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Hatori M, Tsuji D, Suzuki K, Yokokawa T, Kawakami K, Moriyama R, Osada-Tsuchiya M, Otake A, Nakao M, Yano T, Arakawa Y, Matsuo K, Ohashi Y, Sakata Y, Kogure Y, Tamaki S, Wada A, Taki Y, Sasahira N, Ishii H, Yamaguchi M, Itoh K. Pharmacogenomic study of gemcitabine efficacy in patients with metastatic pancreatic cancer: A multicenter, prospective, observational cohort study (GENESECT study). Cancer 2024; 130:2988-2999. [PMID: 38682652 DOI: 10.1002/cncr.35343] [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: 02/13/2024] [Revised: 03/23/2024] [Accepted: 04/01/2024] [Indexed: 05/01/2024]
Abstract
BACKGROUND Genetic polymorphisms of molecules are known to cause individual differences in the therapeutic efficacy of anticancer drugs. However, to date, germline mutations (but not somatic mutations) for anticancer drugs have not been adequately studied. The objective of this study was to investigate the association between germline polymorphisms of gemcitabine metabolic and transporter genes with carbohydrate antigen 19-9 (CA 19-9) response (decrease ≥50% from the pretreatment level at 8 weeks) and overall survival (OS) in patients with metastatic pancreatic cancer who receive gemcitabine-based chemotherapy. METHODS This multicenter, prospective, observational study enrolled patients with metastatic pancreatic cancer patients who were receiving gemcitabine monotherapy or gemcitabine plus nanoparticle albumin-bound paclitaxel combination chemotherapy. Thirteen polymorphisms that may be involved in gemcitabine responsiveness were genotyped, and univariate and multivariate logistic regression analyses were used to determine the association of these genotypes with CA 19-9 response and OS. The significance level was set at 5%. RESULTS In total, 180 patients from 11 hospitals in Japan were registered, and 159 patients whose CA 19-9 response could be assessed were included in the final analysis. Patients who had a CA 19-9 response had significantly longer OS (372 vs. 241 days; p = .007). RRM1 2464A>G and RRM2 175T>G polymorphisms suggested a weak association with CA 19-9 response and OS, but it was not statistically significant. COX-2 -765G>C polymorphism did not significantly correlate with CA 19-9 response but was significantly associated with OS (hazard ratio, 2.031; p = .019). CONCLUSIONS Genetic polymorphisms from the pharmacokinetics of gemcitabine did not indicate a significant association with efficacy, but COX-2 polymorphisms involved in tumor cell proliferation might affect OS.
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Affiliation(s)
- Masahiro Hatori
- Department of Pharmacy, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
- Department of Clinical Pharmacology and Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Daiki Tsuji
- Department of Clinical Pharmacology and Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Kenichi Suzuki
- Department of Clinical Pharmacology, School of Pharmacy Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
| | - Takashi Yokokawa
- Department of Pharmacy, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Kazuyoshi Kawakami
- Department of Pharmacy, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Ryo Moriyama
- Department of Clinical Pharmacology and Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Marika Osada-Tsuchiya
- Department of Clinical Pharmacology and Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Aki Otake
- Department of Clinical Pharmacology and Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Masahiko Nakao
- Department of Pharmacy and Clinical Research Center, Osaka City General Hospital, Osaka, Japan
| | - Takuya Yano
- Department of Pharmacy, Sumitomo Besshi Hospital, Niihama, Japan
| | - Yuichiro Arakawa
- Department of Pharmacy, Tochigi Cancer Center, Utsunomiya, Japan
| | - Keisuke Matsuo
- Department of Pharmacy, Beppu Medical Center, Beppu, Japan
| | - Yasukata Ohashi
- Department of Pharmacy, National Center for Global Health and Medicine, Tokyo, Japan
| | - Yasuhiko Sakata
- Department of Pharmacy, Hiroshima Citizens Hospital, Hiroshima, Japan
| | - Yuki Kogure
- Department of Pharmacy, National Center for Higashi-Hiroshima Medical Center, Higashi-Hiroshima, Japan
| | - Shinya Tamaki
- Department of Pharmacy, KKR Sapporo Medical Center, Sapporo, Japan
| | - Atsushi Wada
- Department of Pharmacy, Kobe Minimally Invasive Cancer Center, Kobe, Japan
| | - Yusuke Taki
- Department of Pharmacy, Kikugawa General Hospital, Kikugawa, Japan
| | - Naoki Sasahira
- Department of Gastroenterology, Cancer Institute Hospital, Tokyo, Japan
| | - Hiroshi Ishii
- Division of Gastroenterology, Chiba Cancer Center, Tokyo, Japan
| | - Masakazu Yamaguchi
- Department of Pharmacy, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Kunihiko Itoh
- Department of Clinical Pharmacology and Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
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Alqahtani SS, Koltai T, Ibrahim ME, Bashir AHH, Alhoufie STS, Ahmed SBM, Molfetta DD, Carvalho TMA, Cardone RA, Reshkin SJ, Hifny A, Ahmed ME, Alfarouk KO. Role of pH in Regulating Cancer Pyrimidine Synthesis. J Xenobiot 2022; 12:158-180. [PMID: 35893264 PMCID: PMC9326563 DOI: 10.3390/jox12030014] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 06/17/2022] [Accepted: 06/28/2022] [Indexed: 11/18/2022] Open
Abstract
Replication is a fundamental aspect of cancer, and replication is about reproducing all the elements and structures that form a cell. Among them are DNA, RNA, enzymes, and coenzymes. All the DNA is doubled during each S (synthesis) cell cycle phase. This means that six billion nucleic acids must be synthesized in each cycle. Tumor growth, proliferation, and mutations all depend on this synthesis. Cancer cells require a constant supply of nucleotides and other macromolecules. For this reason, they must stimulate de novo nucleotide synthesis to support nucleic acid provision. When deregulated, de novo nucleic acid synthesis is controlled by oncogenes and tumor suppressor genes that enable increased synthesis and cell proliferation. Furthermore, cell duplication must be achieved swiftly (in a few hours) and in the midst of a nutrient-depleted and hypoxic environment. This also means that the enzymes participating in nucleic acid synthesis must work efficiently. pH is a critical factor in enzymatic efficiency and speed. This review will show that the enzymatic machinery working in nucleic acid synthesis requires a pH on the alkaline side in most cases. This coincides with many other pro-tumoral factors, such as the glycolytic phenotype, benefiting from an increased intracellular pH. An increased intracellular pH is a perfect milieu for high de novo nucleic acid production through optimal enzymatic performance.
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Affiliation(s)
- Saad Saeed Alqahtani
- Department of Pharmacy Practice, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia;
- Pharmacy Practice Research Unit, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia
| | | | - Muntaser E. Ibrahim
- Department of Molecular Biology, Institute of Endemic Diseases, University of Khartoum, Khartoum 11111, Sudan; (M.E.I.); (A.H.H.B.)
| | - Adil H. H. Bashir
- Department of Molecular Biology, Institute of Endemic Diseases, University of Khartoum, Khartoum 11111, Sudan; (M.E.I.); (A.H.H.B.)
| | - Sari T. S. Alhoufie
- Medical Laboratories Technology Department, College of Applied Medical Sciences, Taibah University, Medina 42353, Saudi Arabia;
| | - Samrein B. M. Ahmed
- Department of Biosciences and Chemistry, College of Health, Wellbeing and Life Sciences, Sheffield Hallam University, Sheffield S1 1WB, UK;
| | - Daria Di Molfetta
- Department of Biosciences, Biotechnologies, and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (D.D.M.); (T.M.A.C.); (R.A.C.); (S.J.R.)
| | - Tiago M. A. Carvalho
- Department of Biosciences, Biotechnologies, and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (D.D.M.); (T.M.A.C.); (R.A.C.); (S.J.R.)
| | - Rosa Angela Cardone
- Department of Biosciences, Biotechnologies, and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (D.D.M.); (T.M.A.C.); (R.A.C.); (S.J.R.)
| | - Stephan Joel Reshkin
- Department of Biosciences, Biotechnologies, and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (D.D.M.); (T.M.A.C.); (R.A.C.); (S.J.R.)
| | | | - Mohamed E. Ahmed
- Research Center, Zamzam University College, Khartoum 11123, Sudan;
| | - Khalid Omer Alfarouk
- Research Center, Zamzam University College, Khartoum 11123, Sudan;
- Alfarouk Biomedical Research LLC, Temple Terrace, FL 33617, USA
- Hala Alfarouk Cancer Center, Khartoum 11123, Sudan
- Correspondence:
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Koltai T, Reshkin SJ, Carvalho TMA, Di Molfetta D, Greco MR, Alfarouk KO, Cardone RA. Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma: A Physiopathologic and Pharmacologic Review. Cancers (Basel) 2022; 14:2486. [PMID: 35626089 PMCID: PMC9139729 DOI: 10.3390/cancers14102486] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/11/2022] [Accepted: 05/13/2022] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a poor prognosis and inadequate response to treatment. Many factors contribute to this therapeutic failure: lack of symptoms until the tumor reaches an advanced stage, leading to late diagnosis; early lymphatic and hematic spread; advanced age of patients; important development of a pro-tumoral and hyperfibrotic stroma; high genetic and metabolic heterogeneity; poor vascular supply; a highly acidic matrix; extreme hypoxia; and early development of resistance to the available therapeutic options. In most cases, the disease is silent for a long time, andwhen it does become symptomatic, it is too late for ablative surgery; this is one of the major reasons explaining the short survival associated with the disease. Even when surgery is possible, relapsesare frequent, andthe causes of this devastating picture are the low efficacy ofand early resistance to all known chemotherapeutic treatments. Thus, it is imperative to analyze the roots of this resistance in order to improve the benefits of therapy. PDAC chemoresistance is the final product of different, but to some extent, interconnected factors. Surgery, being the most adequate treatment for pancreatic cancer and the only one that in a few selected cases can achieve longer survival, is only possible in less than 20% of patients. Thus, the treatment burden relies on chemotherapy in mostcases. While the FOLFIRINOX scheme has a slightly longer overall survival, it also produces many more adverse eventsso that gemcitabine is still considered the first choice for treatment, especially in combination with other compounds/agents. This review discusses the multiple causes of gemcitabine resistance in PDAC.
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Affiliation(s)
| | - Stephan Joel Reshkin
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Tiago M. A. Carvalho
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Daria Di Molfetta
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Maria Raffaella Greco
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Khalid Omer Alfarouk
- Zamzam Research Center, Zamzam University College, Khartoum 11123, Sudan;
- Alfarouk Biomedical Research LLC, Temple Terrace, FL 33617, USA
| | - Rosa Angela Cardone
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
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Kato T, Ono H, Fujii M, Akahoshi K, Ogura T, Ogawa K, Ban D, Kudo A, Tanaka S, Tanabe M. Cytoplasmic RRM1 activation as an acute response to gemcitabine treatment is involved in drug resistance of pancreatic cancer cells. PLoS One 2021; 16:e0252917. [PMID: 34111175 PMCID: PMC8191885 DOI: 10.1371/journal.pone.0252917] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 05/25/2021] [Indexed: 12/31/2022] Open
Abstract
Background RRM1 is functionally associated with DNA replication and DNA damage repair. However, the biological activity of RRM1 in pancreatic cancer remains undetermined. Methods To determine relationships between RRM1 expression and the prognosis of pancreatic cancer, and to explore RRM1 function in cancer biology, we investigated RRM1 expression levels in 121 pancreatic cancer patients by immunohistochemical staining and performed in vitro experiments to analyze the functional consequences of RRM1 expression. Results Patients with high RRM1 expression had significantly poorer clinical outcomes (overall survival; p = 0.006, disease-free survival; p = 0.0491). In particular, high RRM1 expression was also associated with poorer overall survival on adjuvant chemotherapy (p = 0.008). We found that RRM1 expression was increased 24 hours after exposure to gemcitabine and could be suppressed by histone acetyltransferase inhibition. RRM1 activation in response to gemcitabine exposure was induced mainly in the cytoplasm and cytoplasmic RRM1 activation was related to cancer cell viability. In contrast, cancer cells lacking cytoplasmic RRM1 activation were confirmed to show severe DNA damage. RRM1 inhibition with specific siRNA or hydroxyurea enhanced the cytotoxic effects of gemcitabine for pancreatic cancer cells. Conclusions Cytoplasmic RRM1 activation is involved in biological processes related to drug resistance in response to gemcitabine exposure and could be a potential target for pancreatic cancer treatment.
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Affiliation(s)
- Tomotaka Kato
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hiroaki Ono
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
- * E-mail:
| | - Mikiya Fujii
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Keiichi Akahoshi
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Toshiro Ogura
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kosuke Ogawa
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Daisuke Ban
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Atsushi Kudo
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shinji Tanaka
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Minoru Tanabe
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
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Tesfaye AA, Wang H, Hartley ML, He AR, Weiner L, Gabelia N, Kapanadze L, Shezad M, Brody JR, Marshall JL, Pishvaian MJ. A Pilot Trial of Molecularly Tailored Therapy for Patients with Metastatic Pancreatic Ductal Adenocarcinoma. J Pancreat Cancer 2019; 5:12-21. [PMID: 31065624 PMCID: PMC6503449 DOI: 10.1089/pancan.2019.0003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Purpose: Despite the wide adoption of tumor molecular profiling, there is a dearth of evidence linking molecular biomarkers for treatment selection to prediction of treatment outcomes in patients with metastatic pancreatic cancer. We initiated a pilot study to test the feasibility of designing a larger phase II trial of molecularly tailored treatment for metastatic pancreatic cancer. Methods: Our study aimed to assess the feasibility of following a treatment algorithm based on the expression of three published predictive markers of response to chemotherapy: ribonucleotide reductase catalytic subunit M1 (for gemcitabine); excision repair cross-complementation group 1 (for platinum agents); and thymidylate synthase (for 5-fluorouracil) in patients with untreated, metastatic pancreatic cancer. Results of the tumor biopsy analysis were used to assign patients to one of seven doublet regimens. Key secondary objectives included response rate (RR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Results: Between December 2012 and March 2015, 30 patients were enrolled into the study. Ten patients failed screening primarily due to inadequate tumor tissue availability. Of the remaining 20 patients, 19 were assigned into 6 different chemotherapy doublets, and achieved an RR of 28%, with a DCR rate of 78%. The median PFS and OS were 5.78 and 8.21 months, respectively. Conclusions: The incorporation of biomarkers into a treatment algorithm is feasible and resulted in a PFS and OS similar to other doublet therapies for patients with metastatic pancreatic cancer. Based on the results from this pilot study, a larger phase II randomized trial of molecularly targeted therapy versus physicians' choice of standard of care has been initiated in the second-line setting (NCT02967770).
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Affiliation(s)
- Anteneh A Tesfaye
- Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
| | - Hongkun Wang
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia
| | - Marion L Hartley
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia
| | - Aiwu Ruth He
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia
| | - Louis Weiner
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia
| | - Nina Gabelia
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia
| | - Lana Kapanadze
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia
| | - Muhammad Shezad
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia
| | - Jonathan R Brody
- Department of Surgery, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - John L Marshall
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia
| | - Michael J Pishvaian
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia
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Elander NO, Aughton K, Ghaneh P, Neoptolemos JP, Palmer DH, Cox TF, Campbell F, Costello E, Halloran CM, Mackey JR, Scarfe AG, Valle JW, McDonald AC, Carter R, Tebbutt NC, Goldstein D, Shannon J, Dervenis C, Glimelius B, Deakin M, Charnley RM, Anthoney A, Lerch MM, Mayerle J, Oláh A, Büchler MW, Greenhalf W. Intratumoural expression of deoxycytidylate deaminase or ribonuceotide reductase subunit M1 expression are not related to survival in patients with resected pancreatic cancer given adjuvant chemotherapy. Br J Cancer 2018; 118:1084-1088. [PMID: 29523831 PMCID: PMC5931097 DOI: 10.1038/s41416-018-0005-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 01/04/2018] [Accepted: 01/04/2018] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Deoxycytidylate deaminase (DCTD) and ribonucleotide reductase subunit M1 (RRM1) are potential prognostic and predictive biomarkers for pyrimidine-based chemotherapy in pancreatic adenocarcinoma. METHODS Immunohistochemical staining of DCTD and RRM1 was performed on tissue microarrays representing tumour samples from 303 patients in European Study Group for Pancreatic Cancer (ESPAC)-randomised adjuvant trials following pancreatic resection, 272 of whom had received gemcitabine or 5-fluorouracil with folinic acid in ESPAC-3(v2), and 31 patients from the combined ESPAC-3(v1) and ESPAC-1 post-operative pure observational groups. RESULTS Neither log-rank testing on dichotomised strata or Cox proportional hazard regression showed any relationship of DCTD or RRM1 expression levels to survival overall or by treatment group. CONCLUSIONS Expression of either DCTD or RRM1 was not prognostic or predictive in patients with pancreatic adenocarcinoma who had had post-operative chemotherapy with either gemcitabine or 5-fluorouracil with folinic acid.
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Affiliation(s)
- N O Elander
- Cancer Research U.K. Liverpool Cancer Trials Unit, University of Liverpool, Liverpool, UK
| | - K Aughton
- Cancer Research U.K. Liverpool Cancer Trials Unit, University of Liverpool, Liverpool, UK
| | - P Ghaneh
- Cancer Research U.K. Liverpool Cancer Trials Unit, University of Liverpool, Liverpool, UK
| | - J P Neoptolemos
- Cancer Research U.K. Liverpool Cancer Trials Unit, University of Liverpool, Liverpool, UK
| | - D H Palmer
- Cancer Research U.K. Liverpool Cancer Trials Unit, University of Liverpool, Liverpool, UK
| | - T F Cox
- Cancer Research U.K. Liverpool Cancer Trials Unit, University of Liverpool, Liverpool, UK
| | - F Campbell
- Cancer Research U.K. Liverpool Cancer Trials Unit, University of Liverpool, Liverpool, UK
| | - E Costello
- Cancer Research U.K. Liverpool Cancer Trials Unit, University of Liverpool, Liverpool, UK
| | - C M Halloran
- Cancer Research U.K. Liverpool Cancer Trials Unit, University of Liverpool, Liverpool, UK
| | - J R Mackey
- Cross Cancer Institute and University of Alberta, Edmonton, Canada
| | - A G Scarfe
- Cross Cancer Institute and University of Alberta, Edmonton, Canada
| | - J W Valle
- University of Manchester/The Christie NHS Foundation Trust, Manchester, UK
| | - A C McDonald
- The Beatson West of Scotland Cancer Centre, Glasgow, UK
| | - R Carter
- Glasgow Royal Infirmary, Glasgow, UK
| | | | - D Goldstein
- Prince of Wales hospital and Clinical School, University of New South Wales, Sydney, NSW, Australia
| | - J Shannon
- Nepean Cancer Centre and University of Sydney, Camperdown, NSW, Australia
| | | | - B Glimelius
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - M Deakin
- University Hospital, North Staffordshire, Staffordshire, UK
| | | | - A Anthoney
- St James's University Hospital, Leeds, UK
| | - M M Lerch
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - J Mayerle
- Department of Medicine II, University Hospital of the Ludwig-Maximilians-University Munich, Munich, Germany
| | - A Oláh
- The Petz Aladar Hospital, Gyor, Hungary
| | - M W Büchler
- Department of Surgery, University of Heidelberg, Heidelberg, Germany
| | - W Greenhalf
- Cancer Research U.K. Liverpool Cancer Trials Unit, University of Liverpool, Liverpool, UK.
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Chen Z, Zheng Y, Shi Y, Cui Z. Overcoming tumor cell chemoresistance using nanoparticles: lysosomes are beneficial for (stearoyl) gemcitabine-incorporated solid lipid nanoparticles. Int J Nanomedicine 2018; 13:319-336. [PMID: 29391792 PMCID: PMC5768424 DOI: 10.2147/ijn.s149196] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Despite recent advances in targeted therapies and immunotherapies, chemotherapy using cytotoxic agents remains an indispensable modality in cancer treatment. Recently, there has been a growing emphasis in using nanomedicine in cancer chemotherapy, and several nanomedicines have already been used clinically to treat cancers. There is evidence that formulating small molecular cancer chemotherapeutic agents into nanomedicines significantly modifies their pharmacokinetics and often improves their efficacy. Importantly, cancer cells often develop resistance to chemotherapy, and formulating anticancer drugs into nanomedicines also helps overcome chemoresistance. In this review, we briefly describe the different classes of cancer chemotherapeutic agents, their mechanisms of action and resistance, and evidence of overcoming the resistance using nanomedicines. We then emphasize on gemcitabine and our experience in discovering the unique (stearoyl) gemcitabine solid lipid nanoparticles that are effective against tumor cells resistant to gemcitabine and elucidate the underlying mechanisms. It seems that lysosomes, which are an obstacle in the delivery of many drugs, are actually beneficial for our (stearoyl) gemcitabine solid lipid nanoparticles to overcome tumor cell resistance to gemcitabine.
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Affiliation(s)
- Zhe Chen
- Inner Mongolia Key Lab of Molecular Biology, School of Basic Medical Sciences, Inner Mongolia Medical University, Hohhot, Inner Mongolia, China
| | - Yuanqiang Zheng
- Inner Mongolia Key Lab of Molecular Biology, School of Basic Medical Sciences, Inner Mongolia Medical University, Hohhot, Inner Mongolia, China
| | - Yanchun Shi
- Inner Mongolia Key Lab of Molecular Biology, School of Basic Medical Sciences, Inner Mongolia Medical University, Hohhot, Inner Mongolia, China
| | - Zhengrong Cui
- Inner Mongolia Key Lab of Molecular Biology, School of Basic Medical Sciences, Inner Mongolia Medical University, Hohhot, Inner Mongolia, China.,Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA
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8
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Han QL, Zhou YH, Lyu Y, Yan H, Dai GH. Effect of ribonucleotide reductase M1 expression on overall survival in patients with pancreatic cancer receiving gemcitabine chemotherapy: A literature-based meta-analysis. J Clin Pharm Ther 2017; 43:163-169. [PMID: 29214667 DOI: 10.1111/jcpt.12655] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Accepted: 11/07/2017] [Indexed: 12/21/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE The prognostic value of ribonucleotide reductase M1 (RRM1) in patients with pancreatic cancer receiving gemcitabine chemotherapy has been evaluated in several studies. However, the conclusions remain controversial. METHODS By searching the PubMed and Embase databases, we conducted a meta-analysis to evaluate the prognostic significance of RRM1 expression in patients with pancreatic cancer receiving gemcitabine chemotherapy. Studies were pooled, and the hazard ratio (HR) and its corresponding 95% confidence interval (CI) were calculated. RESULTS Nine relevant articles were included for this meta-analysis study. Our results revealed that the high-RRM1 expression patients had significantly poorer overall survival (HR = 1.70, 95% CI = 1.33-2.16, Pheterogeneity = .061, I2 = 44.8%) and disease-free survival (HR = 1.84, 95% CI = 1.56-2.18, Pheterogeneity = .669, I2 = 0%) than the low-RRM1 expression patients. Furthermore, a statistically significant association between RRM1 expression and OS was found among both Japanese (HR = 1.80, 95% CI = 1.36-2.37, Pheterogeneity = .843, I2 = 0%) and American patients (HR = 1.76, 95% CI = 1.60-1.94, Pheterogeneity = .439, I2 = 0%). WHAT IS NEW AND CONCLUSION In conclusion, the expression of RRM1 can be considered a predictor of poor survival in patients with pancreatic cancer receiving gemcitabine chemotherapy. RRM1 expression assessment could provide more detailed information for patients with pancreatic cancer and could be used to optimize therapeutic schemes.
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Affiliation(s)
- Q L Han
- Department of Medical Oncology, Chinese PLA General Hospital & Chinese PLA Medical Academy, Beijing, China
| | - Y H Zhou
- Department of Medical Oncology, Chinese PLA General Hospital & Chinese PLA Medical Academy, Beijing, China
| | - Y Lyu
- Department of Medical Oncology, Chinese PLA General Hospital & Chinese PLA Medical Academy, Beijing, China
| | - H Yan
- Department of Medical Oncology, Chinese PLA General Hospital & Chinese PLA Medical Academy, Beijing, China
| | - G H Dai
- Department of Medical Oncology, Chinese PLA General Hospital & Chinese PLA Medical Academy, Beijing, China
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Hesler RA, Huang JJ, Starr MD, Treboschi VM, Bernanke AG, Nixon AB, McCall SJ, White RR, Blobe GC. TGF-β-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3. Carcinogenesis 2017; 37:1041-1051. [PMID: 27604902 DOI: 10.1093/carcin/bgw093] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 08/16/2016] [Indexed: 12/18/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer in part due to inherent resistance to chemotherapy, including the first-line drug gemcitabine. Although low expression of the nucleoside transporters hENT1 and hCNT3 that mediate cellular uptake of gemcitabine has been linked to gemcitabine resistance, the mechanisms regulating their expression in the PDAC tumor microenvironment are largely unknown. Here, we report that the matricellular protein cysteine-rich angiogenic inducer 61 (CYR61) negatively regulates the nucleoside transporters hENT1 and hCNT3. CRISPR/Cas9-mediated knockout of CYR61 increased expression of hENT1 and hCNT3, increased cellular uptake of gemcitabine and sensitized PDAC cells to gemcitabine-induced apoptosis. In PDAC patient samples, expression of hENT1 and hCNT3 negatively correlates with expression of CYR61 . We demonstrate that stromal pancreatic stellate cells (PSCs) are a source of CYR61 within the PDAC tumor microenvironment. Transforming growth factor-β (TGF-β) induces the expression of CYR61 in PSCs through canonical TGF-β-ALK5-Smad2/3 signaling. Activation of TGF-β signaling or expression of CYR61 in PSCs promotes resistance to gemcitabine in PDAC cells in an in vitro co-culture assay. Our results identify CYR61 as a TGF-β-induced stromal-derived factor that regulates gemcitabine sensitivity in PDAC and suggest that targeting CYR61 may improve chemotherapy response in PDAC patients.
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Affiliation(s)
| | | | - Mark D Starr
- Division of Medical Oncology, Department of Medicine
| | | | | | | | | | - Rebekah R White
- Department of Surgery, Duke University, B354 LSRC Research Drive , Box 91004, Durham, NC 27708 , USA
| | - Gerard C Blobe
- Department of Pharmacology and Cancer Biology.,Division of Medical Oncology, Department of Medicine
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10
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Aoyama T, Miyagi Y, Murakawa M, Yamaoku K, Atsumi Y, Shiozawa M, Ueno M, Morimoto M, Oshima T, Yukawa N, Yoshikawa T, Rino Y, Masuda M, Morinaga S. Clinical implications of ribonucleotide reductase subunit M1 in patients with pancreatic cancer who undergo curative resection followed by adjuvant chemotherapy with gemcitabine. Oncol Lett 2017; 13:3423-3430. [PMID: 28521448 PMCID: PMC5431334 DOI: 10.3892/ol.2017.5935] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Accepted: 02/07/2017] [Indexed: 12/12/2022] Open
Abstract
To the best of our knowledge, the clinical implications of using ribonucleoside reductase subunit M1 (RRM1) in patients who undergo curative resection and adjuvant chemotherapy have not been established. In the present study, the clinical data from 101 consecutive patients who underwent macroscopically curative resection, and who received adjuvant gemcitabine chemotherapy for pancreatic cancer at the Kanagawa Cancer Centre (Yokohama, Kanagawa, Japan) between April 2005 and December 2014 were retrospectively analyzed. The association between the RRM1 status and survival and clinicopathological features were assessed. Of the 101 patients, 41 patients expressed high levels of RRM1 expression (40.6%). Although a significant difference was observed in lymphatic invasion, there was no difference between the two groups with regard to any other clinicopathological parameters. The median follow-up period was 67.3 months. There was a significant difference between the recurrence-free survival (RFS) rates at 5 years after surgery, which were 12.9 and 0% in the high RRM1 and low RRM1 groups, respectively (P=0.042). Furthermore, there was a significant difference in the 5-year overall survival (OS) rates following surgery, which were 5.1 and 21.5% in the high RRM1 and low RRM1 groups, respectively (P=0.015). The results of the present study indicated that out of the factors assessed, RRM1 was the most important prognostic factor for OS and RFS in patients with pancreatic cancer who underwent curative resection followed by adjuvant chemotherapy with gemcitabine. Adjuvant chemotherapy with gemcitabine alone may be insufficient for the treatment of pancreatic cancer, particularly in patients with relevant risk factors.
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Affiliation(s)
- Toru Aoyama
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Kanagawa 241-8515, Japan
| | - Yohei Miyagi
- Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Kanagawa 241-8515, Japan
| | - Masaaki Murakawa
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Kanagawa 241-8515, Japan
| | - Koichiro Yamaoku
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Kanagawa 241-8515, Japan
| | - Yosuke Atsumi
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Kanagawa 241-8515, Japan
| | - Manabu Shiozawa
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Kanagawa 241-8515, Japan
| | - Makoto Ueno
- Department of Hepatobiliary Pancreatic Oncology, Kanagawa Cancer Center, Yokohama, Kanagawa 241-8515, Japan
| | - Manabu Morimoto
- Department of Hepatobiliary Pancreatic Oncology, Kanagawa Cancer Center, Yokohama, Kanagawa 241-8515, Japan
| | - Takashi Oshima
- Department of Surgery, Yokohama City University, Yokohama, Kanagawa 236-0004, Japan
| | - Norio Yukawa
- Department of Surgery, Yokohama City University, Yokohama, Kanagawa 236-0004, Japan
| | - Takaki Yoshikawa
- Department of Surgery, Yokohama City University, Yokohama, Kanagawa 236-0004, Japan
| | - Yasushi Rino
- Department of Surgery, Yokohama City University, Yokohama, Kanagawa 236-0004, Japan
| | - Munetaka Masuda
- Department of Surgery, Yokohama City University, Yokohama, Kanagawa 236-0004, Japan
| | - Soichiro Morinaga
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Kanagawa 241-8515, Japan
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11
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Chen S, Wang Y, Zhang WL, Dong MS, Zhang JH. Sclareolide enhances gemcitabine‑induced cell death through mediating the NICD and Gli1 pathways in gemcitabine‑resistant human pancreatic cancer. Mol Med Rep 2017; 15:1461-1470. [PMID: 28259943 PMCID: PMC5365005 DOI: 10.3892/mmr.2017.6182] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Accepted: 11/11/2016] [Indexed: 12/13/2022] Open
Abstract
Pancreatic cancer is a type of cancer, which rapidly develops resistance to chemotherapy. Gemcitabine is the treatment used clinically, however, gemcitabine resistance leads to limited efficacy and patient survival rates of only a few months following diagnosis. The aim of the present study was to investigate the mechanisms underlying gemcitabine resistance in pancreatic cancer and to select targeted agents combined with gemcitabine to promote the treatment of pancreatic cancer. Panc-1 and ASPC-1 human pancreatic cancer cells (HPCCs) were used to establish the experimental model, and HPCCs were exposed to gemcitabine of serially increased concentrations to generate gemcitabine-resistant cells (GR-HPCCs). The anticancer effect of gemcitabine combined with sclareolide was then assessed. Epithelial to mesenchymal transition (EMT), human equilibrative nucleoside transporter 1 (hENT1) and ribonucleoside diphosphate reductase 1 (RRM1) were detected in the HPCCs and GR-HPCCs, and the mechanisms were investigated. Sclareolide resensitized the GR-HPCCs to gemcitabine. The expression levels of hENT1 and RRM1 were lower and higher, respectively, in GR-HPCCs, compared with HPCCs. Sclareolide upregulated hENT1, downregulated RRM1 and inhibited gemcitabine-induced EMT through the TWIST1/Slug pathway in the GR-HPCCs. In addition, sclareolide mediated the NOTCH 1 intracellular cytoplasmic domain (NICD)/glioma-associated oncogene 1 (Gli1) pathway, which triggered TWIST1/Slug-hENT1/RRM1 signaling and resensitized GR-HPCCs to gemcitabine. Finally, sclareolide resensitized GR-HPCCs to gemcitabine through inducing apoptosis; in vivo, the co-administraion of sclareolide and gemcitabine effectively suppressed tumor growth. Sclareolide may be a novel agent in combination with gemcitabine for the treatment of gemcitabine-resistant pancreatic cancer, which resensitizes GR-HPCCs to gemcitabine through mediating NICD and Gli1.
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Affiliation(s)
- Sheng Chen
- Department of General Surgery, The General Hospital of the PLA Rocket Force, Beijing 100088, P.R. China
| | - Ye Wang
- Department of Pathology, China‑Japan Friendship Hospital, Beijing 100029, P.R. China
| | - Wen-Long Zhang
- Department of General Surgery, The General Hospital of the PLA Rocket Force, Beijing 100088, P.R. China
| | - Mao-Sheng Dong
- Department of General Surgery, The General Hospital of the PLA Rocket Force, Beijing 100088, P.R. China
| | - Jian-Hua Zhang
- Department of General Surgery, The General Hospital of the PLA Rocket Force, Beijing 100088, P.R. China
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12
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Matsumura N, Nakamura Y, Kohjimoto Y, Nishizawa S, Kikkawa K, Iba A, Kodama Y, Hara I. Overexpression of ribonucleotide reductase subunit M1 protein predicts shorter survival in metastatic bladder cancer patients treated with gemcitabine-containing combination chemotherapy. Int J Urol 2017; 24:230-235. [PMID: 28066957 DOI: 10.1111/iju.13274] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2016] [Accepted: 11/14/2016] [Indexed: 01/06/2023]
Abstract
OBJECTIVES To identify biomarkers predicting prognosis in bladder cancer patients undergoing the gemcitabine and cisplatin regimen. METHODS We studied 52 patients with metastatic bladder cancer treated with the gemcitabine and cisplatin regimen by evaluating the relationship between the expression of two biomarkers, ribonucleotide reductase subunit M1 and excision repair cross complementing 1, by immunohistochemistry and clinical outcomes. RESULTS The patients with low expression of ribonucleotide reductase subunit M1 showed a higher objective response rate by the gemcitabine and cisplatin regimen than those with high expression of ribonucleotide reductase subunit M1 (80.0% and 45.5%, respectively). No differences were observed according to the expression level of excision repair cross complementing 1. Low expression of ribonucleotide reductase subunit M1 significantly prolonged overall survival and progression-free survival compared with the high expression group. Low expression of excision repair cross complementing 1 tended to prolong overall survival and progression-free survival, but there were no significant differences (P = 0.07 and 0.10, respectively). Multivariate analysis showed that the expression of ribonucleotide reductase subunit M1 was the only independent prognostic factor (P = 0.012). CONCLUSIONS The expressions of ribonucleotide reductase subunit M1 seem to be associated with clinical response and survival in patients with metastatic bladder cancer treated with gemcitabine and cisplatin-based chemotherapy.
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Affiliation(s)
| | - Yasushi Nakamura
- Department of Clinical Laboratory Medicine, Wakayama Medical University, Wakayama, Japan
| | - Yasuo Kohjimoto
- Department of Urology, Wakayama Medical University, Wakayama, Japan
| | | | - Kazuro Kikkawa
- Department of Urology, Wakayama Medical University, Wakayama, Japan
| | - Akinori Iba
- Department of Urology, Wakayama Medical University, Wakayama, Japan
| | | | - Isao Hara
- Department of Urology, Wakayama Medical University, Wakayama, Japan
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13
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Abstract
OBJECTIVES There is a need for validated predictive markers of gemcitabine response to guide precision medicine treatment in pancreatic cancer. We previously validated human equilibrative nucleoside transporter 1 as a predictive marker of gemcitabine treatment response using Radiation Therapy Oncology Group 9704. Controversy exists about the predictive value of gemcitabine metabolism pathway biomarkers: deoxycytidine kinase (DCK), ribonucleotide reductase 1 (RRM1), RRM2, and p53R2. METHODS Radiation Therapy Oncology Group 9704 prospectively randomized 538 patients after pancreatic resection to receive either 5-fluorouracil or gemcitabine. Tumor DCK, RRM1, RRM2, and p53R protein expressions were analyzed using a tissue microarray and immunohistochemistry and correlated with treatment outcome (overall survival and disease-free survival) by unconditional logistic regression analysis. RESULTS There were 229 patients eligible for analysis from both the 5-fluorouracil and gemcitabine arms. Only RRM2 protein expression, and not DCK, RRM1, or p53R2 protein expression, was associated with survival in the gemcitabine treatment arm. CONCLUSIONS Despite limited data from other nonrandomized treatment data, our data do not support the predictive value of DCK, RRM1, or p53R2. Efforts should focus on human equilibrative nucleoside transporter 1 and possibly RRM2 as valid predictive markers of the treatment response of gemcitabine in pancreatic cancer.
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14
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D'Aronzo M, Vinciguerra M, Mazza T, Panebianco C, Saracino C, Pereira SP, Graziano P, Pazienza V. Fasting cycles potentiate the efficacy of gemcitabine treatment in in vitro and in vivo pancreatic cancer models. Oncotarget 2016; 6:18545-57. [PMID: 26176887 PMCID: PMC4621909 DOI: 10.18632/oncotarget.4186] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2015] [Accepted: 05/12/2015] [Indexed: 12/18/2022] Open
Abstract
Background/aims Pancreatic cancer (PC) is ranked as the fourth leading cause of cancer-related deaths worldwide. Despite recent advances in treatment options, a modest impact on the outcome of the disease is observed so far. Short-term fasting cycles have been shown to potentiate the efficacy of chemotherapy against glioma. The aim of this study was to assess the effect of fasting cycles on the efficacy of gemcitabine, a standard treatment for PC patients, in vitro and in an in vivo pancreatic cancer mouse xenograft model. Materials and Methods BxPC-3, MiaPaca-2 and Panc-1 cells were cultured in standard and fasting mimicking culturing condition to evaluate the effects of gemcitabine. Pancreatic cancer xenograft mice were subjected to 24h starvation prior to gemcitabine injection to assess the tumor volume and weight as compared to mice fed ad libitum. Results Fasted pancreatic cancer cells showed increased levels of equilibrative nucleoside transporter (hENT1), the transporter of gemcitabine across the cell membrane, and decreased ribonucleotide reductase M1 (RRM1) levels as compared to those cultured in standard medium. Gemcitabine was more effective in inducing cell death on fasted cells as compared to controls. Consistently, xenograft pancreatic cancer mice subjected to fasting cycles prior to gemcitabine injection displayed a decrease of more than 40% in tumor growth. Conclusion Fasting cycles enhance gemcitabine effect in vitro and in the in vivo PC xenograft mouse model. These results suggest that restrictive dietary interventions could enhance the efficacy of existing cancer treatments in pancreatic cancer patients.
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Affiliation(s)
- Martina D'Aronzo
- Gastroenterology Unit, I.R.C.C.S. "Casa Sollievo della Sofferenza" Hospital San Giovanni Rotondo (FG), Italy
| | - Manlio Vinciguerra
- Gastroenterology Unit, I.R.C.C.S. "Casa Sollievo della Sofferenza" Hospital San Giovanni Rotondo (FG), Italy.,Institute for Liver and Digestive Health, Division of Medicine, University College London (UCL), London, United Kingdom.,School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom
| | - Tommaso Mazza
- Bioinformatics Unit, I.R.C.C.S. "Casa Sollievo della Sofferenza", Istituto Mendel, Italy
| | - Concetta Panebianco
- Gastroenterology Unit, I.R.C.C.S. "Casa Sollievo della Sofferenza" Hospital San Giovanni Rotondo (FG), Italy
| | - Chiara Saracino
- Gastroenterology Unit, I.R.C.C.S. "Casa Sollievo della Sofferenza" Hospital San Giovanni Rotondo (FG), Italy
| | - Stephen P Pereira
- Institute for Liver and Digestive Health, Division of Medicine, University College London (UCL), London, United Kingdom
| | - Paolo Graziano
- Pathology Unit, I.R.C.C.S. "Casa Sollievo della Sofferenza" Hospital San Giovanni Rotondo (FG), Italy
| | - Valerio Pazienza
- Gastroenterology Unit, I.R.C.C.S. "Casa Sollievo della Sofferenza" Hospital San Giovanni Rotondo (FG), Italy
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15
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Fontana A, Copetti M, Di Gangi IM, Mazza T, Tavano F, Gioffreda D, Mattivi F, Andriulli A, Vrhovsek U, Pazienza V. Development of a metabolites risk score for one-year mortality risk prediction in pancreatic adenocarcinoma patients. Oncotarget 2016; 7:8968-78. [PMID: 26840268 PMCID: PMC4891018 DOI: 10.18632/oncotarget.7108] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Accepted: 11/29/2015] [Indexed: 02/06/2023] Open
Abstract
PURPOSE Survival among patients with adenocarcinoma pancreatic cancer (PDCA) is highly variable, which ranges from 0% to 20% at 5 years. Such a wide range is due to tumor size and stage, as well other patients' characteristics. We analyzed alterations in the metabolomic profile, of PDCA patients, which are potentially predictive of patient's one-year mortality. EXPERIMENTAL DESIGN A targeted metabolomic assay was conducted on serum samples of patients diagnosed with pancreatic cancer. Statistical analyses were performed only for those 27 patients with information on vital status at follow-up and baseline clinical features. Random Forest analysis was performed to identify all metabolites and clinical variables with the best capability to predict patient's mortality risk at one year. Regression coefficients were estimated from multivariable Weibull survival model, which included the most associated metabolites. Such coefficients were used as weights to build a metabolite risk score (MRS) which ranged from 0 (lowest mortality risk) to 1 (highest mortality risk). The stability of these weights were evaluated performing 10,000 bootstrap resamplings. RESULTS MRS was built as a weighted linear combination of the following five metabolites: Valine (HR = 0.62, 95%CI: 0.11-1.71 for each standard deviation (SD) of 98.57), Sphingomyeline C24:1 (HR = 2.66, 95%CI: 1.30-21.09, for each SD of 20.67), Lysine (HR = 0.36, 95%CI: 0.03-0.77, for each SD of 51.73), Tripentadecanoate TG15 (HR = 0.25, 95%CI: 0.01-0.82, for each SD of 2.88) and Symmetric dimethylarginine (HR = 2.24, 95%CI: 1.28-103.08, for each SD of 0.62), achieving a very high discrimination ability (survival c-statistic of 0.855, 95%CI: 0.816-0.894). Such association was still present even after adjusting for the most associated clinical variables (confounders). CONCLUSIONS The mass spectrometry-based metabolomic profiling of serum represents a valid tool for discovering novel candidate biomarkers with prognostic ability to predict one-year mortality risk in patients with pancreatic adenocarcinoma.
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Affiliation(s)
- Andrea Fontana
- Unit of Biostatistics I.R.C.C.S. “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo (FG), Italy
| | - Massimiliano Copetti
- Unit of Biostatistics I.R.C.C.S. “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo (FG), Italy
| | - Iole Maria Di Gangi
- Department of Food Quality and Nutrition, Research and Innovation Centre, Fondazione Edmund Mach (FEM), San Michele all'Adige, Italy
| | - Tommaso Mazza
- Unit of Bioinformatics, I.R.C.C.S. “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo (FG), Italy
| | - Francesca Tavano
- Gastroenterology Unit, I.R.C.C.S. “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo (FG), Italy
| | - Domenica Gioffreda
- Gastroenterology Unit, I.R.C.C.S. “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo (FG), Italy
| | - Fulvio Mattivi
- Department of Food Quality and Nutrition, Research and Innovation Centre, Fondazione Edmund Mach (FEM), San Michele all'Adige, Italy
| | - Angelo Andriulli
- Gastroenterology Unit, I.R.C.C.S. “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo (FG), Italy
| | - Urska Vrhovsek
- Department of Food Quality and Nutrition, Research and Innovation Centre, Fondazione Edmund Mach (FEM), San Michele all'Adige, Italy
| | - Valerio Pazienza
- Gastroenterology Unit, I.R.C.C.S. “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo (FG), Italy
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16
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Sun L, Lu J, Niu Z, Ding K, Bi D, Liu S, Li J, Wu F, Zhang H, Zhao Z, Ding S. A Potent Chemotherapeutic Strategy with Eg5 Inhibitor against Gemcitabine Resistant Bladder Cancer. PLoS One 2015; 10:e0144484. [PMID: 26658059 PMCID: PMC4675549 DOI: 10.1371/journal.pone.0144484] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 11/19/2015] [Indexed: 11/30/2022] Open
Abstract
Development of resistance to gemcitabine is a major concern in bladder cancer therapy, and the mechanism remains unclear. Eg5 has been recently identified as an attractive target in cancer chemotherapy, so novel targeted chemotherapy with Eg5 inhibitor is expected to improve the anticancer effect in gemcitabine-resistant bladder cancer. In this research, RT112-Gr cells were 350-fold less sensitive to gemcitabine than the parental cell lines, while KU7-Gr cells were 15-fold less sensitive to gemcitabine than the parental cell lines. Human OneArray Microarray analysis was performed to obtain broad spectrum information about the genes differentially expressed in RT112 and RT112-Gr cells. The anti-proliferative activity of S(MeO)TLC, an Eg5 inhibitor, was analyzed in RT112-Gr cell lines using a cell viability assay. Furthermore, the inhibitory effect was evaluated in vivo using subcutaneous xenograft tumor model. According to the result of Human OneArray GeneChip, RRM1 and RRM2 were up-regulated, while there was no significant change in Eg5. Trypan blue staining confirmed that in S(MeO)TLC and Gemcitabine combining S(MeO)TLC group cell viability were significantly decreased in RT112-Gr cells as compared with other groups. S(MeO)TLC and S(MeO)TLC+gemcitabine groups prominently suppressed tumor growth in comparison with other groups' in vivo. There were no significant differences in S(MeO)TLC and gemcitabine+S(MeO)TLC group in the effect of inhibition of bladder cancer in vivo and in vitro. Our data collectively demonstrated that S(MeO)TLC represents a novel strategy for the treatment of gemcitabine resistant bladder cancer.
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Affiliation(s)
- Liang Sun
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, ShanDong, China
- Department of Cardiac Surgery, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, ShanDong, China
| | - Jiaju Lu
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, ShanDong, China
| | - Zhihong Niu
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, ShanDong, China
| | - Kejia Ding
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, ShanDong, China
| | - Dongbin Bi
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, ShanDong, China
| | - Shuai Liu
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, ShanDong, China
| | - Jiamei Li
- Department of pathology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, ShanDong, China
| | - Fei Wu
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, ShanDong, China
| | - Hui Zhang
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, ShanDong, China
| | - Zuohui Zhao
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, ShanDong, China
| | - Sentai Ding
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, ShanDong, China
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17
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Abraham A, Varatharajan S, Karathedath S, Philip C, Lakshmi KM, Jayavelu AK, Mohanan E, Janet NB, Srivastava VM, Shaji RV, Zhang W, Abraham A, Viswabandya A, George B, Chandy M, Srivastava A, Mathews V, Balasubramanian P. RNA expression of genes involved in cytarabine metabolism and transport predicts cytarabine response in acute myeloid leukemia. Pharmacogenomics 2015; 16:877-90. [PMID: 26083014 DOI: 10.2217/pgs.15.44] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Variation in terms of outcome and toxic side effects of treatment exists among acute myeloid leukemia (AML) patients on chemotherapy with cytarabine (Ara-C) and daunorubicin (Dnr). Candidate Ara-C metabolizing gene expression in primary AML cells is proposed to account for this variation. METHODS Ex vivo Ara-C sensitivity was determined in primary AML samples using MTT assay. mRNA expression of candidate Ara-C metabolizing genes were evaluated by RQPCR analysis. Global gene expression profiling was carried out for identifying differentially expressed genes between exvivo Ara-C sensitive and resistant samples. RESULTS Wide interindividual variations in ex vivo Ara-C cytotoxicity were observed among samples from patients with AML and were stratified into sensitive, intermediately sensitive and resistant, based on IC50 values obtained by MTT assay. RNA expression of deoxycytidine kinase (DCK), human equilibrative nucleoside transporter-1 (ENT1) and ribonucleotide reductase M1 (RRM1) were significantly higher and cytidine deaminase (CDA) was significantly lower in ex vivo Ara-C sensitive samples. Higher DCK and RRM1 expression in AML patient's blast correlated with better DFS. Ara-C resistance index (RI), a mathematically derived quotient was proposed based on candidate gene expression pattern. Ara-C ex vivo sensitive samples were found to have significantly lower RI compared with resistant as well as samples from patients presenting with relapse. Patients with low RI supposedly highly sensitive to Ara-C were found to have higher incidence of induction death (p = 0.002; RR: 4.35 [95% CI: 1.69-11.22]). Global gene expression profiling undertaken to find out additional contributors of Ara-C resistance identified many apoptosis as well as metabolic pathway genes to be differentially expressed between Ara-C resistant and sensitive samples. CONCLUSION This study highlights the importance of evaluating expression of candidate Ara-C metabolizing genes in predicting ex vivo drug response as well as treatment outcome. RI could be a predictor of ex vivo Ara-C response irrespective of cytogenetic and molecular risk groups and a potential biomarker for AML treatment outcome and toxicity. Original submitted 22 December 2014; Revision submitted 9 April 2015.
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Affiliation(s)
- Ajay Abraham
- Department of Haematology, Christian Medical College, Vellore, India
| | | | | | - Chepsy Philip
- Department of Haematology, Christian Medical College, Vellore, India
| | - Kavitha M Lakshmi
- Department of Haematology, Christian Medical College, Vellore, India
| | | | | | - Nancy Beryl Janet
- Department of Haematology, Christian Medical College, Vellore, India
| | | | | | - Wei Zhang
- Department of Preventive Medicine, Northwestern University, Chicago, IL, USA
| | - Aby Abraham
- Department of Haematology, Christian Medical College, Vellore, India
| | - Auro Viswabandya
- Department of Haematology, Christian Medical College, Vellore, India
| | - Biju George
- Department of Haematology, Christian Medical College, Vellore, India
| | - Mammen Chandy
- Department of Haematology, Christian Medical College, Vellore, India
| | - Alok Srivastava
- Department of Haematology, Christian Medical College, Vellore, India
| | - Vikram Mathews
- Department of Haematology, Christian Medical College, Vellore, India
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18
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Goel G, Sun W. Novel approaches in the management of pancreatic ductal adenocarcinoma: potential promises for the future. J Hematol Oncol 2015; 8:44. [PMID: 25935754 PMCID: PMC4431030 DOI: 10.1186/s13045-015-0141-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Accepted: 04/21/2015] [Indexed: 02/08/2023] Open
Abstract
Despite a few breakthroughs in therapy for advanced disease in the recent years, pancreatic ductal adenocarcinoma continues to remain one of the most challenging human malignancies to treat. The overall prognosis for the majority of patients with pancreatic cancer is rather dismal, and therefore, more effective treatment options are being desperately sought. The practical goals of management are to improve the cure rates for patients with resectable disease, achieve a higher conversion rate of locally advanced tumor into potentially resectable disease, and finally, prolong the overall survival for those who develop metastatic disease. Our understanding of the complex genetic alterations, the implicated molecular pathways, and the role of desmoplastic stroma in pancreatic cancer tumorigenesis has increased several folds in the recent years. This has facilitated the development of novel therapeutic strategies against pancreatic cancer, some of which are currently under evaluation in ongoing preclinical and clinical studies. This review will summarize the existing treatment approaches for this devastating disease and also discuss the promising therapeutic approaches that are currently in different stages of clinical development.
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Affiliation(s)
- Gaurav Goel
- Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5150 Centre Avenue, Fifth Floor, Pittsburgh, PA, 15232, USA.
| | - Weijing Sun
- Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5150 Centre Avenue, Fifth Floor, Pittsburgh, PA, 15232, USA.
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Arensman MD, Telesca D, Lay AR, Kershaw KM, Wu N, Donahue TR, Dawson DW. The CREB-binding protein inhibitor ICG-001 suppresses pancreatic cancer growth. Mol Cancer Ther 2014; 13:2303-14. [PMID: 25082960 PMCID: PMC4188417 DOI: 10.1158/1535-7163.mct-13-1005] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer due in part to a lack of highly robust cytotoxic or molecular-based therapies. Recent studies investigating ligand-mediated Wnt/β-catenin signaling have highlighted its importance in pancreatic cancer initiation and progression, as well as its potential as a therapeutic target in PDAC. The small-molecule ICG-001 binds cAMP-responsive element binding (CREB)-binding protein (CBP) to disrupt its interaction with β-catenin and inhibit CBP function as a coactivator of Wnt/β-catenin-mediated transcription. Given its ability to inhibit Wnt/β-catenin-mediated transcription in vitro and in vivo, as well as its efficacy in preclinical models of colorectal cancer and other Wnt-driven diseases, we examined ICG-001 and its potential role as a therapeutic in PDAC. ICG-001 alone significantly inhibited anchorage-dependent and -independent growth of multiple PDAC lines, and augmented in vitro growth inhibition when used in combination with gemcitabine. ICG-001 had only variable modest effects on PDAC apoptosis and instead mediated PDAC growth inhibition primarily through robust induction of G₁ cell-cycle arrest. These effects, however, seemed decoupled from its inhibition of Wnt/β-catenin-mediated transcription. DNA microarrays performed on PDAC cells in the context of ICG-001 treatment revealed ICG-001 altered the expression of several genes with well-established roles in DNA replication and cell-cycle progression, including direct actions on SKP2 and CDKN1A. ICG-001 also significantly prolonged survival in an in vivo orthotopic xenograft model of PDAC, indicating ICG-001 or derived compounds that disrupt CBP activity are potentially useful small-molecule therapeutics for pancreatic cancer.
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Affiliation(s)
- Michael D Arensman
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Donatello Telesca
- Department of Biostatistics, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Anna R Lay
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Kathleen M Kershaw
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Nanping Wu
- Deparment of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Timothy R Donahue
- Deparment of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - David W Dawson
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California. Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, California.
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Kruger S, Haas M, Ormanns S, Bächmann S, Siveke JT, Kirchner T, Heinemann V, Boeck S. Translational research in pancreatic ductal adenocarcinoma: current evidence and future concepts. World J Gastroenterol 2014; 20:10769-77. [PMID: 25152580 PMCID: PMC4138457 DOI: 10.3748/wjg.v20.i31.10769] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2013] [Revised: 01/26/2014] [Accepted: 04/08/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDA) is one of the major causes for cancer death worldwide. Treatment of metastatic disease remains challenging as only certain patients benefit from advances made with the intensified chemotherapy regimen folinic acid, irinotecan and oxaliplatin, the epidermal growth factor receptor inhibitor erlotinib or the recently FDA-approved nab-paclitaxel. Up to date, no established approach for prediction of treatment response or specific treatment allocation exists. Translational research was able to identify a number of potential biomarkers that might help to improve the dismal prognosis of PDA by facilitating upfront treatment allocation. This topic highlight is focused on current evidence on potential biomarkers for tumor biology, prognosis and prediction of treatment efficacy.
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Lamarca A, Feliu J. Pancreatic biomarkers: Could they be the answer? World J Gastroenterol 2014; 20:7819-7829. [PMID: 24976720 PMCID: PMC4069311 DOI: 10.3748/wjg.v20.i24.7819] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 12/11/2013] [Accepted: 01/15/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDA) is known for its poor prognosis. Most of the patients are diagnosed with advanced stages, when no curative treatment is available. Currently, despite extensive clinical research on PDA, the median overall survival remains short. Diagnosis delay and primary chemo-resistance due to its intrinsic biological nature may explain the challenges to improve our results. Our knowledge about the molecular biology of PDA has exponentially increased during the last decades and its use for the development of biomarkers could help to reach better results in the clinical setting. These biomarkers could be the clue for the improvement in PDA clinical research by earlier detection strategies with diagnostic biomarkers, and by an individualization of treatment approach with prognostic and predictive biomarkers. This review summarizes the current knowledge about the molecular biology of PDA and the status of the most important prognostic and predictive biomarkers.
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Wu GQ, Liu NN, Xue XL, Cai LT, Zhang C, Qu QR, Yan XJ. Multiplex Real-time PCR for RRM1, XRCC1, TUBB3 and TS mRNA for Prediction of Response of Non-small Cell Lung Cancer to Chemoradiotherapy. Asian Pac J Cancer Prev 2014; 15:4153-8. [DOI: 10.7314/apjcp.2014.15.10.4153] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Jordheim LP, Dumontet C. Do hENT1 and RRM1 predict the clinical benefit of gemcitabine in pancreatic cancer? Biomark Med 2014; 7:663-71. [PMID: 23905902 DOI: 10.2217/bmm.13.48] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Gemcitabine is a nucleoside analog that is indicated in the treatment of pancreatic cancer. In order to provide a better use of this drug, the search for immunohistological markers is a hot topic in the field of pancreatic cancer. In particular, the use of nucleoside transporter hENT1 and the intracellular target of gemcitabine RRM1 are current subjects for discussion. We have analyzed the majority of studies of hENT1 and RRM1 on pancreatic cancer, and will discuss the further directions that might be followed in order to integrate these proteins in routine clinical practice. The data that is currently available would benefit from the completion of well-designed randomized trials in order to confirm the clinical value of hENT1 and RRM1 as biomarkers in pancreatic cancer patients.
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Aird KM, Zhang R. Nucleotide metabolism, oncogene-induced senescence and cancer. Cancer Lett 2014; 356:204-10. [PMID: 24486217 DOI: 10.1016/j.canlet.2014.01.017] [Citation(s) in RCA: 104] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Revised: 01/06/2014] [Accepted: 01/22/2014] [Indexed: 01/28/2023]
Abstract
Senescence is defined as a stable cell growth arrest. Oncogene-induced senescence (OIS) occurs when an activated oncogene is expressed in a normal cell. OIS acts as a bona fide tumor suppressor mechanism by driving stable growth arrest of cancer progenitor cells harboring the initial oncogenic hit. OIS is often characterized by aberrant DNA replication and the associated DNA damage response. Nucleotides, in particular deoxyribonucleotide triphosphates (dNTPs), are necessary for both DNA replication and repair. Imbalanced dNTP pools play a role in a number of human diseases, including during the early stages of cancer development. This review will highlight what is currently known about the role of decreased nucleotide metabolism in OIS, how nucleotide metabolism leads to transformation and tumor progression, and how this pathway can be targeted as a cancer therapeutic by inducing senescence of cancer cells.
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Affiliation(s)
- Katherine M Aird
- Gene Expression and Regulation Program, The Wistar Institute Cancer Center, The Wistar Institute, Philadelphia, PA 19104, United States
| | - Rugang Zhang
- Gene Expression and Regulation Program, The Wistar Institute Cancer Center, The Wistar Institute, Philadelphia, PA 19104, United States.
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Zhang X, Jin FS, Zhang LG, Chen RX, Zhao JH, Wang YN, Wang EF, Jiang ZD. Predictive and Prognostic Roles of Ribonucleotide Reductase M1 in Patients with Pancreatic Cancer Treated with Gemcitabine: A Meta-analysis. Asian Pac J Cancer Prev 2013; 14:4261-5. [DOI: 10.7314/apjcp.2013.14.7.4261] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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26
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Wonganan P, Lansakara-P DSP, Zhu S, Holzer M, Sandoval MA, Warthaka M, Cui Z. Just getting into cells is not enough: mechanisms underlying 4-(N)-stearoyl gemcitabine solid lipid nanoparticle's ability to overcome gemcitabine resistance caused by RRM1 overexpression. J Control Release 2013; 169:17-27. [PMID: 23570983 DOI: 10.1016/j.jconrel.2013.03.033] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2012] [Revised: 03/28/2013] [Accepted: 03/31/2013] [Indexed: 10/27/2022]
Abstract
Gemcitabine is a deoxycytidine analog that is widely used in the chemotherapy of many solid tumors. However, acquired tumor cell resistance often limits its use. Previously, we discovered that 4-(N)-stearoyl gemcitabine solid lipid nanoparticles (4-(N)-GemC18-SLNs) can overcome multiple acquired gemcitabine resistance mechanisms, including RRM1 overexpression. The present study was designed to elucidate the mechanisms underlying the 4-(N)-GemC18-SLNs' ability to overcome gemcitabine resistance. The 4-(N)-GemC18 in the 4-(N)-GemC18-SLNs entered tumor cells due to clathrin-mediated endocytosis of the 4-(N)-GemC18-SLNs into the lysosomes of the cells, whereas the 4-(N)-GemC18 alone in solution entered cells by diffusion. We substantiated that it is the way the 4-(N)-GemC18-SLNs deliver the 4-(N)-GemC18 into tumor cells that allows the gemcitabine hydrolyzed from the 4-(N)-GemC18 to be more efficiently converted into its active metabolite, gemcitabine triphosphate (dFdCTP), and thus more potent against gemcitabine-resistant tumor cells than 4-(N)-GemC18 or gemcitabine alone. Moreover, we also showed that the RRM1-overexpressing tumor cells were also cross-resistant to cytarabine, another nucleoside analog commonly used in cancer therapy, and 4-(N)-stearoyl cytarabine carried by solid lipid nanoparticles can also overcome the resistance. Therefore, formulating the long-chain fatty acid amide derivatives of nucleoside analogs into solid lipid nanoparticles may represent a platform technology to increase the antitumor activity of the nucleoside analogs and to overcome tumor cell resistance to them.
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Affiliation(s)
- Piyanuch Wonganan
- Pharmaceutics Division, The University of Texas at Austin, College of Pharmacy, Austin, TX 78712, USA
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Xie H, Jiang W, Xiao SY, Liu X. High expression of survivin is prognostic of shorter survival but not predictive of adjuvant gemcitabine benefit in patients with resected pancreatic adenocarcinoma. J Histochem Cytochem 2012; 61:148-55. [PMID: 23124118 DOI: 10.1369/0022155412468137] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Overexpression of survivin has been associated with gemcitabine resistance in pancreatic adenocarcinoma, but previous studies have shown conflicting results. This study aims to determine its prognostic value in resected pancreatic adenocarcinoma with or without adjuvant therapy and its predictive value in adjuvant gemcitabine benefit in patients with resected pancreatic adenocarcinoma. This study included 118 patients who underwent pancreaticoduodectomy from 1999 to 2007, with no neoadjuvant chemoradiation. Forty-five patients received adjuvant gemcitabine. Survivin expression was assessed immunohistochemically and was graded as low (≤10% positive cells) and high (>10% positive cells) by recursive partitioning analysis. Prognostic factors, including tumor size, number of positive lymph nodes, perineural invasion, and stage, were identified for overall survival (OS) and progression-free survival (PFS) using Cox proportional hazards models. Multivariable analysis of the entire cohort revealed that both high survivin expression and perineural invasion predict significantly shorter OS (hazard ratio [HR] 2.0, p=0.01; HR 1.9, p=0.01, respectively) and shorter PFS (HR 1.9, p=0.04; HR 3.1, p=0.0006, respectively). Expression of survivin predicts neither OS nor PFS in patients treated with adjuvant gemcitabine. In summary, high expression of survivin is associated with shorter OS and PFS in patients with resected pancreatic adenocarcinoma after adjusting for other histopathological factors. However, survivin has no predictive value of adjuvant gemcitabine benefit.
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Affiliation(s)
- Hao Xie
- Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA
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