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Laila UE, Zhao ZL, Liu H, Xu ZX. Aspirin in Cancer Therapy: Pharmacology and Nanotechnology Advances. Int J Nanomedicine 2025; 20:2327-2365. [PMID: 40017626 PMCID: PMC11866938 DOI: 10.2147/ijn.s505636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 02/04/2025] [Indexed: 03/01/2025] Open
Abstract
Aspirin, a non-steroidal anti-inflammatory drug (NSAID), has garnered significant attention for its anti-cancer potential. This review explores the pharmacological properties, chemical dynamics, and evolving therapeutic applications of aspirin, with an emphasis on its integration into advanced cancer therapies. Aspirin demonstrates broad-spectrum efficacy across diverse cancer types by modulating signaling pathways such as COX-dependent and COX-independent mechanisms, including Wnt, NF-κB, β-catenin/TCF, and IL-6/STAT3. Recent advancements highlight the role of nanotechnology in enhancing aspirin's targeted delivery, therapeutic effectiveness, and patient outcomes. Nanoparticle-based formulations, including liposomes, solid lipid nanoparticles, and mesoporous silica nanoparticles, offer improved solubility, stability, and bioavailability, enabling controlled drug release and tumor-specific targeting. These innovations reduce systemic toxicity and enhance therapeutic effects, paving the way for aspirin's integration into personalized cancer treatments. Ongoing clinical studies reinforce its safety profile, underscoring aspirin's role in cancer pharmacotherapy. This review calls for continued research into aspirin's repurposing in combination therapies and novel delivery systems to maximize its therapeutic potential.
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Affiliation(s)
- Umm E Laila
- School of Life Sciences, Henan University, Kaifeng, Henan Province, 475001, People’s Republic of China
| | - Zi Lon Zhao
- School of Life Sciences, Henan University, Kaifeng, Henan Province, 475001, People’s Republic of China
| | - Huai Liu
- School of Life Sciences, Henan University, Kaifeng, Henan Province, 475001, People’s Republic of China
| | - Zhi-Xiang Xu
- School of Life Sciences, Henan University, Kaifeng, Henan Province, 475001, People’s Republic of China
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2
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Cerviño RH, Gómez N, Sahores A, Gouts A, González B, Shayo C, Davio C, Yaneff A. Flurbiprofen inhibits cAMP transport by MRP4/ABCC4 increasing the potency of gemcitabine treatment in PDAC cell models. Int J Biol Macromol 2024; 280:136386. [PMID: 39378921 DOI: 10.1016/j.ijbiomac.2024.136386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 10/04/2024] [Accepted: 10/05/2024] [Indexed: 10/10/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a highly malignant cancer with a grim prognosis due to its early metastasis and resistance to current chemotherapies, such as Gemcitabine (GEM). We have previously demonstrated that cAMP exclusion by MRP4 is critical for PDAC cell proliferation, establishing this transporter as a promising prognostic marker and therapeutic target. In search for novel therapeutic options to improve GEM efficacy, we conducted a drug repositioning screening to identify potential inhibitors of cAMP transport by MRP4. Several non-steroidal anti-inflammatory drugs (NSAIDs) can inhibit the transport of certain MRP4 substrates. In this study, we assessed the efficacy of sixteen NSAIDs in inhibiting cAMP transport mediated by MRP4, identifying seven potent inhibitors based on their IC50 values. The most potent inhibitors were further tested for their effect on cell proliferation and migration. Flurbiprofen emerged as the most potent inhibitor of both MRP4-mediated cAMP transport and cell proliferation. Overexpression of MRP4 in BxPC-3 cells significantly increased GEM resistance, and co-administration of flurbiprofen with GEM markedly enhanced the latter's potency inhibiting PDAC cells proliferation. These findings position flurbiprofen as a potent inhibitor of cAMP transport by MRP4 and a promising adjunctive therapy to enhance GEM effectiveness in PDAC treatment.
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Affiliation(s)
- Ramiro Héctor Cerviño
- Instituto de Investigaciones Farmacológicas (Universidad de Buenos Aires - Consejo Nacional de Investigaciones Científicas y Técnicas), Facultad de Farmacia y Bioquímica, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - Natalia Gómez
- Instituto de Investigaciones Farmacológicas (Universidad de Buenos Aires - Consejo Nacional de Investigaciones Científicas y Técnicas), Facultad de Farmacia y Bioquímica, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - Ana Sahores
- Instituto de Investigaciones Farmacológicas (Universidad de Buenos Aires - Consejo Nacional de Investigaciones Científicas y Técnicas), Facultad de Farmacia y Bioquímica, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - Agustín Gouts
- Instituto de Investigaciones Farmacológicas (Universidad de Buenos Aires - Consejo Nacional de Investigaciones Científicas y Técnicas), Facultad de Farmacia y Bioquímica, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - Betina González
- Instituto de Investigaciones Farmacológicas (Universidad de Buenos Aires - Consejo Nacional de Investigaciones Científicas y Técnicas), Facultad de Farmacia y Bioquímica, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - Carina Shayo
- Instituto de Biología y Medicina Experimental (Consejo Nacional de Investigaciones Científicas y Técnicas), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - Carlos Davio
- Instituto de Investigaciones Farmacológicas (Universidad de Buenos Aires - Consejo Nacional de Investigaciones Científicas y Técnicas), Facultad de Farmacia y Bioquímica, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - Agustín Yaneff
- Instituto de Investigaciones Farmacológicas (Universidad de Buenos Aires - Consejo Nacional de Investigaciones Científicas y Técnicas), Facultad de Farmacia y Bioquímica, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina.
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3
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Djamgoz MBA, Jentzsch V. Integrative Management of Pancreatic Cancer (PDAC): Emerging Complementary Agents and Modalities. Nutr Cancer 2021; 74:1139-1162. [PMID: 34085871 DOI: 10.1080/01635581.2021.1934043] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 04/19/2021] [Accepted: 05/10/2021] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. The standard first-line treatment for PDAC is gemcitabine chemotherapy which, unfortunately, offers only limited chance of a lasting cure. This review further evaluates the hypothesis that the effectiveness of gemcitabine can be improved by combining it with evidence-based complementary measures. Previously, supported by clinical trial data, we suggested that a number of dietary factors and nutraceuticals can be integrated with gemcitabine therapy. Here, we evaluate a further 10 agents for which no clinical trials have (yet) been carried out but there are promising data from in vivo and/or in vitro studies including experiments involving combined treatments with gemcitabine. Two groups of complementary agents are considered: Dietary factors (resveratrol, epigallocatechin gallate, vitamin B9, capsaicin, quercetin and sulforaphane) and nutraceutical agents (artemisinin, garcinol, thymoquinone and emodin). In addition, we identified seven promising agents for which there is currently only basic (mostly in vitro) data. Finally, as a special case of combination therapy, we highlighted synergistic drug combinations involving gemcitabine with "repurposed" aspirin or metformin. We conclude overall that integrated management of PDAC currently is likely to produce the best outcome for patients and for this a wide range of complementary measures is available.
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Affiliation(s)
- Mustafa B A Djamgoz
- Department of Life Sciences, Imperial College London, London, UK
- Biotechnology Research Centre, Cyprus International University, Nicosia, Cyprus
| | - Valerie Jentzsch
- Department of Life Sciences, Imperial College London, London, UK
- Department of Health Policy, London School of Economics and Political Science, London, UK
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4
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Pretzsch E, D'Haese JG, Renz B, Ilmer M, Schiergens T, Miksch RC, Albertsmeier M, Guba M, Angele MK, Werner J, Nieß H. Effect of platelet inhibition with perioperative aspirin on survival in patients undergoing curative resection for pancreatic cancer: a propensity score matched analysis. BMC Surg 2021; 21:98. [PMID: 33618686 PMCID: PMC7901208 DOI: 10.1186/s12893-021-01083-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 02/01/2021] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND The importance of platelets in the pathogenesis of metastasis formation is increasingly recognized. Although evidence from epidemiologic studies suggests positive effects of aspirin on metastasis formation, there is little clinical data on the perioperative use of this drug in pancreatic cancer patients. METHODS From all patients who received curative intent surgery for pancreatic cancer between 2014 and 2016 at our institution, we identified 18 patients that took aspirin at time of admission and continued to throughout the inpatient period. Using propensity score matching, we selected a control group of 64 patients without aspirin intake from our database and assessed the effect of aspirin medication on overall, disease-free, and hematogenous metastasis-free survival intervals as endpoints. RESULTS Aspirin intake proved to be independently associated with improved mean overall survival (OS) (46.5 vs. 24.6 months, *p = 0.006), median disease-free survival (DFS) (26 vs. 10.5 months, *p = 0.001) and mean hematogenous metastasis-free survival (HMFS) (41.9 vs. 16.3 months, *p = 0.005). Three-year survival rates were 61.1% in patients with aspirin intake vs. 26.3% in patients without aspirin intake. Multivariate cox regression showed significant independent association of aspirin with all three survival endpoints with hazard ratios of 0.36 (95% CI 0.15-0.86) for OS (*p = 0.021), 0.32 (95% CI 0.16-0.63) for DFS (**p = 0.001), and 0.36 (95% CI 0.16-0.77) for HMFS (*p = 0.009). CONCLUSIONS Patients in our retrospective, propensity-score matched study showed significantly better overall survival when taking aspirin while undergoing curative surgery for pancreatic cancer. This was mainly due to a prolonged metastasis-free interval following surgery.
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Affiliation(s)
- E Pretzsch
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - J G D'Haese
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - B Renz
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - M Ilmer
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - T Schiergens
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - R C Miksch
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - M Albertsmeier
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - M Guba
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - M K Angele
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - J Werner
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - H Nieß
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany.
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Dugnani E, Pasquale V, Marra P, Liberati D, Canu T, Perani L, De Sanctis F, Ugel S, Invernizzi F, Citro A, Venturini M, Doglioni C, Esposito A, Piemonti L. Four-class tumor staging for early diagnosis and monitoring of murine pancreatic cancer using magnetic resonance and ultrasound. Carcinogenesis 2018; 39:1197-1206. [DOI: 10.1093/carcin/bgy094] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Accepted: 07/23/2018] [Indexed: 02/07/2023] Open
Affiliation(s)
- Erica Dugnani
- Division of Immunology, Transplantation and Infectious diseases, Diabetes Research Institute, Milan, Italy
| | - Valentina Pasquale
- Division of Immunology, Transplantation and Infectious diseases, Diabetes Research Institute, Milan, Italy
| | - Paolo Marra
- Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Via Olgettina, Milan, Italy
| | - Daniela Liberati
- Division of Genetics and Cell Biology, Genomic Unit for the diagnosis of human pathologies, IRCCS San Raffaele Scientific Institute, Via Olgettina, Milan, Italy
| | - Tamara Canu
- Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Via Olgettina, Milan, Italy
| | - Laura Perani
- Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Via Olgettina, Milan, Italy
| | - Francesco De Sanctis
- University Hospital and Department of Medicine, Immunology Section, Verona, Italy
| | - Stefano Ugel
- University Hospital and Department of Medicine, Immunology Section, Verona, Italy
| | - Francesca Invernizzi
- Department of Pathology, IRCCS San Raffaele Scientific Institute, Via Olgettina, Milan, Italy
| | - Antonio Citro
- Division of Immunology, Transplantation and Infectious diseases, Diabetes Research Institute, Milan, Italy
| | - Massimo Venturini
- Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Via Olgettina, Milan, Italy
| | - Claudio Doglioni
- Department of Pathology, IRCCS San Raffaele Scientific Institute, Via Olgettina, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Antonio Esposito
- Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Via Olgettina, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Lorenzo Piemonti
- Division of Immunology, Transplantation and Infectious diseases, Diabetes Research Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
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6
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Waldmann J, Fendrich V, Reichert M, Hecker A, Bartsch DK, Padberg W, Holler JP. Expression of neuropeptide Y and its receptors Y1 and Y2 in pancreatic intraepithelial neoplasia and invasive pancreatic cancer in a transgenic mouse model and human samples of pancreatic cancer. J Surg Res 2018; 223:230-236. [DOI: 10.1016/j.jss.2017.11.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Revised: 10/02/2017] [Accepted: 11/03/2017] [Indexed: 12/20/2022]
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Jiang MJ, Dai JJ, Gu DN, Huang Q, Tian L. Aspirin in pancreatic cancer: chemopreventive effects and therapeutic potentials. Biochim Biophys Acta Rev Cancer 2016; 1866:163-176. [PMID: 27567928 DOI: 10.1016/j.bbcan.2016.08.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 08/04/2016] [Accepted: 08/23/2016] [Indexed: 12/20/2022]
Abstract
Pancreatic cancer is one of the most aggressive malignancies with dismal prognosis. Recently, aspirin has been found to be an effective chemopreventive agent for many solid tumors. However, the function of aspirin use in pancreatic cancer largely remains unknown. We herein argued that aspirin could also lower the risk of pancreatic cancer. Importantly, aspirin assumes pleiotropic effects by targeting multiple molecules. It could further target the unique tumor biology of pancreatic cancer and modify the cancer microenvironment, thus showing remarkable therapeutic potentials. Besides, aspirin could reverse the chemoradiation resistance by repressing tumor repopulation and exert synergistic potentials with metformin on pancreatic cancer chemoprevention. Moreover, aspirin secondarily benefits pancreatic cancer patients through modestly reducing cancer pain and the risk of venous thromboembolism. Furthermore, new aspirin derivatives and delivery systems might help to improve risk-to-benefit ratio. In brief, aspirin is a promising chemopreventive agent and exerts significant therapeutic potentials in pancreatic cancer.
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Affiliation(s)
- Ming-Jie Jiang
- Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China; Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
| | - Juan-Juan Dai
- Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China; Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
| | - Dian-Na Gu
- Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China; Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
| | - Qian Huang
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China; Comprehensive Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
| | - Ling Tian
- Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China; Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.
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8
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Tingle SJ, Moir JA, White SA. Role of anti-stromal polypharmacy in increasing survival after pancreaticoduodenectomy for pancreatic ductal adenocarcinoma. World J Gastrointest Pathophysiol 2015; 6:235-242. [PMID: 26600982 PMCID: PMC4644888 DOI: 10.4291/wjgp.v6.i4.235] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Revised: 07/30/2015] [Accepted: 10/19/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the survival impact of common pharmaceuticals, which target stromal interactions, following a pancreaticoduodenectomy for pancreatic ductal adenocarcinoma.
METHODS: Data was collected retrospectively for 164 patients who underwent a pancreaticoduodenectomy for pancreatic ductal adenocarcinoma (PDAC). Survival analysis was performed on patients receiving the following medications: angiotensin-converting enzyme inhibitors (ACEI)/angiotensin II receptor blockers (ARB), calcium channel blockers (CCB), aspirin, and statins. Statistical analysis included Kaplan-meier survival estimates and cox multivariate regression; the latter of which allowed for any differences in a range of prognostic indicators between groups. Medications showing a significant survival benefit were investigated in combination with other medications to evaluate synergistic effects.
RESULTS: No survival benefit was observed with respect to ACEI/ARB (n = 41), aspirin or statins on individual drug analysis (n = 39). However, the entire CCB group (n = 26) showed a significant survival benefit on multivariate cox regression; hazard ratio (HR) of 0.475 (CI = 0.250-0.902, P = 0.023). Further analysis revealed that this was influenced by a group of patients who were taking aspirin in combination with CCB; median survival was significantly higher in the CCB + aspirin group (n = 15) compared with the group taking neither drug (n = 98); 1414 d vs 601 d (P = 0.029, log-rank test). Multivariate cox regression revealed neither aspirin nor CCB had a statistically significant impact on survival when given alone, however in combination the survival benefit was significant; HR = 0.332 (CI = 0.126-0.870, P = 0.025). None of the other medications showed a survival benefit in any combination.
CONCLUSION: Aspirin + CCB in combination appears to increase survival in patients with PDAC, highlighting the potential clinical use of combination therapy to target stromal interactions in pancreatic cancer.
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Gopinathan A, Morton JP, Jodrell DI, Sansom OJ. GEMMs as preclinical models for testing pancreatic cancer therapies. Dis Model Mech 2015; 8:1185-200. [PMID: 26438692 PMCID: PMC4610236 DOI: 10.1242/dmm.021055] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Pancreatic ductal adenocarcinoma is the most common form of pancreatic tumour, with a very limited survival rate and currently no available disease-modifying treatments. Despite recent advances in the production of genetically engineered mouse models (GEMMs), the development of new therapies for pancreatic cancer is still hampered by a lack of reliable and predictive preclinical animal models for this disease. Preclinical models are vitally important for assessing therapies in the first stages of the drug development pipeline, prior to their transition to the clinical arena. GEMMs carry mutations in genes that are associated with specific human diseases and they can thus accurately mimic the genetic, phenotypic and physiological aspects of human pathologies. Here, we discuss different GEMMs of human pancreatic cancer, with a focus on the Lox-Stop-Lox (LSL)-Kras(G12D); LSL-Trp53(R172H); Pdx1-cre (KPC) model, one of the most widely used preclinical models for this disease. We describe its application in preclinical research, highlighting its advantages and disadvantages, its potential for predicting clinical outcomes in humans and the factors that can affect such outcomes, and, finally, future developments that could advance the discovery of new therapies for pancreatic cancer.
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Affiliation(s)
- Aarthi Gopinathan
- Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge, CB2 0RE, UK
| | | | - Duncan I Jodrell
- Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge, CB2 0RE, UK
| | - Owen J Sansom
- Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK
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Yue W, Zheng X, Lin Y, Yang CS, Xu Q, Carpizo D, Huang H, DiPaola RS, Tan XL. Metformin combined with aspirin significantly inhibit pancreatic cancer cell growth in vitro and in vivo by suppressing anti-apoptotic proteins Mcl-1 and Bcl-2. Oncotarget 2015; 6:21208-24. [PMID: 26056043 PMCID: PMC4673260 DOI: 10.18632/oncotarget.4126] [Citation(s) in RCA: 84] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2014] [Accepted: 05/02/2015] [Indexed: 12/16/2022] Open
Abstract
Metformin and aspirin have been studied extensively as cancer preventive or therapeutic agents. However, the effects of their combination on pancreatic cancer cells have not been investigated. Herein, we evaluated the effects of metformin and aspirin, alone or in combination, on cell viability, migration, and apoptosis as well as the molecular changes in mTOR, STAT3 and apoptotic signaling pathways in PANC-1 and BxPC3 cells. Metformin and aspirin, at relatively low concentrations, demonstrated synergistically inhibitory effects on cell viability. Compared to the untreated control or individual drug, the combination of metformin and aspirin significantly inhibited cell migration and colony formation of both PANC-1 and BxPC-3 cells. Metformin combined with aspirin significantly inhibited the phosphorylation of mTOR and STAT3, and induced apoptosis as measured by caspase-3 and PARP cleavage. Remarkably, metformin combined with aspirin significantly downregulated the anti-apoptotic proteins Mcl-1 and Bcl-2, and upregulated the pro-apoptotic proteins Bim and Puma, as well as interrupted their interactions. The downregulation of Mcl-1 and Bcl-2 was independent of AMPK or STAT3 pathway but partially through mTOR signaling and proteasome degradation. In a PANC-1 xenograft mouse model, we demonstrated that the combination of metformin and aspirin significantly inhibited tumor growth and downregulated the protein expression of Mcl-1 and Bcl-2 in tumors. Taken together, the combination of metformin and aspirin significantly inhibited pancreatic cancer cell growth in vitro and in vivo by regulating the pro- and anti-apoptotic Bcl-2 family members, supporting the continued investigation of this two drug combination as chemopreventive or chemotherapeutic agents for pancreatic cancer.
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Affiliation(s)
- Wen Yue
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
| | - Xi Zheng
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Yong Lin
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
- Department of Biostatistics, School of Public Health, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Chung S. Yang
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
- Department of Biostatistics, School of Public Health, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Qing Xu
- Department of Oncology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, P. R. China
| | - Darren Carpizo
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
| | - Huarong Huang
- Department of Oncology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, P. R. China
- Allan H. Conney Laboratory for Anticancer Research, Guangdong University of Technology, Guangzhou, P. R. China
| | - Robert S. DiPaola
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
| | - Xiang-Lin Tan
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
- Department of Epidemiology, School of Public Health, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
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11
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Mohammed A, Janakiram NB, Pant S, Rao CV. Molecular Targeted Intervention for Pancreatic Cancer. Cancers (Basel) 2015; 7:1499-542. [PMID: 26266422 PMCID: PMC4586783 DOI: 10.3390/cancers7030850] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Revised: 07/24/2015] [Accepted: 08/04/2015] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) remains one of the worst cancers, with almost uniform lethality. PC risk is associated with westernized diet, tobacco, alcohol, obesity, chronic pancreatitis, and family history of pancreatic cancer. New targeted agents and the use of various therapeutic combinations have yet to provide adequate treatments for patients with advanced cancer. To design better preventive and/or treatment strategies against PC, knowledge of PC pathogenesis at the molecular level is vital. With the advent of genetically modified animals, significant advances have been made in understanding the molecular biology and pathogenesis of PC. Currently, several clinical trials and preclinical evaluations are underway to investigate novel agents that target signaling defects in PC. An important consideration in evaluating novel drugs is determining whether an agent can reach the target in concentrations effective to treat the disease. Recently, we have reported evidence for chemoprevention of PC. Here, we provide a comprehensive review of current updates on molecularly targeted interventions, as well as dietary, phytochemical, immunoregulatory, and microenvironment-based approaches for the development of novel therapeutic and preventive regimens. Special attention is given to prevention and treatment in preclinical genetically engineered mouse studies and human clinical studies.
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Affiliation(s)
- Altaf Mohammed
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, PC Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
| | - Naveena B Janakiram
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, PC Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
| | - Shubham Pant
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, PC Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
| | - Chinthalapally V Rao
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, PC Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
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12
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Zhang Y, Liu L, Fan P, Bauer N, Gladkich J, Ryschich E, Bazhin AV, Giese NA, Strobel O, Hackert T, Hinz U, Gross W, Fortunato F, Herr I. Aspirin counteracts cancer stem cell features, desmoplasia and gemcitabine resistance in pancreatic cancer. Oncotarget 2015; 6:9999-10015. [PMID: 25846752 PMCID: PMC4496413 DOI: 10.18632/oncotarget.3171] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2015] [Accepted: 01/18/2015] [Indexed: 12/17/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDA) is characterized by an extremely poor prognosis. An inflammatory microenvironment triggers the pronounced desmoplasia, the selection of cancer stem-like cells (CSCs) and therapy resistance. The anti-inflammatory drug aspirin is suggested to lower the risk for PDA and to improve the treatment, although available results are conflicting and the effect of aspirin to CSC characteristics and desmoplasia in PDA has not yet been investigated. We characterized the influence of aspirin on CSC features, stromal reactions and gemcitabine resistance. Four established and 3 primary PDA cell lines, non-malignant cells, 3 patient tumor-derived CSC-enriched spheroidal cultures and tissues from patients who did or did not receive aspirin before surgery were analyzed using MTT assays, flow cytometry, colony and spheroid formation assays, Western blot analysis, antibody protein arrays, electrophoretic mobility shift assays (EMSAs), immunohistochemistry and in vivo xenotransplantation. Aspirin significantly induced apoptosis and reduced the viability, self-renewal potential, and expression of proteins involved in inflammation and stem cell signaling. Aspirin also reduced the growth and invasion of tumors in vivo, and it significantly prolonged the survival of mice with orthotopic pancreatic xenografts in combination with gemcitabine. This was associated with a decreased expression of markers for progression, inflammation and desmoplasia. These findings were confirmed in tissue samples obtained from patients who had or had not taken aspirin before surgery. Importantly, aspirin sensitized cells that were resistant to gemcitabine and thereby enhanced the therapeutic efficacy. Aspirin showed no obvious toxic effects on normal cells, chick embryos or mice. These results highlight aspirin as an effective, inexpensive and well-tolerated co-treatment to target inflammation, desmoplasia and CSC features PDA.
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Affiliation(s)
- Yiyao Zhang
- Molecular OncoSurgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Section Surgical Research, University of Heidelberg, Heidelberg, Germany
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
- Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, China
| | - Li Liu
- Molecular OncoSurgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Section Surgical Research, University of Heidelberg, Heidelberg, Germany
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Pei Fan
- Molecular OncoSurgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Section Surgical Research, University of Heidelberg, Heidelberg, Germany
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Nathalie Bauer
- Molecular OncoSurgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Section Surgical Research, University of Heidelberg, Heidelberg, Germany
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Jury Gladkich
- Molecular OncoSurgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Section Surgical Research, University of Heidelberg, Heidelberg, Germany
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Eduard Ryschich
- Section Surgical Research, University of Heidelberg, Heidelberg, Germany
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Alexandr V. Bazhin
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Nathalia A. Giese
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Oliver Strobel
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Thilo Hackert
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Ulf Hinz
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Wolfgang Gross
- Molecular OncoSurgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Section Surgical Research, University of Heidelberg, Heidelberg, Germany
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Franco Fortunato
- Section Surgical Research, University of Heidelberg, Heidelberg, Germany
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Ingrid Herr
- Molecular OncoSurgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Section Surgical Research, University of Heidelberg, Heidelberg, Germany
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
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