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Xu J, Chen J, Wang D, Li Y, Lian P, Wu X, Yan R. Nafamostat mesylate sensitizes ovarian cancer cells to carboplatin by promoting the ZNF24-mediated inhibition of WNT2B. J Toxicol Sci 2024; 49:467-479. [PMID: 39496384 DOI: 10.2131/jts.49.467] [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] [Indexed: 11/06/2024]
Abstract
Resistance to chemotherapeutic medicines complicates and eventually kills people with ovarian cancer. Nafamostat mesylate (NM) has been used as an adjuvant therapy to enhance chemotherapy sensitivity in several cancers. This study aimed to evaluate the effect of NM on ovarian cancer cells susceptible to carboplatin (CBP) and to determine the underlying mechanism involved. Herein, qRT-PCR, western blot, and IHC were used to analyze mRNA and protein expression. Cell viability and proliferation were measured using the MTT and colony formation assays. Cell migration and invasion were examined using the Transwell assay. Flow cytometry was employed to detect cell apoptosis. The interaction between zinc finger protein 24 (ZNF24) and wingless-type MMTV integration site family member 2b (WNT2B) was validated via the dual-luciferase reporter and Chromatin immunoprecipitation assays. A xenograft nude mouse model was used to assess the effect of NM on CBP sensitivity in vivo. Our results showed that NM intervention inhibited the viability, proliferation, migration, and invasion and facilitated the apoptosis of CBP-resistant ovarian cancer cells. Furthermore, NM sensitized ovarian cancer cells to CBP by upregulating ZNF24. ZNF24 inactivated Wnt/β-catenin signaling by inhibiting the transcription of WNT2B. Additionally, NM enhanced the inhibitory effect of CBP on tumor growth in vivo. Taken together, NM enhanced the CBP sensitivity of ovarian cancer cells by promoting the ZNF24-mediated inactivation of the WNT2B/Wnt/β-catenin axis. These findings suggest a viable treatment approach for improving CBP resistance in ovarian cancer.
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Affiliation(s)
- Jiehuan Xu
- Changsha Health Vocational College, China
| | - Jianlin Chen
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The Second Xiangya Hospital, Central South University, China
| | - Dao Wang
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The Second Xiangya Hospital, Central South University, China
| | - Yaojun Li
- Changsha Health Vocational College, China
| | - Ping Lian
- Changsha Health Vocational College, China
| | - Xiaozhu Wu
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The Second Xiangya Hospital, Central South University, China
| | - Rong Yan
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The Second Xiangya Hospital, Central South University, China
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Fang YT, Yang WW, Niu YR, Sun YK. Recent advances in targeted therapy for pancreatic adenocarcinoma. World J Gastrointest Oncol 2023; 15:571-595. [PMID: 37123059 PMCID: PMC10134207 DOI: 10.4251/wjgo.v15.i4.571] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 11/11/2022] [Accepted: 03/16/2023] [Indexed: 04/12/2023] Open
Abstract
Pancreatic adenocarcinoma (PDAC) is a fatal disease with a 5-year survival rate of 8% and a median survival of 6 mo. In PDAC, several mutations in the genes are involved, with Kirsten rat sarcoma oncogene (90%), cyclin-dependent kinase inhibitor 2A (90%), and tumor suppressor 53 (75%–90%) being the most common. Mothers against decapentaplegic homolog 4 represents 50%. In addition, the self-preserving cancer stem cells, dense tumor microenvironment (fibrous accounting for 90% of the tumor volume), and suppressive and relatively depleted immune niche of PDAC are also constitutive and relevant elements of PDAC. Molecular targeted therapy is widely utilized and effective in several solid tumors. In PDAC, targeted therapy has been extensively evaluated; however, survival improvement of this aggressive disease using a targeted strategy has been minimal. There is currently only one United States Food and Drug Administration-approved targeted therapy for PDAC – erlotinib, but the absolute benefit of erlotinib in combination with gemcitabine is also minimal (2 wk). In this review, we summarize current targeted therapies and clinical trials targeting dysregulated signaling pathways and components of the PDAC oncogenic process, analyze possible reasons for the lack of positive results in clinical trials, and suggest ways to improve them. We also discuss emerging trends in targeted therapies for PDAC: combining targeted inhibitors of multiple pathways. The PubMed database and National Center for Biotechnology Information clinical trial website (www.clinicaltrials.gov) were queried to identify completed and published (PubMed) and ongoing (clinicaltrials.gov) clinical trials (from 2003-2022) using the keywords pancreatic cancer and targeted therapy. The PubMed database was also queried to search for information about the pathogenesis and molecular pathways of pancreatic cancer using the keywords pancreatic cancer and molecular pathways.
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Affiliation(s)
- Yu-Ting Fang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Wen-Wei Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Ya-Ru Niu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yong-Kun Sun
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Hebei Cancer Hospital, Chinese Academy of Medical Sciences, Langfang 065001, Hebei Province, China
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Hamura R, Haruki K, Fujiwara Y, Tsunematsu M, Shirai Y, Furukawa K, Onda S, Gocho T, Shiba H, Uwagawa T, Usuba T, Fujioka S, Okamoto T, Ikegami T. The effectiveness of adjuvant chemotherapy for Stage I pancreatic cancer based on the UICC 8 th edition. Langenbecks Arch Surg 2022; 407:3437-3446. [PMID: 36173461 DOI: 10.1007/s00423-022-02686-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 09/13/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Adjuvant chemotherapy is recommended for patients with pancreatic cancer after curative resection. However, there is limited evidence regarding the efficacy and prognostic factors for adjuvant chemotherapy in patients with stage I pancreatic cancer. This study aimed to identify patients in whom chemotherapy was effective and to detect prognostic factors for stage I pancreatic cancer based on guidelines of the 8th edition of the Union for International Cancer Control (UICC). METHODS Between 2009 and 2017, 108 patients diagnosed with stage I pancreatic cancer were enrolled in this study. They were distributed into invasion (n = 68) and non-invasion (n = 40) groups. The relationship between clinicopathological variables, including various prognostic factors, disease-free survival (DFS), and overall survival (OS), were investigated by univariate and multivariate analyses. RESULTS Five-year survival in all patients with stage I pancreatic cancer was 38.9%. Adjuvant chemotherapy failed to improve DFS or OS in patients with stage I cancer (DFS, p = 0.26; OS, p = 0.30). In subgroup analysis, adjuvant chemotherapy significantly improved DFS (multivariate-adjusted hazard ratio (HR), 0.40; 95% confidence interval [CI], 0.21-0.78; p = 0.007) and OS (multivariate-adjusted HR, 0.32; 95% CI, 0.15-0.68; p = 0.003) in the invasion group than in non-invasion group. In contrast, in the non-invasion group, adjuvant chemotherapy failed to improve DFS and OS in univariate analysis (DFS, p = 0.992; OS, p = 0.808). CONCLUSION For stage I pancreatic cancer, based on guidelines of the UICC 8th edition, adjuvant chemotherapy may benefit patients with extrapancreatic invasion.
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Affiliation(s)
- Ryoga Hamura
- Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Koichiro Haruki
- Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan.
| | - Yuki Fujiwara
- Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Masashi Tsunematsu
- Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Yoshihiro Shirai
- Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Kenei Furukawa
- Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Shinji Onda
- Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Takeshi Gocho
- Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Hiroaki Shiba
- Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Tadashi Uwagawa
- Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Teruyuki Usuba
- Department of Surgery, The Jikei University Katsushika Medical Center, Tokyo, Japan
| | - Shuichi Fujioka
- Department of Surgery, The Jikei University Kashiwa Hospital, Chiba, Japan
| | - Tomoyoshi Okamoto
- Department of Surgery, The Jikei University Daisan Hospital, Tokyo, Japan
| | - Toru Ikegami
- Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan
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Uwagawa T, Sakamoto T, Gocho T, Shiba H, Onda S, Yasuda J, Shirai Y, Hamura R, Furukawa K, Yanaga K, Ikegami T. Phase II trial of nafamostat mesilate/gemcitabin/S-1 for unresectable pancreatic cancer. PLoS One 2022; 17:e0267623. [PMID: 35544539 PMCID: PMC9094514 DOI: 10.1371/journal.pone.0267623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 04/08/2022] [Indexed: 12/03/2022] Open
Abstract
PURPOSE To assess the efficacy of combination chemotherapy with nafamostat mesilate, gemcitabine and S-1 for unresectable pancreatic cancer patients. MATERIALS AND METHODS The study was conducted as a single-arm, single center, institutional review board-approved phase II trial. Patients received nafamosntat mesilate (4.8 mg/kg continuous transregional arterial infusion) with gemcitabine (1000 mg/m2 transvenous) on days 1 and15, and with oral S-1 [(80 mg/day (BSA<1.25 m2), 100 mg/day (1.25 ≤ BSA<1.5 m2), or 120 mg/day (BSA ≥1.5 m2)] on days 1-14 or, days 1-7 and 15-21. This regimen was repeated at 28-day intervals. RESULTS Forty-seven evaluable patients (Male/Female: 31/16, Age (median): 66 (range 35-78) yrs, Stage III/IV 10/37.) were candidates in this study. Two patients in stage III (20%) could undergo conversion surgery. Twenty-four patients (51%) underwent subsequent treatment (1st line/ 2nd line / 4th line, 13/ 10/ 1, FOLFIRINOX: 12, GEM/nab-PTX: 18, TAS-118: 3, chemoradiation with S-1: 2, GEM/Erlotinib: 1, nal-IRI: 1, surgery: 2). Median PFS and OS were 9.7 (95% CI, 8.9-14.7 mo) and 14.2 months (99% CI, 13.3-23.9 mo), respectively. Median PFS in stage IV patients was 9.2 months (95% CI, 8.4-12.0 mo). Median OS in patients without subsequent treatment was 10.8 months (95% CI, 9.1-13.8 mo). Median OS in patients with subsequent treatment was 19.3 months (95% CI, 18.9-31.9 mo). Grade 4 treatment-related hematological toxicities were encountered in 7 patients. Two patients developed grade 3 allergic reaction after 6 cycles or later. No febrile neutropenia has been observed. CONCLUSION NAM/GEM/S-1 therapy is safe and could be promising option for unresectable pancreatic cancer, especially for stage IV cancer.
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Affiliation(s)
- Tadashi Uwagawa
- Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Taro Sakamoto
- Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Takeshi Gocho
- Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Hiroaki Shiba
- Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Shinji Onda
- Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Jungo Yasuda
- Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Yoshihiro Shirai
- Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Ryoga Hamura
- Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Kenei Furukawa
- Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | | | - Toru Ikegami
- Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
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