COX-2/sEH Dual Inhibitor PTUPB Potentiates the Antitumor Efficacy of Cisplatin
| العنوان: | COX-2/sEH Dual Inhibitor PTUPB Potentiates the Antitumor Efficacy of Cisplatin |
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| المؤلفون: | Hongyong Zhang, Susan D. Airhart, Bruce D. Hammock, Daniel Zhu, Jianlin Yuan, Fuli Wang, Chong-Xian Pan, Tzu-yin Lin, Weimin Yu, Ralph W deVere White, Paul T. Henderson, Maike Zimmermann, Jun Yang, Michael A. Malfatti, Kenneth W. Turteltaub, Ai Hong Ma, Sung Hee Hwang |
| المصدر: | Molecular Cancer Therapeutics. 17:474-483 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Epoxide hydrolase 2, Cancer Research, Antineoplastic Agents, Pharmacology, Article, Mice, 03 medical and health sciences, 0302 clinical medicine, In vivo, Cell Line, Tumor, medicine, Animals, Humans, PI3K/AKT/mTOR pathway, Cisplatin, Chemistry, Combination chemotherapy, Gemcitabine, 030104 developmental biology, Urinary Bladder Neoplasms, Oncology, Cyclooxygenase 2, Apoptosis, 030220 oncology & carcinogenesis, Toxicity, Female, medicine.drug |
| الوصف: | 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 study 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. In conclusion, 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. Mol Cancer Ther; 17(2); 474–83. ©2017 AACR. |
| تدمد: | 1538-8514 1535-7163 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::35373753760f524b64f8a04f40789d67 https://doi.org/10.1158/1535-7163.mct-16-0818 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....35373753760f524b64f8a04f40789d67 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15388514 15357163 |
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