geffen School of Medicine at the University of California, Los Angeles, California
| | - Venu Lagishetty
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, California
- CURE: Digestive Diseases Research Center, David Geffen School of Medicine at the University of California, Los Angeles, California
- University of California Los Angeles Microbiome Center, David Geffen School of Medicine at the University of California, Los Angeles, California
| | - William Katzka
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, California
- CURE: Digestive Diseases Research Center, David Geffen School of Medicine at the University of California, Los Angeles, California
- University of California Los Angeles Microbiome Center, David Geffen School of Medicine at the University of California, Los Angeles, California
| | - Enrique Rozengurt
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, California
- CURE: Digestive Diseases Research Center, David Geffen School of Medicine at the University of California, Los Angeles, California
- Division of Gastroenterology, Hepatology, and Parenteral Nutrition, Veterans' Affairs Greater Los Angeles Healthcare System, Los Angeles, California
| | - Jonathan P Jacobs
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, California
- CURE: Digestive Diseases Research Center, David Geffen School of Medicine at the University of California, Los Angeles, California
- University of California Los Angeles Microbiome Center, David Geffen School of Medicine at the University of California, Los Angeles, California
- Division of Gastroenterology, Hepatology, and Parenteral Nutrition, Veterans' Affairs Greater Los Angeles Healthcare System, Los Angeles, California
| | - Guido Eibl
- CURE: Digestive Diseases Research Center, David Geffen School of Medicine at the University of California, Los Angeles, California
- Department of Surgery, David Geffen School of Medicine at the University of California, Los Angeles, California
| |
Collapse
|
|
20
|
Rozengurt E, Eibl G. Central role of Yes-associated protein and WW-domain-containing transcriptional co-activator with PDZ-binding motif in pancreatic cancer development. World J Gastroenterol 2019; 25:1797-1816. [PMID: 31057295 PMCID: PMC6478619 DOI: 10.3748/wjg.v25.i15.1797] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 03/20/2019] [Accepted: 03/25/2019] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease with no efficacious treatment options. PDAC incidence is projected to increase, which may be caused at least partially by the obesity epidemic. Significantly enhanced efforts to prevent or intercept this cancer are clearly warranted. Oncogenic KRAS mutations are recognized initiating events in PDAC development, however, they are not entirely sufficient for the development of fully invasive PDAC. Additional genetic alterations and/or environmental, nutritional, and metabolic signals, as present in obesity, type-2 diabetes mellitus, and inflammation, are required for full PDAC formation. We hypothesize that oncogenic KRAS increases the intensity and duration of the growth-promoting signaling network. Recent exciting studies from different laboratories indicate that the activity of the transcriptional co-activators Yes-associated protein (YAP) and WW-domain-containing transcriptional co-activator with PDZ-binding motif (TAZ) play a critical role in the promotion and maintenance of PDAC operating as key downstream target of KRAS signaling. While initially thought to be primarily an effector of the tumor-suppressive Hippo pathway, more recent studies revealed that YAP/TAZ subcellular localization and co-transcriptional activity is regulated by multiple upstream signals. Overall, YAP has emerged as a central node of transcriptional convergence in growth-promoting signaling in PDAC cells. Indeed, YAP expression is an independent unfavorable prognostic marker for overall survival of PDAC. In what follows, we will review studies implicating YAP/TAZ in pancreatic cancer development and consider different approaches to target these transcriptional regulators.
Collapse
Affiliation(s)
- Enrique Rozengurt
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, United States
- CURE: Digestive Diseases Research Center, Los Angeles, CA 90095, United States
| | - Guido Eibl
- Department of Surgery, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, United States
- CURE: Digestive Diseases Research Center, Los Angeles, CA 90095, United States
| |
Collapse
|
|
21
|
Teh JT, Zhu WL, Newgard CB, Casey PJ, Wang M. Respiratory Capacity and Reserve Predict Cell Sensitivity to Mitochondria Inhibitors: Mechanism-Based Markers to Identify Metformin-Responsive Cancers. Mol Cancer Ther 2019; 18:693-705. [DOI: 10.1158/1535-7163.mct-18-0766] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 11/22/2018] [Accepted: 01/14/2019] [Indexed: 11/16/2022]
|
|
22
|
da Veiga Moreira J, Hamraz M, Abolhassani M, Schwartz L, Jolicœur M, Peres S. Metabolic therapies inhibit tumor growth in vivo and in silico. Sci Rep 2019; 9:3153. [PMID: 30816152 PMCID: PMC6395653 DOI: 10.1038/s41598-019-39109-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 01/09/2019] [Indexed: 12/12/2022] Open
Abstract
In the recent years, cancer research succeeded with sensitive detection methods, targeted drug delivery systems, and the identification of a large set of genes differently expressed. However, although most therapies are still based on antimitotic agents, which are causing wide secondary effects, there is an increasing interest for metabolic therapies that can minimize side effects. In the early 20th century, Otto Warburg revealed that cancer cells rely on the cytoplasmic fermentation of glucose to lactic acid for energy synthesis (called "Warburg effect"). Our investigations aim to reverse this effect in reprogramming cancer cells' metabolism. In this work, we present a metabolic therapy specifically targeting the activity of specific enzymes of central carbon metabolism, combining the METABLOC bi-therapeutic drugs combination (Alpha Lipoic Acid and Hydroxycitrate) to Metformin and Diclofenac, for treating tumors implanted in mice. Furthermore, a dynamic metabolic model describing central carbon metabolism as well as fluxes targeted by the drugs allowed to simulate tumors progression in both treated and non-treated mice, in addition to draw hypotheses on the effects of the drugs on tumor cells metabolism. Our model predicts metabolic therapies-induced reversed Warburg effect on tumor cells.
Collapse
Affiliation(s)
- Jorgelindo da Veiga Moreira
- Research Laboratory in Applied Metabolic Engineering, Department of Chemical Engineering, École Polytechnique de Montréal, P.O. Box 6079, Centre-ville Station, Montréal, Québec, Canada
| | - Minoo Hamraz
- Institut Cochin, Université Paris- Descartes, 75014, Paris, France
| | | | - Laurent Schwartz
- Assistance Publique des Hôpitaux de Paris, 149 avenue Victoria, 75004, Paris, France
| | - Mario Jolicœur
- Research Laboratory in Applied Metabolic Engineering, Department of Chemical Engineering, École Polytechnique de Montréal, P.O. Box 6079, Centre-ville Station, Montréal, Québec, Canada
| | - Sabine Peres
- LRI, Université Paris-Sud, CNRS, Université Paris-Saclay, 91405, Orsay, France.
- MaIAGE, INRA, Université Paris-Saclay, 78350, Jouy-en-Josas, France.
| |
Collapse
|
|
23
|
Bigelsen S. Evidence-based complementary treatment of pancreatic cancer: a review of adjunct therapies including paricalcitol, hydroxychloroquine, intravenous vitamin C, statins, metformin, curcumin, and aspirin. Cancer Manag Res 2018; 10:2003-2018. [PMID: 30034255 PMCID: PMC6049054 DOI: 10.2147/cmar.s161824] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Despite new and exciting research and renewed optimism about future therapy, current statistics of survival from pancreatic cancer remains dismal. Patients seeking alternative or complementary treatments should be warned to avoid the hype and instead look to real science. A variety of relatively safe and inexpensive treatment options that have shown success in preclinical models and/or retrospective studies are currently available. Patients require their physicians to provide therapeutic guidance and assistance in obtaining and administrating these various therapies. Paricalcitol, an analog of vitamin D, has been shown by researchers at the Salk Institute for Biological Studies to break though the protective stroma surrounding tumor cells. Hydroxychloroquine has been shown to inhibit autophagy, a process by which dying cells recycle injured organelles and internal toxins to generate needed energy for survival and reproduction. Intravenous vitamin C creates a toxic accumulation of hydrogen peroxide within cancer cells, hastening their death. Metformin inhibits mitochondrial oxidative metabolism utilized by cancer stem cells. Statins inhibit not only cholesterol but also other factors in the same pathway that affect cancer cell growth, protein synthesis, and cell cycle progression. A novel formulation of curcumin may prevent resistance to chemotherapy and inhibit pancreatic cancer cell proliferation. Aspirin therapy has been shown to prevent pancreatic cancer and may be useful to prevent recurrence. These therapies are all currently available and are reviewed in this paper with emphasis on the most recent laboratory research and clinical studies.
Collapse
Affiliation(s)
- Stephen Bigelsen
- Department of Allergy, Asthma and Immunology, Rutgers New Jersey Medical School, Newark, NJ, USA,
| |
Collapse
|
|
24
|
Lu R, Yang J, Wei R, Ke J, Tian Q, Yu F, Liu J, Zhang J, Hong T. Synergistic anti-tumor effects of liraglutide with metformin on pancreatic cancer cells. PLoS One 2018; 13:e0198938. [PMID: 29897998 PMCID: PMC5999272 DOI: 10.1371/journal.pone.0198938] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Accepted: 05/29/2018] [Indexed: 12/13/2022] Open
Abstract
Either metformin or liraglutide has been reported to have anti-tumor effects on pancreatic cancer cells. However, it is not clear whether their combined treatment has additive or synergistic anti-tumor effects on pancreatic cancer cells. In this study, the human pancreatic cancer cell line MiaPaca-2 was incubated with liraglutide and/or metformin. The cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, and wound-healing and transwell migration assays were used to detect cell viability, clonogenic survival, cell cycle and cell migration, respectively. RT-PCR and western blot analyses were used to determine the mRNA and protein levels of related molecules. Results showed that combination treatment with liraglutide (100 nmol/L) and metformin (0.75 mmol/L) significantly decreased cell viability and colony formation, caused cell cycle arrest, upregulated the level of pro-apoptotic proteins Bax and cleaved caspase-3, and inhibited cell migration in the cells, although their single treatment did not exhibit such effects. Combination index value for cell viability indicated a synergistic interaction of liraglutide and metformin. Moreover, the combined treatment with liraglutide and metformin could activate the phosphorylation of AMP-activated protein kinase (AMPK) more potently than their single treatment in the cells. These results suggest that liraglutide in combination with metformin has a synergistic anti-tumor effect on the pancreatic cancer cells, which may be at least partly due to activation of AMPK signaling. Our study provides new insights into the treatment of patients with type 2 diabetes and pancreatic cancer.
Collapse
Affiliation(s)
- Ran Lu
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Jin Yang
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Rui Wei
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Jing Ke
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Qing Tian
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Fei Yu
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Junling Liu
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Jingjing Zhang
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Tianpei Hong
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
- * E-mail:
| |
Collapse
|
|
25
|
Yes-associated protein (YAP) in pancreatic cancer: at the epicenter of a targetable signaling network associated with patient survival. Signal Transduct Target Ther 2018; 3:11. [PMID: 29682330 PMCID: PMC5908807 DOI: 10.1038/s41392-017-0005-2] [Citation(s) in RCA: 102] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 11/27/2017] [Accepted: 12/13/2017] [Indexed: 12/14/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is generally a fatal disease with no efficacious treatment modalities. Elucidation of signaling mechanisms that will lead to the identification of novel targets for therapy and chemoprevention is urgently needed. Here, we review the role of Yes-associated protein (YAP) and WW-domain-containing Transcriptional co-Activator with a PDZ-binding motif (TAZ) in the development of PDAC. These oncogenic proteins are at the center of a signaling network that involves multiple upstream signals and downstream YAP-regulated genes. We also discuss the clinical significance of the YAP signaling network in PDAC using a recently published interactive open-access database (www.proteinatlas.org/pathology) that allows genome-wide exploration of the impact of individual proteins on survival outcomes. Multiple YAP/TEAD-regulated genes, including AJUBA, ANLN, AREG, ARHGAP29, AURKA, BUB1, CCND1, CDK6, CXCL5, EDN2, DKK1, FOSL1,FOXM1, HBEGF, IGFBP2, JAG1, NOTCH2, RHAMM, RRM2, SERP1, and ZWILCH, are associated with unfavorable survival of PDAC patients. Similarly, components of AP-1 that synergize with YAP (FOSL1), growth factors (TGFα, EPEG, and HBEGF), a specific integrin (ITGA2), heptahelical receptors (P2Y2R, GPR87) and an inhibitor of the Hippo pathway (MUC1), all of which stimulate YAP activity, are associated with unfavorable survival of PDAC patients. By contrast, YAP inhibitory pathways (STRAD/LKB-1/AMPK, PKA/LATS, and TSC/mTORC1) indicate a favorable prognosis. These associations emphasize that the YAP signaling network correlates with poor survival of pancreatic cancer patients. We conclude that the YAP pathway is a major determinant of clinical aggressiveness in PDAC patients and a target for therapeutic and preventive strategies in this disease. Yes-associated protein (YAP) signaling contributes to pancreatic cancer progression and is associated with poor patient survival. Previous studies have shown that YAP activates genes involved in cell proliferation to incite tumor growth and metastasis. Enrique Rozengurt and colleagues at University of California Los Angeles review the latest knowledge on YAP signaling and used the open access database The Human Protein Atlas to analyze the gene expression profile and prognosis of 176 patients with pancreatic ductal adenocarcinoma. Activation of upstream or downstream elements of the YAP signaling pathway correlated with shorter survival in patients. Conversely, the activation of signaling pathways that oppose YAP signaling were associated with a more favorable prognosis. These findings highlight YAP signaling pathway components as both prognostic markers and potential targets for developing much needed therapeutic and preventative strategies.
Collapse
|
|
26
|
Yang Q, Guo X, Yang L. Metformin Enhances the Effect of Regorafenib and Inhibits Recurrence and Metastasis of Hepatic Carcinoma After Liver Resection via Regulating Expression of Hypoxia Inducible Factors 2α (HIF-2α) and 30 kDa HIV Tat-Interacting Protein (TIP30). Med Sci Monit 2018; 24:2225-2234. [PMID: 29654226 PMCID: PMC5912093 DOI: 10.12659/msm.906687] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background Regorafenib (RGF) is the drug of choice for treating hepatic carcinoma (HCC), but the drug has drawbacks due to resistance and associated adverse effects. Thus, it becomes crucial to understand the causal ‘map’ of the resistance conferred by RGF, so that its clinical potency can be amplified, resulting in enhanced efficacy with reduced adverse effects. Metformin (MTF) has been reported to target NLK (Nemo-like kinase) to inhibit non-small lung cancer cells. Based on the literature, the present investigation was carried out to reveal the effect of RGF and MTF, with an expectation that MTF can synergize therapeutic potential as well reduce chances of resistance. Material/Methods Protein expression of hypoxia inducible factors (HIF)-2α, 30 kDa HIV Tat-interacting protein (TIP30), E-cadherin, N-cadherin, and pAMPK were assessed by Western blot analysis. RGF and MTF were exposed to MHCC97H cell and proliferation was quantified by assay of cell viability. Gene silencing and chromatin immunoprecipitation assay were done to reveal the relationship between TIP30 and HIF-2α. The impact of RGF and MTF together on postoperative recurrence and lung metastasis of hepatocellular carcinoma was investigated using tumor engrafted mice after administration of MTF and RGF once daily for 35 days. Immunohistochemistry was used to reveal CD31, Ki67, and TUNEL. Results The results suggested MTF-RGF combination lowered expression of HIF-2α gene silencing and suggested increased TIP30 after reduction of HIF-2α. The chromatin immunoprecipitation study indicated that under hypoxia, HIF-2α could bind with TIP30 promoter. Cell number quantification (CCK8), viable cell count, and apoptosis data (using Annexin V-FITC) indicated co-administration of RGF and MTF reduced cell proliferation, encouraging cell apoptosis, and reduced epithelial-mesenchymal transition course. Thus, in orthotopic mice, the RGF-MTF combination exhibited substantial reduction of HCC in lung metastasis and postoperative relapse. Conclusions MTF can enhance the potential of RGF and inhibit the recurrence and metastasis of HCC after postoperative liver section by regulating the levels of TIP30 and HIF-2α.
Collapse
Affiliation(s)
- Qing Yang
- Department of Nuclear Medical, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China (mainland)
| | - Xintao Guo
- Department of Cardiothoracic Surgery, Tianjin 4th Central Hospital, Tianjin, China (mainland)
| | - LingLi Yang
- Department of Science and Education, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China (mainland)
| |
Collapse
|
|
27
|
Metformin Decreases the Incidence of Pancreatic Ductal Adenocarcinoma Promoted by Diet-induced Obesity in the Conditional KrasG12D Mouse Model. Sci Rep 2018; 8:5899. [PMID: 29651002 PMCID: PMC5897574 DOI: 10.1038/s41598-018-24337-8] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Accepted: 03/27/2018] [Indexed: 12/14/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a particularly deadly disease. Chronic conditions, including obesity and type-2 diabetes are risk factors, thus making PDAC amenable to preventive strategies. We aimed to characterize the chemo-preventive effects of metformin, a widely used anti-diabetic drug, on PDAC development using the KrasG12D mouse model subjected to a diet high in fats and calories (HFCD). LSL-KrasG12D/+;p48-Cre (KC) mice were given control diet (CD), HFCD, or HFCD with 5 mg/ml metformin in drinking water for 3 or 9 months. After 3 months, metformin prevented HFCD-induced weight gain, hepatic steatosis, depletion of intact acini, formation of advanced PanIN lesions, and stimulation of ERK and mTORC1 in pancreas. In addition to reversing hepatic and pancreatic histopathology, metformin normalized HFCD-induced hyperinsulinemia and hyperleptinemia among the 9-month cohort. Importantly, the HFCD-increased PDAC incidence was completely abrogated by metformin (p < 0.01). The obesogenic diet also induced a marked increase in the expression of TAZ in pancreas, an effect abrogated by metformin. In conclusion, administration of metformin improved the metabolic profile and eliminated the promoting effects of diet-induced obesity on PDAC formation in KC mice. Given the established safety profile of metformin, our findings have a strong translational potential for novel chemo-preventive strategies for PDAC.
Collapse
|
|
28
|
Eibl G, Cruz-Monserrate Z, Korc M, Petrov MS, Goodarzi MO, Fisher WE, Habtezion A, Lugea A, Pandol SJ, Hart PA, Andersen DK. Diabetes Mellitus and Obesity as Risk Factors for Pancreatic Cancer. J Acad Nutr Diet 2018; 118:555-567. [PMID: 28919082 PMCID: PMC5845842 DOI: 10.1016/j.jand.2017.07.005] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 07/10/2017] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest types of cancer. The worldwide estimates of its incidence and mortality in the general population are eight cases per 100,000 person-years and seven deaths per 100,000 person-years, and they are significantly higher in the United States than in the rest of the world. The incidence of this disease in the United States is more than 50,000 new cases in 2017. Indeed, total deaths due to PDAC are projected to increase dramatically to become the second leading cause of cancer-related deaths before 2030. Considering the failure to date to efficiently treat existing PDAC, increased effort should be undertaken to prevent this disease. A better understanding of the risk factors leading to PDAC development is of utmost importance to identify and formulate preventive strategies. Large epidemiologic and cohort studies have identified risk factors for the development of PDAC, including obesity and type 2 diabetes mellitus. This review highlights the current knowledge of obesity and type 2 diabetes as risk factors for PDAC development and progression, their interplay and underlying mechanisms, and the relation to diet. Research gaps and opportunities to address this deadly disease are also outlined.
Collapse
|
|
29
|
Sirolimus and metformin synergistically inhibit hepatocellular carcinoma cell proliferation and improve long-term survival in patients with HCC related to hepatitis B virus induced cirrhosis after liver transplantation. Oncotarget 2018; 7:62647-62656. [PMID: 27577068 PMCID: PMC5308754 DOI: 10.18632/oncotarget.11591] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Accepted: 08/11/2016] [Indexed: 02/06/2023] Open
Abstract
Immunosuppressive agents used postoperatively after liver transplantation (LT) for hepatocellular carcinoma (HCC) favor recurrence and metastasis. Therefore, new effective immunosuppressants are needed. This retrospective study assessed combined sirolimus and metformin on survival of HCC patients after LT. In 2001-2013, 133 HCC patients with LT were divided into four groups: sirolimus and metformin combination (Sir+Met), sirolimus monotherapy (Sir), other immunosuppressants in diabetes mellitus (DM) patients without metformin (No Sir with DM), and other immunosuppressants in patients without DM (No Sir without DM). Kaplan-Meier and Log-rank tests were used to assess survival. Cell proliferation and tumor xenograft assays were performed to disclose the mechanisms underlying the sirolimus and metformin effects. The Sir+Met group showed significantly prolonged survival compared to the other groups. The most significant cytotoxicity was seen in the Sir+Met group, with significantly decreased levels of phosphorylated PI3K, AKT, AMPK, mTOR, 4EBP1 and S6K, compared with the other groups. In agreement, Sir+Met had the highest suppressive effect on tumor growth among all groups (P<0.01). In summary, Sir+Met treatment significantly prolonged survival, likely by suppressing cell proliferation. Therefore, this combination could represent a potential routine-regimen for patients post LT.
Collapse
|
|
30
|
Association between metformin use and mortality in patients with type 2 diabetes mellitus and localized resectable pancreatic cancer: a nationwide population-based study in korea. Oncotarget 2018; 8:9587-9596. [PMID: 28077783 PMCID: PMC5354755 DOI: 10.18632/oncotarget.14525] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2016] [Accepted: 11/24/2016] [Indexed: 12/16/2022] Open
Abstract
Background Preclinical studies support an antitumor effect of metformin. However, clinical studies have conflicting results and metformin's effect remains controversial. The aim of this study was to evaluate metformin's effect on clinical outcomes in diabetic patients with pancreatic cancer treated with curative resection. Results A total of 764 patients underwent curative resection, met none of the exclusion criteria, and were prescribed oral hypoglycemic agents. The cancer-specific survival (5-year, 31.9% vs. 22.2%, p < 0.001) was significantly higher in the 530 metformin users than in the 234 diabetic metformin non-users. After multivariable adjustments, metformin users had significantly lower cancer-specific mortality as compared with metformin non-users (hazard ratio, 0.727; 95% confidence interval, 0.611–0.868). Cubic spline regression analysis demonstrated significantly decreased cancer-specific mortality with increasing dose of metformin (p = 0.0047). Materials and Methods Data were provided from the Korea Central Cancer Registry and the National Health Insurance Service in the Republic of Korea. The study cohort consisted of 28,862 patients newly diagnosed with pancreatic cancer between 2005 and 2011. Metformin exposure was determined from prescription information from 6 months before the first diagnosis of pancreatic cancer to last follow-up. The main outcome was cancer-specific survival. Conclusions This large study indicates that metformin might decrease cancer-specific mortality rates in localized resectable pancreatic cancer patients with pre-existing diabetes, independently of other factors, with a dose-response relationship.
Collapse
|
|
31
|
Saini N, Yang X. Metformin as an anti-cancer agent: actions and mechanisms targeting cancer stem cells. Acta Biochim Biophys Sin (Shanghai) 2018; 50:133-143. [PMID: 29342230 DOI: 10.1093/abbs/gmx106] [Citation(s) in RCA: 111] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Accepted: 09/14/2017] [Indexed: 12/21/2022] Open
Abstract
Metformin, a first line medication for type II diabetes, initially entered the spotlight as a promising anti-cancer agent due to epidemiologic reports that found reduced cancer risk and improved clinical outcomes in diabetic patients taking metformin. To uncover the anti-cancer mechanisms of metformin, preclinical studies determined that metformin impairs cellular metabolism and suppresses oncogenic signaling pathways, including receptor tyrosine kinase, PI3K/Akt, and mTOR pathways. Recently, the anti-cancer potential of metformin has gained increasing interest due to its inhibitory effects on cancer stem cells (CSCs), which are associated with tumor metastasis, drug resistance, and relapse. Studies using various cancer models, including breast, pancreatic, prostate, and colon, have demonstrated the potency of metformin in attenuating CSCs through the targeting of specific pathways involved in cell differentiation, renewal, metastasis, and metabolism. In this review, we provide a comprehensive overview of the anti-cancer actions and mechanisms of metformin, including the regulation of CSCs and related pathways. We also discuss the potential anti-cancer applications of metformin as mono- or combination therapies.
Collapse
Affiliation(s)
- Nipun Saini
- Julius L. Chambers Biomedical/Biotechnology Research Institute, Department of Biological and Biomedical Sciences, North Carolina Central University, North Carolina Research Campus, Kannapolis, NC 28081, USA
| | - Xiaohe Yang
- Julius L. Chambers Biomedical/Biotechnology Research Institute, Department of Biological and Biomedical Sciences, North Carolina Central University, North Carolina Research Campus, Kannapolis, NC 28081, USA
| |
Collapse
|
|
32
|
Eibl G, Rozengurt E. KRAS, YAP, and obesity in pancreatic cancer: A signaling network with multiple loops. Semin Cancer Biol 2017; 54:50-62. [PMID: 29079305 DOI: 10.1016/j.semcancer.2017.10.007] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 10/22/2017] [Indexed: 02/08/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) continues to be a lethal disease with no efficacious treatment modalities. The incidence of PDAC is expected to increase, at least partially because of the obesity epidemic. Increased efforts to prevent or intercept this disease are clearly needed. Mutations in KRAS are initiating events in pancreatic carcinogenesis supported by genetically engineered mouse models of the disease. However, oncogenic KRAS is not entirely sufficient for the development of fully invasive PDAC. Additional genetic mutations and/or environmental, nutritional, and metabolic stressors, e.g. inflammation and obesity, are required for efficient PDAC formation with activation of KRAS downstream effectors. Multiple factors "upstream" of KRAS associated with obesity, including insulin resistance, inflammation, changes in gut microbiota and GI peptides, can enhance/modulate downstream signals. Multiple signaling networks and feedback loops "downstream" of KRAS have been described that respond to obesogenic diets. We propose that KRAS mutations potentiate a signaling network that is promoted by environmental factors. Specifically, we envisage that KRAS mutations increase the intensity and duration of the growth-promoting signaling network. As the transcriptional activator YAP plays a critical role in the network, we conclude that the rationale for targeting the network (at different points), e.g. with FDA approved drugs such as statins and metformin, is therefore compelling.
Collapse
Affiliation(s)
- Guido Eibl
- Departments of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States; CURE: Digestive Diseases Research Center, University of California at Los Angeles, Los Angeles, CA, United States.
| | - Enrique Rozengurt
- Departments of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States; CURE: Digestive Diseases Research Center, University of California at Los Angeles, Los Angeles, CA, United States
| |
Collapse
|
|
33
|
Ruess DA, Görgülü K, Wörmann SM, Algül H. Pharmacotherapeutic Management of Pancreatic Ductal Adenocarcinoma: Current and Emerging Concepts. Drugs Aging 2017; 34:331-357. [PMID: 28349415 DOI: 10.1007/s40266-017-0453-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Pancreatic ductal adenocarcinoma is a devastating malignancy, which is the result of late diagnosis, aggressive disease, and a lack of effective treatment options. Thus, pancreatic ductal adenocarcinoma is projected to become the second leading cause of cancer-related death by 2030. This review summarizes recent developments of oncological therapy in the palliative setting of metastatic pancreatic ductal adenocarcinoma. It further compiles novel targets and therapeutic approaches as well as promising treatment combinations, which are presently in preclinical evaluation, covering several aspects of the hallmarks of cancer. Finally, challenges to the implementation of an individualized therapy approach in the context of precision medicine are discussed.
Collapse
Affiliation(s)
- Dietrich A Ruess
- Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany.
| | - Kivanc Görgülü
- Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany
| | - Sonja M Wörmann
- Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany
| | - Hana Algül
- Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany.
| |
Collapse
|
|
34
|
Leonel C, Borin TF, de Carvalho Ferreira L, Moschetta MG, Bajgelman MC, Viloria-Petit AM, de Campos Zuccari DAP. Inhibition of Epithelial-Mesenchymal Transition and Metastasis by Combined TGFbeta Knockdown and Metformin Treatment in a Canine Mammary Cancer Xenograft Model. J Mammary Gland Biol Neoplasia 2017; 22:27-41. [PMID: 28078601 DOI: 10.1007/s10911-016-9370-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 12/19/2016] [Indexed: 12/18/2022] Open
Abstract
Epithelial mesenchymal transition (EMT) is a process by which epithelial cells acquire mesenchymal properties, generating metastases. Transforming growth factor beta (TGF-β) is associated with this malignancy by having the ability to induce EMT. Metformin, has been shown to inhibit EMT in breast cancer cells. Based on this evidence we hypothesize that treatment with metformin and the silencing of TGF-β, inhibits the EMT in cancer cells. Canine metastatic mammary tumor cell line CF41 was stably transduced with a shRNA-lentivirus, reducing expression level of TGF-β1. This was combined with metformin treatment, to look at effects on cell migration and the expression of EMT markers. For in vivo study, unmodified or TGF-β1sh cells were injected in the inguinal region of nude athymic female mice followed by metformin treatment. The mice's lungs were collected and metastatic nodules were subsequently assessed for EMT markers expression. The migration rate was lower in TGF-β1sh cells and when combined with metformin treatment. Metformin treatment reduced N-cadherin and increased E-cadherin expression in both CF41 and TGF-β1sh cells. Was demonstrated that metformin treatment reduced the number of lung metastases in animals bearing TGF-β1sh tumors. This paralleled a decreased N-cadherin and vimentin expression, and increased E-cadherin and claudin-7 expression in lung metastases. This study confirms the benefits of TGF-β1 silencing in addition to metformin as potential therapeutic agents for breast cancer patients, by blocking EMT process. To the best of our knowledge, we are the first to report metformin treatment in cells with TGF-β1 silencing and their effect on EMT.
Collapse
Affiliation(s)
- Camila Leonel
- Universidade Estadual Paulista "Julio de Mesquita Filho" (UNESP/IBILCE), PostGraduate Program in Genetics, Cristovao Colombo Street, 2265, Jardim Nazareth, Sao Jose do Rio Preto, SP, Brazil
- Faculdade de Medicina de Sao Jose do Rio Preto (FAMERP), Laboratory of Molecular Investigation of Cancer (LIMC), Brigadeiro Faria Lima Avenue, 5416, Vila São Pedro, Sao Jose do Rio Preto, SP, Brazil
| | - Thaiz Ferraz Borin
- Faculdade de Medicina de Sao Jose do Rio Preto (FAMERP), Laboratory of Molecular Investigation of Cancer (LIMC), Brigadeiro Faria Lima Avenue, 5416, Vila São Pedro, Sao Jose do Rio Preto, SP, Brazil
- Faculdade de Medicina de Sao Jose do Rio Preto (FAMERP), PostGraduate Program in Health Sciences, Brigadeiro Faria Lima Avenue, 5416, Vila São Pedro, Sao Jose do Rio Preto, SP, Brazil
| | - Lívia de Carvalho Ferreira
- Universidade Estadual Paulista "Julio de Mesquita Filho" (UNESP/IBILCE), PostGraduate Program in Genetics, Cristovao Colombo Street, 2265, Jardim Nazareth, Sao Jose do Rio Preto, SP, Brazil
- Faculdade de Medicina de Sao Jose do Rio Preto (FAMERP), Laboratory of Molecular Investigation of Cancer (LIMC), Brigadeiro Faria Lima Avenue, 5416, Vila São Pedro, Sao Jose do Rio Preto, SP, Brazil
| | - Marina Gobbe Moschetta
- Faculdade de Medicina de Sao Jose do Rio Preto (FAMERP), Laboratory of Molecular Investigation of Cancer (LIMC), Brigadeiro Faria Lima Avenue, 5416, Vila São Pedro, Sao Jose do Rio Preto, SP, Brazil
- Faculdade de Medicina de Sao Jose do Rio Preto (FAMERP), PostGraduate Program in Health Sciences, Brigadeiro Faria Lima Avenue, 5416, Vila São Pedro, Sao Jose do Rio Preto, SP, Brazil
| | - Marcio Chaim Bajgelman
- National Center for Research in Energy and Materials - CNPEM, Brazilian Biosciences National Laboratory - LNBio, Giuseppe Máximo Scolfaro Street, Campinas, SP, 10000, Brazil
| | - Alicia M Viloria-Petit
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, 50 Stone Rd E, Guelph, ON, N1G 2W1, Canada
| | - Debora Aparecida Pires de Campos Zuccari
- Universidade Estadual Paulista "Julio de Mesquita Filho" (UNESP/IBILCE), PostGraduate Program in Genetics, Cristovao Colombo Street, 2265, Jardim Nazareth, Sao Jose do Rio Preto, SP, Brazil.
- Faculdade de Medicina de Sao Jose do Rio Preto (FAMERP), Laboratory of Molecular Investigation of Cancer (LIMC), Brigadeiro Faria Lima Avenue, 5416, Vila São Pedro, Sao Jose do Rio Preto, SP, Brazil.
| |
Collapse
|
|
35
|
Wang X, Zhang YB, Liu JW, Li P. Expression of metastasis related genes S100A4 and MMP-9 in pancreatic cancer cells treated with metformin. Shijie Huaren Xiaohua Zazhi 2017; 25:334-339. [DOI: 10.11569/wcjd.v25.i4.334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the expression of metastasis related genes S100A4 and matrix metalloproteinase (MMP)-9 in pancreatic cancer cell lines BxPC-3 and AsPC-1 treated with metformin.
METHODS Cells were incubated with metformin at different concentrations for 24, 48, or 72 h. Then, cell viability was measured by MTT assay, and IC50 values were calculated. The two cell lines were then treated with metformin at IC50 concentrations for 48 h, and RT-PCR was used to detect the expression of S100A4 and MMP-9 mRNAs.
RESULTS Cell viability was apparently inhibited by metformin in both cell lines, and the inhibitory effect showed a time- and dose-dependent manner. The IC50 values for BxPC-3 cells at 24, 48, and 72 h were 12.13 mmol/L, 10.43 mmol/L, and 9.55 mmol/L, respectively, and the corresponding values for AsPC-1 cells were 23.45 mmol/L, 15.44 mmol/L, and 11.30 mmol/L. After treatment with metformin for 48 h, the expression of S100A4 and MMP-9 mRNAs in the two cell lines was significantly decreased compared with control cells (P < 0.01).
CONCLUSION Metformin inhibits pancreatic cancer cell growth in a time- and dose-dependent manner. Metformin may exert anti-metastasis effects by decreasing the expression of S100A4 and MMP-9 in pancreatic cancer cell lines.
Collapse
|
|
36
|
Yu J, Liu SH, Sanchez R, Nemunaitis J, Rozengurt E, Brunicardi FC. Pancreatic cancer actionable genes in precision medicine and personalized surgery. Surgeon 2017; 15:24-29. [PMID: 27374183 PMCID: PMC5195911 DOI: 10.1016/j.surge.2016.05.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Revised: 05/02/2016] [Accepted: 05/22/2016] [Indexed: 12/17/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with an overall 5-year survival rate less than 5% due to the poor early diagnosis and lack of effective therapeutic options. The most effective therapy remains surgery, however post-operative survival could be enhanced with effective adjuvant therapy. The massive information gained from Omics techniques on PDAC at the beginning of the 21st century is a remarkable accomplishment. However, the information gained from the omics data, including next generation sequencing data, has yet to successfully affect care of patients suffering with PDAC. Therefore, we propose the development of an actionable genomic platform that matches a patient's PDAC clinically actionable genes with potential targeted adjuvant therapies. Using this platform, PDX1 has been identified as a potential actionable gene for PDAC, therefore, RNAi therapy, gene therapy and small inhibitory drugs, all targeting PDX1, serve as potential targeted adjuvant therapies. Preclinical studies support the hypothesis that identification of PDAC actionable genes could permit translation of a patient's genomic information into precision targeted adjuvant therapy for PDAC.
Collapse
Affiliation(s)
- Juehua Yu
- Division of General Surgery, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, CA, USA
| | - Shi-He Liu
- Division of General Surgery, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, CA, USA
| | - Robbi Sanchez
- Division of General Surgery, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, CA, USA
| | | | - Enrique Rozengurt
- Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, CA, USA
| | - F Charles Brunicardi
- Division of General Surgery, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, CA, USA.
| |
Collapse
|
|
37
|
Fukumura D, Incio J, Shankaraiah RC, Jain RK. Obesity and Cancer: An Angiogenic and Inflammatory Link. Microcirculation 2016; 23:191-206. [PMID: 26808917 DOI: 10.1111/micc.12270] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2015] [Accepted: 01/20/2016] [Indexed: 12/15/2022]
Abstract
With the current epidemic of obesity, a large number of patients diagnosed with cancer are overweight or obese. Importantly, this excess body weight is associated with tumor progression and poor prognosis. The mechanisms for this worse outcome, however, remain poorly understood. We review here the epidemiological evidence for the association between obesity and cancer, and discuss potential mechanisms focusing on angiogenesis and inflammation. In particular, we will discuss how the dysfunctional angiogenesis and inflammation occurring in adipose tissue in obesity may promote tumor progression, resistance to chemotherapy, and targeted therapies such as anti-angiogenic and immune therapies. Better understanding of how obesity fuels tumor progression and therapy resistance is essential to improve the current standard of care and the clinical outcome of cancer patients. To this end, we will discuss how an anti-diabetic drug such as metformin can overcome these adverse effects of obesity on the progression and treatment resistance of tumors.
Collapse
Affiliation(s)
- Dai Fukumura
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Joao Incio
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.,I3S, Institute for Innovation and Research in Heath, Metabolism, Nutrition and Endocrinology Group, Biochemistry Department, Faculty of Medicine, Porto University, Porto, Portugal.,Department of Internal Medicine, Hospital S. João, Porto, Portugal
| | - Ram C Shankaraiah
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.,Department of Morphology, Surgery and Experimental Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy
| | - Rakesh K Jain
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| |
Collapse
|
|
38
|
Boukalova S, Stursa J, Werner L, Ezrova Z, Cerny J, Bezawork-Geleta A, Pecinova A, Dong L, Drahota Z, Neuzil J. Mitochondrial Targeting of Metformin Enhances Its Activity against Pancreatic Cancer. Mol Cancer Ther 2016; 15:2875-2886. [PMID: 27765848 DOI: 10.1158/1535-7163.mct-15-1021] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Revised: 08/30/2016] [Accepted: 09/20/2016] [Indexed: 11/16/2022]
Abstract
Pancreatic cancer is one of the hardest-to-treat types of neoplastic diseases. Metformin, a widely prescribed drug against type 2 diabetes mellitus, is being trialed as an agent against pancreatic cancer, although its efficacy is low. With the idea of delivering metformin to its molecular target, the mitochondrial complex I (CI), we tagged the agent with the mitochondrial vector, triphenylphosphonium group. Mitochondrially targeted metformin (MitoMet) was found to kill a panel of pancreatic cancer cells three to four orders of magnitude more efficiently than found for the parental compound. Respiration assessment documented CI as the molecular target for MitoMet, which was corroborated by molecular modeling. MitoMet also efficiently suppressed pancreatic tumors in three mouse models. We propose that the novel mitochondrially targeted agent is clinically highly intriguing, and it has a potential to greatly improve the bleak prospects of patients with pancreatic cancer. Mol Cancer Ther; 15(12); 2875-86. ©2016 AACR.
Collapse
Affiliation(s)
- Stepana Boukalova
- Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czech Republic.
| | - Jan Stursa
- Institute of Chemical Technology in Prague, Czech Republic
| | - Lukas Werner
- Institute of Chemical Technology in Prague, Czech Republic
- Biomedical Research Centre, University Hospital Hradec Kralove, Czech Republic
| | - Zuzana Ezrova
- Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czech Republic
| | - Jiri Cerny
- Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czech Republic
| | | | - Alena Pecinova
- Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic
| | - Lanfeng Dong
- School of Medical Science, Griffith University, Southport, Qld, Australia
| | - Zdenek Drahota
- Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic
| | - Jiri Neuzil
- Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czech Republic.
- School of Medical Science, Griffith University, Southport, Qld, Australia
| |
Collapse
|
|
39
|
Bhaw-Luximon A, Jhurry D. Metformin in pancreatic cancer treatment: from clinical trials through basic research to biomarker quantification. J Cancer Res Clin Oncol 2016; 142:2159-71. [PMID: 27160287 DOI: 10.1007/s00432-016-2178-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Accepted: 05/02/2016] [Indexed: 12/19/2022]
Abstract
PURPOSE Three major chemotherapy strategies have emerged in the treatment of PDAC in the recent past: multiple drug combination, stroma depletion, and use of nanodrug therapy. Anti-diabetic metformin was shown to improve the outcome of a number of cancer types the first seminal report on an observational study published in 2005 and the first hospital-based case-control study on pancreatic cancer in 2009. METHODS In this review paper, we confront the findings of a selected number of epidemiological studies and clinical trials on the use of metformin in pancreatic cancer treatment with basic knowledge and research. We particularly emphasize on the point that contradictory clinical results likely originate from heterogeneous study design due to a trial and error approach rather than an evidence-based and scientific approach. A non-rigorous selection of patients suffering from PDAC and often a poor understanding of the biological mechanism of metformin coupled with lack of scientific data has led to general statements on metformin positive or negative action, another aspect which we highlight in the review. RESULTS We here present a few pathways which in our opinion are predominant for pancreatic cancer specifically: mitochondrial activity, AMPK activation, mTOR inhibition, and decreased IGF-1R and HIF-1α expression. CONCLUSION We stress on the need for a better stratification of patients and a more rigorous planning of clinical trials not only focusing on classical parameters but also on potential predictive biomarkers (AMPK, mTOR, HIF-1α, IGF-1R) and metformin dosage for positive outcome.
Collapse
Affiliation(s)
- Archana Bhaw-Luximon
- Centre for Biomedical and Biomaterials Research (CBBR), University of Mauritius, MSIRI Building, Réduit, Mauritius
| | - Dhanjay Jhurry
- Centre for Biomedical and Biomaterials Research (CBBR), University of Mauritius, MSIRI Building, Réduit, Mauritius.
| |
Collapse
|
|
40
|
Elmaci İ, Altinoz MA. A Metabolic Inhibitory Cocktail for Grave Cancers: Metformin, Pioglitazone and Lithium Combination in Treatment of Pancreatic Cancer and Glioblastoma Multiforme. Biochem Genet 2016; 54:573-618. [PMID: 27377891 DOI: 10.1007/s10528-016-9754-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Accepted: 06/23/2016] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer (PC) and glioblastoma multiforme (GBM) are among the human cancers with worst prognosis which require an urgent need for efficient therapies. Here, we propose to apply to treat both malignancies with a triple combination of drugs, which are already in use for different indications. Recent studies demonstrated a considerable link between risk of PC and diabetes. In experimental models, anti-diabetogenic agents suppress growth of PC, including metformin (M), pioglitazone (P) and lithium (L). L is used in psychiatric practice, yet also bears anti-diabetic potential and selectively inhibits glycogen synthase kinase-3 beta (GSK-3β). M, a biguanide class anti-diabetic agent shows anticancer activity via activating AMP-activated protein kinase (AMPK). Glitazones bind to PPAR-γ and inhibit NF-κB, triggering cell proliferation, apoptosis resistance and synthesis of inflammatory cytokines in cancer cells. Inhibition of inflammatory cytokines could simultaneously decrease tumor growth and alleviate cancer cachexia, having a major role in PC mortality. Furthermore, mutual synergistic interactions exist between PPAR-γ and GSK-3β, between AMPK and GSK-3β and between AMPK and PPAR-γ. In GBM, M blocks angiogenesis and migration in experimental models. Very noteworthy, among GBM patients with type 2 diabetes, usage of M significantly correlates with better survival while reverse is true for sulfonylureas. In experimental models, P synergies with ligands of RAR, RXR and statins in reducing growth of GBM. Further, usage of P was found to be lesser in anaplastic astrocytoma and GBM patients, indicating a protective effect of P against high-grade gliomas. L is accumulated in GBM cells faster and higher than in neuroblastoma cells, and its levels further increase with chronic exposure. Recent studies revealed anti-invasive potential of L in GBM cell lines. Here, we propose that a triple-agent regime including drugs already in clinical usage may provide a metabolic adjuvant therapy for PC and GBM.
Collapse
Affiliation(s)
- İlhan Elmaci
- Department of Neurosurgery, Memorial Hospital, Istanbul, Turkey
- Neuroacademy Group, Istanbul, Turkey
| | - Meric A Altinoz
- Department of Immunology, Experimental Medicine Research Center, Istanbul, Turkey.
| |
Collapse
|
|
41
|
Zechner D, Bürtin F, Albert AC, Zhang X, Kumstel S, Schönrogge M, Graffunder J, Shih HY, Müller S, Radecke T, Jaster R, Vollmar B. Intratumoral heterogeneity of the therapeutical response to gemcitabine and metformin. Oncotarget 2016; 7:56395-56407. [PMID: 27486761 PMCID: PMC5302922 DOI: 10.18632/oncotarget.10892] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Accepted: 07/18/2016] [Indexed: 12/15/2022] Open
Abstract
Cancer heterogeneity and microenvironmental aspects within a tumor are considered key factors influencing resistance of carcinoma cells to distinct chemotherapeutical agents. We evaluated a high concentration of metformin in combination with gemcitabine on a syngeneic orthotopic mouse model using 6606PDA cells. We observed reduced tumor size and reduced cancer cell proliferation after three weeks of chemotherapy with either compound and noticed an additive effect between gemcitabine and metformin on tumor weight. Interestingly, distinct areas of the carcinoma responded differently to either compound. Metformin inhibited the proliferation of cancer cells close to the desmoplastic reaction, whereas gemcitabine inhibited the proliferation of cancer cells mainly 360-570 μm distant to the desmoplastic reaction. Indeed, co-culture of pancreatic stellate cells with 6606PDA, 7265PDA or MIA PaCa-2 cells increased gemcitabine resistance. Metformin resistance, however, was increased by high glucose concentration in the medium. Other factors such as hypoxia or the pH of the medium had no influence on gemcitabine or metformin induced inhibition of cancer cell proliferation. These data demonstrate a spatial heterogeneity in drug resistance within pancreatic adenocarcinomas and that microenvironmental aspects such as supply of glucose and the presence of pancreatic stellate cells regulate cancer cell sensitivity towards metformin or gemcitabine.
Collapse
Affiliation(s)
- Dietmar Zechner
- Institute for Experimental Surgery, Rostock University Medical Center, 18057 Rostock, Germany
| | - Florian Bürtin
- Institute for Experimental Surgery, Rostock University Medical Center, 18057 Rostock, Germany
| | - Ann-Christin Albert
- Institute for Experimental Surgery, Rostock University Medical Center, 18057 Rostock, Germany
| | - Xianbin Zhang
- Institute for Experimental Surgery, Rostock University Medical Center, 18057 Rostock, Germany
| | - Simone Kumstel
- Institute for Experimental Surgery, Rostock University Medical Center, 18057 Rostock, Germany
| | - Maria Schönrogge
- Institute for Experimental Surgery, Rostock University Medical Center, 18057 Rostock, Germany
| | - Josefine Graffunder
- Institute for Experimental Surgery, Rostock University Medical Center, 18057 Rostock, Germany
| | - Hao-Yu Shih
- Institute for Experimental Surgery, Rostock University Medical Center, 18057 Rostock, Germany
| | - Sarah Müller
- Division of Gastroenterology, Department of Medicine II, Rostock University Medical Center, 18057 Rostock, Germany
| | - Tobias Radecke
- Institute for Experimental Surgery, Rostock University Medical Center, 18057 Rostock, Germany
| | - Robert Jaster
- Division of Gastroenterology, Department of Medicine II, Rostock University Medical Center, 18057 Rostock, Germany
| | - Brigitte Vollmar
- Institute for Experimental Surgery, Rostock University Medical Center, 18057 Rostock, Germany
| |
Collapse
|
|
42
|
Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer. Proc Natl Acad Sci U S A 2016; 113:E5328-36. [PMID: 27559084 DOI: 10.1073/pnas.1611406113] [Citation(s) in RCA: 184] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Targeting glutamine metabolism via pharmacological inhibition of glutaminase has been translated into clinical trials as a novel cancer therapy, but available drugs lack optimal safety and efficacy. In this study, we used a proprietary emulsification process to encapsulate bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES), a selective but relatively insoluble glutaminase inhibitor, in nanoparticles. BPTES nanoparticles demonstrated improved pharmacokinetics and efficacy compared with unencapsulated BPTES. In addition, BPTES nanoparticles had no effect on the plasma levels of liver enzymes in contrast to CB-839, a glutaminase inhibitor that is currently in clinical trials. In a mouse model using orthotopic transplantation of patient-derived pancreatic tumor tissue, BPTES nanoparticle monotherapy led to modest antitumor effects. Using the HypoxCR reporter in vivo, we found that glutaminase inhibition reduced tumor growth by specifically targeting proliferating cancer cells but did not affect hypoxic, noncycling cells. Metabolomics analyses revealed that surviving tumor cells following glutaminase inhibition were reliant on glycolysis and glycogen synthesis. Based on these findings, metformin was selected for combination therapy with BPTES nanoparticles, which resulted in significantly greater pancreatic tumor reduction than either treatment alone. Thus, targeting of multiple metabolic pathways, including effective inhibition of glutaminase by nanoparticle drug delivery, holds promise as a novel therapy for pancreatic cancer.
Collapse
|
|
43
|
Soliman GA, Steenson SM, Etekpo AH. Effects of Metformin and a Mammalian Target of Rapamycin (mTOR) ATP-Competitive Inhibitor on Targeted Metabolomics in Pancreatic Cancer Cell Line. ACTA ACUST UNITED AC 2016; 6. [PMID: 28217402 DOI: 10.4172/2153-0769.1000183] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Pancreatic Cancer (PC) is a devastating lethal disease. Therefore, there is an urgent need to develop new intervention strategies. The mammalian Target of Rapamycin (mTOR) is a conserved kinase and master regulator of metabolism and cell growth. mTOR is dysregulated in chronic diseases including diabetes and pancreatic cancer. Recent reports indicate that 50% of Pancreatic Ductal Adenocarcinoma (PDAC) patients are diabetic at the time of diagnosis. Furthermore, the anti-diabetic drug, metformin, which indirectly inhibits mTOR, has emerged as a potential therapeutic target for PC. The objective of this study is to determine the targeted-metabolomics profile in PDAC cell line (HPAF-II) with mTOR inhibition and the interaction between mTOR ATP-competitive inhibitor (Torin 2) and metformin as potential combined therapy in PC. HPAF-II cell lines were cultured in the presence of either Torin 2, metformin, both, or control vehicle. We utilized targeted LC/MS/MS to characterize the alterations in glycolytic and tricarboxylic acid cycle metabolomics, and employed Western Blot analysis for cell signaling activation by phosphorylation. Comparisons between groups were analyzed using one-way Analysis of Variance followed by secondary post-hoc analysis. After 1 h incubation with metformin, AMP concentration was significantly increased compared to other groups (p<0.03). After 24 h, Torin-2 significantly decreased glycolysis intermediates (fructose 1,6-bisphosphate (FBP), and 2-phosphoglycerate/3-phosphoglycerate), TCA intermediate metabolites (citrate/isocitrate, and malate), as well as Nicotinamide Adenine Dinucleotide (NAD+) and Flavin Adenine Dinucleotide (FAD), and ATP levels. When HPAF-II cells were incubated with both Torin-2 and metformin, there was a significant reduction in NAD+ and FAD, suggesting decreased levels of the energy equivalents that are available to the electron transport chain. Targeted metabolomics data indicate that mTOR complexes inhibition by Torin 2 reduced glycolytic intermediates and TCA metabolites in HPAF- II and may synergize with metformin to decrease the electron acceptors NAD+ and FAD which may lead to reduced energy production.
Collapse
Affiliation(s)
- Ghada A Soliman
- Department of Health Promotion, Social and Behavioral Health College of Public Health, University of Nebraska Medical Center, Omaha, Nebraska, 68198 USA
| | - Sharalyn M Steenson
- Department of Health Promotion, Social and Behavioral Health College of Public Health, University of Nebraska Medical Center, Omaha, Nebraska, 68198 USA
| | - Asserewou H Etekpo
- Department of Health Promotion, Social and Behavioral Health College of Public Health, University of Nebraska Medical Center, Omaha, Nebraska, 68198 USA
| |
Collapse
|
|
44
|
Shi Y, He Z, Jia Z, Xu C. Inhibitory effect of metformin combined with gemcitabine on pancreatic cancer cells in vitro and in vivo. Mol Med Rep 2016; 14:2921-8. [PMID: 27499118 PMCID: PMC5042754 DOI: 10.3892/mmr.2016.5592] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 06/02/2016] [Indexed: 12/29/2022] Open
Abstract
Pancreatic cancer is a malignant digestive system tumor with a particularly poor prognosis, and is the fourth leading cause of cancer-associated mortality in the USA. The anti-diabetic therapeutic agent, metformin (MET) has been demonstrated to exert anti-tumor effects. The present study assessed the ability of MET, alone or in combination with gemcitabine (GEM), to inhibit the growth of the human CFPAC-1 pancreatic cancer cell line in vitro and in vivo. Cell counting kit-8 assays were performed to measure CFPAC-1 cell viability and apoptosis was detected with annexin V/propidium iodide. Cell cycle analysis was conducted by flow cytometry. The mRNA and protein levels of B-cell lymphoma-extra large (Bcl-xL), Bcl2 associated X protein (Bax), caspase-3, survivin and cyclin D1 in CFPAC-1 cells and tumor tissues were detected by reverse transcription-polymerase chain reaction and western blotting, respectively. Furthermore, the expression levels of caspase-3 and proliferating cell nuclear antigen in tumor tissues were detected by immunohistochemistry. The results demonstrated that following MET treatment, the growth of CFPAC-1 cells and xenografts in nude mice was inhibited, the expression levels of Bcl-xL, survivin and cyclin D1 were downregulated, while the expression levels of Bax and caspase-3 were upregulated. These effects were enhanced when MET was administered in combination with GEM. The mechanism underlying the anti-tumor effect of MET may be associated with the induction of cell apoptosis and the inhibition of proliferation.
Collapse
Affiliation(s)
- Yuqi Shi
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Zhilong He
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Zhenyu Jia
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Chunfang Xu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| |
Collapse
|
|
45
|
Sośnicki S, Kapral M, Węglarz L. Molecular targets of metformin antitumor action. Pharmacol Rep 2016; 68:918-25. [PMID: 27362768 DOI: 10.1016/j.pharep.2016.04.021] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Revised: 04/29/2016] [Accepted: 04/29/2016] [Indexed: 12/28/2022]
Abstract
Epidemiological studies have shown that metformin, a first line therapeutic agent for diabetes mellitus, reduced the risk of developing various malignancies. Several preclinical studies established some possible mechanisms of its anticancer effects. The primary effect of metformin action is a decrease in cell energy status, which activates AMP-activated kinase (AMPK), a cellular metabolic sensor. This event is followed by a decrease in serum concentrations of insulin and insulin growth factor I (IGF-I), the potent mitogens for cancer cells. In addition to the indirect mode of action, metformin may exhibit direct inhibitory effect on cancer cells by targeting mammalian target of rapamycin (mTOR) signaling and anabolic processes. This review gathers information on mechanisms of metformin antitumor activity, with special attention given to the impact of this antidiabetic drug on insulin/PI3K/mTOR and AMPK signaling. Furthermore, the factors required for this novel activity of metformin are discussed.
Collapse
Affiliation(s)
- Stanisław Sośnicki
- School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Katowice, Poland, Department of Biochemistry, Sosnowiec, Poland.
| | - Małgorzata Kapral
- School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Katowice, Poland, Department of Biochemistry, Sosnowiec, Poland.
| | - Ludmiła Węglarz
- School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Katowice, Poland, Department of Biochemistry, Sosnowiec, Poland.
| |
Collapse
|
|
46
|
Lee SH, Yoon SH, Lee HS, Chung MJ, Park JY, Park SW, Song SY, Chung JB, Bang S. Can metformin change the prognosis of pancreatic cancer? Retrospective study for pancreatic cancer patients with pre-existing diabetes mellitus type 2. Dig Liver Dis 2016; 48:435-440. [PMID: 26775128 DOI: 10.1016/j.dld.2015.12.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Revised: 12/05/2015] [Accepted: 12/11/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUNDS The effect of metformin on survival in patients with pancreatic cancer is controversial. AIMS To investigate the beneficial effect of metformin in pancreatic cancer patients. METHODS We retrospectively analyzed patients with pancreatic cancer and pre-existing diabetes mellitus type 2 who were treated at Severance Hospital (Seoul, South Korea) between May 2005 and December 2013. RESULTS Among 237 enrolled patients, 117 patients (49.4%) were exposed to metformin. The median overall survival was 13.7 months for the metformin group versus 8.9 months for the non-metformin group (P=0.001) In univariate analysis, metformin exposure, low serum carbohydrate antigen 19-9 levels (<1000 U/mL), small tumor size (≤20 mm), no tail involvement, good performance status (ECOG 0 vs. 1 or 2), and resectable cancer stage were associated with favorable survival outcomes (all P<0.05). In multivariate analysis, in addition to low serum carbohydrate antigen 19-9 levels (<1000 U/mL) and resectable cancer stage, metformin exposure was significantly associated with longer survival with a hazard ratio of 0.61 (P=0.001). Additionally, the cumulative duration of metformin use was significantly correlated with a favorable survival outcome. CONCLUSION Our findings supported that metformin exposure was associated with survival benefits in patients with pancreatic cancer and pre-existing type 2 diabetes mellitus, especially among those with an advanced cancer stage.
Collapse
Affiliation(s)
- Sang Hoon Lee
- Division of Gastroenterology, Department of Internal Medicine, Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sang Hyun Yoon
- Division of Gastroenterology, Department of Internal Medicine, Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hee Seung Lee
- Division of Gastroenterology, Department of Internal Medicine, Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Moon Jae Chung
- Division of Gastroenterology, Department of Internal Medicine, Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jeong Youp Park
- Division of Gastroenterology, Department of Internal Medicine, Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Seung Woo Park
- Division of Gastroenterology, Department of Internal Medicine, Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Si Young Song
- Division of Gastroenterology, Department of Internal Medicine, Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jae Bock Chung
- Division of Gastroenterology, Department of Internal Medicine, Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Seungmin Bang
- Division of Gastroenterology, Department of Internal Medicine, Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea.
| |
Collapse
|
|
47
|
You A, Cao M, Guo Z, Zuo B, Gao J, Zhou H, Li H, Cui Y, Fang F, Zhang W, Song T, Li Q, Zhu X, Yin H, Sun H, Zhang T. Metformin sensitizes sorafenib to inhibit postoperative recurrence and metastasis of hepatocellular carcinoma in orthotopic mouse models. J Hematol Oncol 2016; 9:20. [PMID: 26957312 PMCID: PMC4784359 DOI: 10.1186/s13045-016-0253-6] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2016] [Accepted: 03/03/2016] [Indexed: 12/19/2022] Open
Abstract
Background Sorafenib is recognized as a standard treatment for advanced hepatocellular carcinoma (HCC). However, many patients have to adopt dose reduction or terminate the use of sorafenib because of side effects. In addition, a large number of patients are resistant to sorafenib. Thus, it is essential to investigate the underlying mechanisms of the resistance to sorafenib and seek potential strategy to enhance its efficacy. Methods The protein expression of hypoxia-inducible factors (HIF)-2α, 30-kDa HIV Tat-interacting protein (TIP30), E-cadherin, N-cadherin, and pAMPK was detected by Western blot. Cell viability assays were performed to study the influence of metformin and sorafenib on cell proliferation. Annexin V-FITC apoptosis assays were used to detect the influence of metformin and sorafenib on cell apoptosis. The relationship between HIF-2α and TIP30 was studied using gene silencing approach and chromatin immunoprecipitation assay. To investigate the effect of metformin and sorafenib on postoperative recurrence and lung metastasis of HCC in tumor-bearing mice, the mice were orally treated either with metformin or sorafenib once a day for continuous 37 days after the operation to remove the lobe where the tumor was implanted. CD31, Ki67, and TUNEL were examined by immunohistochemistry. Results Our study demonstrated that metformin synergized with sorafenib reduced HIF-2α expression as examined by Western blot. Gene silencing approach indicated TIP30 was upregulated after knocking-down of HIF-2α and chromatin immunoprecipitation assay revealed that HIF-2α could bind to TIP30 promoter under hypoxic condition. Cell Counting Kit-8 (CCK8) cell viability assay and Annexin V-FITC apoptosis assay showed that metformin in combination with sorafenib suppressed cell proliferation and promoted cell apoptosis. Besides, combined therapy suppressed epithelial-mesenchymal transition (EMT) process both in vitro and in vivo. Moreover, metformin in combination with sorafenib significantly minimized postoperative recurrence and lung metastasis of HCC in orthotopic mouse model. Combined therapy inhibited CD31 and Ki67 expression but promoted TUNEL expression. Conclusions Metformin may potentially enhance the effect of sorafenib to inhibit HCC recurrence and metastasis after liver resection by regulating the expression of HIF-2α and TIP30. Electronic supplementary material The online version of this article (doi:10.1186/s13045-016-0253-6) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Abin You
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key laboratory of Cancer Prevention and Therapy, 24 Bin Shui Road, Hexi District, Tianjin, 300060, People's Republic of China
| | - Manqing Cao
- Liver Cancer Institute and Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 180 Fenglin Road, Shanghai, 200032, China
| | - Zhigui Guo
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key laboratory of Cancer Prevention and Therapy, 24 Bin Shui Road, Hexi District, Tianjin, 300060, People's Republic of China
| | - Bingfeng Zuo
- Research Center of Basic Medical Science, Tianjin Medical University, Qixiangtai Road, Heping District, Tianjin, 300070, China
| | - Junrong Gao
- Academy of Medical Image, Tianjin Medical University, Tianjin, 300070, People's Republic of China
| | - Hongyuan Zhou
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key laboratory of Cancer Prevention and Therapy, 24 Bin Shui Road, Hexi District, Tianjin, 300060, People's Republic of China
| | - Huikai Li
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key laboratory of Cancer Prevention and Therapy, 24 Bin Shui Road, Hexi District, Tianjin, 300060, People's Republic of China
| | - Yunlong Cui
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key laboratory of Cancer Prevention and Therapy, 24 Bin Shui Road, Hexi District, Tianjin, 300060, People's Republic of China
| | - Feng Fang
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key laboratory of Cancer Prevention and Therapy, 24 Bin Shui Road, Hexi District, Tianjin, 300060, People's Republic of China
| | - Wei Zhang
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key laboratory of Cancer Prevention and Therapy, 24 Bin Shui Road, Hexi District, Tianjin, 300060, People's Republic of China
| | - Tianqiang Song
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key laboratory of Cancer Prevention and Therapy, 24 Bin Shui Road, Hexi District, Tianjin, 300060, People's Republic of China
| | - Qiang Li
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key laboratory of Cancer Prevention and Therapy, 24 Bin Shui Road, Hexi District, Tianjin, 300060, People's Republic of China
| | - Xiaolin Zhu
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key laboratory of Cancer Prevention and Therapy, 24 Bin Shui Road, Hexi District, Tianjin, 300060, People's Republic of China
| | - Haifang Yin
- Research Center of Basic Medical Science, Tianjin Medical University, Qixiangtai Road, Heping District, Tianjin, 300070, China.
| | - Huichuan Sun
- Liver Cancer Institute and Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China. .,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 180 Fenglin Road, Shanghai, 200032, China.
| | - Ti Zhang
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key laboratory of Cancer Prevention and Therapy, 24 Bin Shui Road, Hexi District, Tianjin, 300060, People's Republic of China.
| |
Collapse
|
|
48
|
Zhou G, Yu J, Wang A, Liu SH, Sinnett-Smith J, Wu J, Sanchez R, Nemunaitis J, Ricordi C, Rozengurt E, Brunicardi FC. Metformin Restrains Pancreatic Duodenal Homeobox-1 (PDX-1) Function by Inhibiting ERK Signaling in Pancreatic Ductal Adenocarcinoma. Curr Mol Med 2016; 16:83-90. [PMID: 26695692 PMCID: PMC4994969 DOI: 10.2174/1566524016666151222145551] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 11/20/2015] [Accepted: 12/15/2015] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most potent and perilous diseases known, with a median survival rate of 3-5 months due to the combination of only advanced stage diagnosis and ineffective therapeutic options. Metformin (1,1-Dimethylbiguanide hydrochloride), the leading drug used for type 2 diabetes mellitus, emerges as a potential therapy for PDAC and other human cancers. Metformin exerts its anticancer action via a variety of adenosine monophosphate (AMP)-activated protein kinase (AMPK)- dependent and/or AMPK-independent mechanisms. We present data here showing that metformin downregulated pancreatic transcription factor pancreatic duodenal homeobox-1 (PDX-1), suggesting a potential novel mechanism by which metformin exerts its anticancer action. Metformin inhibited PDX-1 expression at both protein and mRNA levels and PDX-1 transactivity as well in PDAC cells. Extracellular signal-regulated kinase (ERK) was identified as a PDX-1-interacting protein by antibody array screening in GFP-PDX-1 stable HEK293 cells. Co-transfection of ERK1 with PDX-1 resulted in an enhanced PDX-1 expression in HEK293 cells in a dose-dependent manner. Immunoprecipitation/Western blotting analysis confirmed the ERK-PDX-1 interaction in PANC-1 cells stimulated by epidermal growth factor (EGF). EGF induced an enhanced PDX-1 expression in PANC-1 cells and this stimulation was inhibited by MEK inhibitor PD0325901. Metformin inhibited EGF-stimulated PDX-1 expression with an accompanied inhibition of ERK kinase activation in PANC- 1 cells. Taken together, our studies show that PDX-1 is a potential novel target for metformin in PDAC cells and that metformin may exert its anticancer action in PDAC by down-regulating PDX-1 via a mechanism involving inhibition of ERK signaling.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - F C Brunicardi
- Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, CA, USA.
| |
Collapse
|
|
49
|
Abstract
OBJECTIVES The aim of this study was to investigate the impact of statin and metformin therapy on disease outcome for patients with pancreatic ductal adenocarcinoma (PDAC). METHODS This retrospective study included 171 PDAC patients who underwent surgical resection at the Stanford Cancer Institute between 1998 and 2013. No patients received neoadjuvant therapy. Statin and metformin use was defined as use during initial consult and continuing upon discharge from the hospital after surgery. Dose of each medication was recorded, as was the type of statin taken. RESULTS The median follow-up for all patients was 11.23 months (range, 0.2-105.0 months). Among the 171 patients included in our analysis, 18 patients (10.5%) took metformin and 34 patients (19.9%) took statins. Statin use was associated with better overall survival (OS) in patients with PDAC (P = 0.011). Metformin use was also associated with better OS (P = 0.035). The use of statins remained significant on multivariate analysis for OS (P = 0.014; hazards ratio, 0.33; 95% confidence interval, 0.139-0.799), but metformin use did not (P = 0.33; hazards ratio 0.60, 95% confidence interval, 0.211-1.675). CONCLUSIONS Statin and metformin use is associated with improved OS in patients with resectable PDAC. These medications should be further investigated for possible long-term use in the general population.
Collapse
|
|
50
|
Incio J, Suboj P, Chin SM, Vardam-Kaur T, Liu H, Hato T, Babykutty S, Chen I, Deshpande V, Jain RK, Fukumura D. Metformin Reduces Desmoplasia in Pancreatic Cancer by Reprogramming Stellate Cells and Tumor-Associated Macrophages. PLoS One 2015; 10:e0141392. [PMID: 26641266 PMCID: PMC4671732 DOI: 10.1371/journal.pone.0141392] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2015] [Accepted: 10/06/2015] [Indexed: 02/06/2023] Open
Abstract
Background Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic tumor with a dismal prognosis for most patients. Fibrosis and inflammation are hallmarks of tumor desmoplasia. We have previously demonstrated that preventing the activation of pancreatic stellate cells (PSCs) and alleviating desmoplasia are beneficial strategies in treating PDAC. Metformin is a widely used glucose-lowering drug. It is also frequently prescribed to diabetic pancreatic cancer patients and has been shown to associate with a better outcome. However, the underlying mechanisms of this benefit remain unclear. Metformin has been found to modulate the activity of stellate cells in other disease settings. In this study, we examine the effect of metformin on PSC activity, fibrosis and inflammation in PDACs. Methods/Results In overweight, diabetic PDAC patients and pre-clinical mouse models, treatment with metformin reduced levels of tumor extracellular matrix (ECM) components, in particular hyaluronan (HA). In vitro, we found that metformin reduced TGF-ß signaling and the production of HA and collagen-I in cultured PSCs. Furthermore, we found that metformin alleviates tumor inflammation by reducing the expression of inflammatory cytokines including IL-1β as well as infiltration and M2 polarization of tumor-associated macrophages (TAMs) in vitro and in vivo. These effects on macrophages in vitro appear to be associated with a modulation of the AMPK/STAT3 pathway by metformin. Finally, we found in our preclinical models that the alleviation of desmoplasia by metformin was associated with a reduction in ECM remodeling, epithelial-to-mesenchymal transition (EMT) and ultimately systemic metastasis. Conclusion Metformin alleviates the fibro-inflammatory microenvironment in obese/diabetic individuals with pancreatic cancer by reprogramming PSCs and TAMs, which correlates with reduced disease progression. Metformin should be tested/explored as part of the treatment strategy in overweight diabetic PDAC patients.
Collapse
Affiliation(s)
- Joao Incio
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts, United States of America
- Department of Internal Medicine, Hospital S. Joao, Porto, Portugal
- I3S, Institute for Innovation and Research in Heath, Metabolism, Nutrition and Endocrinology group, Biochemistry Department, Faculty of Medicine, Porto University, Porto, Portugal
| | - Priya Suboj
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts, United States of America
- Department of Botany and Biotechnology, St. Xaviers College, Thumba, Trivandrum, Kerala, India
| | - Shan M. Chin
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Trupti Vardam-Kaur
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Hao Liu
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts, United States of America
- Program of Biology and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Tai Hato
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts, United States of America
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Suboj Babykutty
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts, United States of America
- Department of Zoology, Mar Ivanios College, Nalanchira, Trivandrum, Kerala, India
| | - Ivy Chen
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts, United States of America
- School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, United States of America
| | - Vikram Deshpande
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Rakesh K. Jain
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts, United States of America
- * E-mail: (RKJ); (DF)
| | - Dai Fukumura
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts, United States of America
- * E-mail: (RKJ); (DF)
| |
Collapse
|