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Title: COX-2/sEH Dual Inhibitor PTUPB Potentiates the Antitumor Efficacy of Cisplatin

Abstract

Cisplatin-based therapy is highly toxic, but moderately effective in most cancers. Concurrent inhibition of cyclooxygenase-2 (COX-2) and soluble epoxide hydrolase (sEH) results in antitumor activity and has organ-protective effects. The goal of this paper was to determine the antitumor activity of PTUPB, an orally bioavailable COX-2/sEH dual inhibitor, in combination with cisplatin and gemcitabine (GC) therapy. NSG mice bearing bladder cancer patient-derived xenografts were treated with vehicle, PTUPB, cisplatin, GC, or combinations thereof. Mouse experiments were performed with two different PDX models. PTUPB potentiated cisplatin and GC therapy, resulting in significantly reduced tumor growth and prolonged survival. PTUPB plus cisplatin was no more toxic than cisplatin single-agent treatment as assessed by body weight, histochemical staining of major organs, blood counts, and chemistry. The combination of PTUPB and cisplatin increased apoptosis and decreased phosphorylation in the MAPK/ERK and PI3K/AKT/mTOR pathways compared with controls. PTUPB treatment did not alter platinum–DNA adduct levels, which is the most critical step in platinum-induced cell death. The in vitro study using the combination index method showed modest synergy between PTUPB and platinum agents only in 5637 cell line among several cell lines examined. However, PTUPB is very active in vivo by inhibiting angiogenesis. Finally, PTUPB potentiatedmore » the antitumor activity of cisplatin-based treatment without increasing toxicity in vivo and has potential for further development as a combination chemotherapy partner.« less

Authors:
 [1];  [2];  [3];  [4];  [2];  [5];  [5];  [2];  [2];  [6];  [6];  [2];  [7];  [5];  [8];  [9];  [10]
  1. Univ. of California Davis, Sacramento, CA (United States). Dept. of Internal Medicine. School of Medicine; Fourth Military Medical Univ., Xi'an (China). Dept. of Urology. Xijing Hospital
  2. Univ. of California Davis, Sacramento, CA (United States). Dept. of Internal Medicine. School of Medicine
  3. Univ. of California Davis, Sacramento, CA (United States). Dept. of Biochemistry and Molecular Medicine. School of Medicine
  4. Univ. of California Davis, Sacramento, CA (United States). Dept. of Internal Medicine. School of Medicine; Wuhan Univ. (China). Dept. of Urology. Renmin Hospital
  5. Univ. of California, Davis, CA (United States). Dept. of Entomology and Nematology
  6. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
  7. The Jackson Lab., Bar Harbor, ME (United States)
  8. Fourth Military Medical Univ., Xi'an (China). Dept. of Urology. Xijing Hospital
  9. Univ. of California Davis, Sacramento, CA (United States). Dept. of Urology. School of Medicine. Comprehensive Cancer Center
  10. Univ. of California Davis, Sacramento, CA (United States). Dept. of Internal Medicine. Dept. of Urology. School of Medicine. Comprehensive Cancer Center; VA Northern California Health Care System, Rancho Cordova, CA (United States)
Publication Date:
Research Org.:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Univ. of California Davis, Sacramento, CA (United States)
Sponsoring Org.:
USDOE; Dept. of Veterans Affairs (VA) (United States); National Inst. of Health (NIH) (United States)
OSTI Identifier:
1438685
Report Number(s):
LLNL-JRNL-741222
Journal ID: ISSN 1535-7163
Grant/Contract Number:  
AC52-07NA27344; I01 BX001784; 2 P30 CA 0933730; R01 ES002710; P42 ES04699; HHSN261201200048C; R01 DK103616; U54 NS079202
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Molecular Cancer Therapeutics
Additional Journal Information:
Journal Volume: 17; Journal Issue: 2; Journal ID: ISSN 1535-7163
Publisher:
American Association for Cancer Research (AACR)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Wang, Fuli, Zhang, Hongyong, Ma, Ai-Hong, Yu, Weimin, Zimmermann, Maike, Yang, Jun, Hwang, Sung Hee, Zhu, Daniel, Lin, Tzu-yin, Malfatti, Michael, Turteltaub, Kenneth W., Henderson, Paul T., Airhart, Susan, Hammock, Bruce D., Yuan, Jianlin, de Vere White, Ralph W., and Pan, Chong-Xian. COX-2/sEH Dual Inhibitor PTUPB Potentiates the Antitumor Efficacy of Cisplatin. United States: N. p., 2017. Web. doi:10.1158/1535-7163.MCT-16-0818.
Wang, Fuli, Zhang, Hongyong, Ma, Ai-Hong, Yu, Weimin, Zimmermann, Maike, Yang, Jun, Hwang, Sung Hee, Zhu, Daniel, Lin, Tzu-yin, Malfatti, Michael, Turteltaub, Kenneth W., Henderson, Paul T., Airhart, Susan, Hammock, Bruce D., Yuan, Jianlin, de Vere White, Ralph W., & Pan, Chong-Xian. COX-2/sEH Dual Inhibitor PTUPB Potentiates the Antitumor Efficacy of Cisplatin. United States. doi:10.1158/1535-7163.MCT-16-0818.
Wang, Fuli, Zhang, Hongyong, Ma, Ai-Hong, Yu, Weimin, Zimmermann, Maike, Yang, Jun, Hwang, Sung Hee, Zhu, Daniel, Lin, Tzu-yin, Malfatti, Michael, Turteltaub, Kenneth W., Henderson, Paul T., Airhart, Susan, Hammock, Bruce D., Yuan, Jianlin, de Vere White, Ralph W., and Pan, Chong-Xian. Thu . "COX-2/sEH Dual Inhibitor PTUPB Potentiates the Antitumor Efficacy of Cisplatin". United States. doi:10.1158/1535-7163.MCT-16-0818. https://www.osti.gov/servlets/purl/1438685.
@article{osti_1438685,
title = {COX-2/sEH Dual Inhibitor PTUPB Potentiates the Antitumor Efficacy of Cisplatin},
author = {Wang, Fuli and Zhang, Hongyong and Ma, Ai-Hong and Yu, Weimin and Zimmermann, Maike and Yang, Jun and Hwang, Sung Hee and Zhu, Daniel and Lin, Tzu-yin and Malfatti, Michael and Turteltaub, Kenneth W. and Henderson, Paul T. and Airhart, Susan and Hammock, Bruce D. and Yuan, Jianlin and de Vere White, Ralph W. and Pan, Chong-Xian},
abstractNote = {Cisplatin-based therapy is highly toxic, but moderately effective in most cancers. Concurrent inhibition of cyclooxygenase-2 (COX-2) and soluble epoxide hydrolase (sEH) results in antitumor activity and has organ-protective effects. The goal of this paper was to determine the antitumor activity of PTUPB, an orally bioavailable COX-2/sEH dual inhibitor, in combination with cisplatin and gemcitabine (GC) therapy. NSG mice bearing bladder cancer patient-derived xenografts were treated with vehicle, PTUPB, cisplatin, GC, or combinations thereof. Mouse experiments were performed with two different PDX models. PTUPB potentiated cisplatin and GC therapy, resulting in significantly reduced tumor growth and prolonged survival. PTUPB plus cisplatin was no more toxic than cisplatin single-agent treatment as assessed by body weight, histochemical staining of major organs, blood counts, and chemistry. The combination of PTUPB and cisplatin increased apoptosis and decreased phosphorylation in the MAPK/ERK and PI3K/AKT/mTOR pathways compared with controls. PTUPB treatment did not alter platinum–DNA adduct levels, which is the most critical step in platinum-induced cell death. The in vitro study using the combination index method showed modest synergy between PTUPB and platinum agents only in 5637 cell line among several cell lines examined. However, PTUPB is very active in vivo by inhibiting angiogenesis. Finally, PTUPB potentiated the antitumor activity of cisplatin-based treatment without increasing toxicity in vivo and has potential for further development as a combination chemotherapy partner.},
doi = {10.1158/1535-7163.MCT-16-0818},
journal = {Molecular Cancer Therapeutics},
issn = {1535-7163},
number = 2,
volume = 17,
place = {United States},
year = {2017},
month = {12}
}

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Cited by: 8 works
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Figures / Tables:

Figure 1: Figure 1:: Potentiation of cisplatin anti-tumor activity by PTUPB. A). Tumor growth in the NSG-PDX bladder cancer mouse model. When the volume of the tumor xenografts reached approximately 0.1~0.2 cm3, mice were treated with PEG 400 control, single agent cisplatin (2mg/kg, i.v., Day 1, 2, 3, 14, 15, and 16,more » red arrows), single agent PUTUPB (30 mg/kg,orally, once daily), and cisplatin (2 mg/kg) plus PUTUB (30 mg/kg) combination. The tumor dimensions were measured every 3~4 days. The tumor volume was calculated using the formula: 0.5 × length × width2(mm3). Mice were euthanized when the tumor volume reached 1.5~2 cm3 (~7.5 times the baseline volume or 7.5× BL). The median time of the tumor growth to 7.5× BL (blue dotted line) was 20 days for the control and 24.4 days in the PTUPB group (p=0.085) and 35.8 days in the cisplatin group (p=0.0003). The median time to endpoint in the cisplatin and PTUPB combination group was significantly increased to 47.8 days compared to PTUPB (p<0.0001) or cisplatin (p=0.002) monotherapy groups. B). Median survival with statistical analysis. Median survival of the combination treatment group was 60.9 days, significantly longer than that of either PTUPB (39.4 days, p=0.007) or cisplatin (47 days, p=0.02) monotherapy groups.« less

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