COX-2/sEH dual inhibitor PTUPB potentiates the antitumor efficacy of cisplatin

Fuli Wang, Hongyong Zhang, Ai Hong Ma, Weimin Yu, Maike Zimmermann, Jun Yang, Sung Hee Hwang, Daniel Zhu, Tzu-Yin Lin, Michael Malfatti, Ken W Turteltaub, Paul Henderson, Susan Airhart, Bruce D. Hammock, Jianlin Yuan, Ralph W deVere White, Chong-Xian Pan

Research output: Contribution to journalArticle

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Abstract

Cisplatin-based therapy is highly toxic, but moderately effective inmost 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.

Original languageEnglish (US)
Pages (from-to)474-483
Number of pages10
JournalMolecular Cancer Therapeutics
Volume17
Issue number2
DOIs
StatePublished - Feb 1 2018

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Epoxide Hydrolases
Cyclooxygenase 2
Cisplatin
gemcitabine
Platinum
Poisons
Therapeutics
Cell Line
DNA Adducts
Combination Drug Therapy
Phosphatidylinositol 3-Kinases
Heterografts
Urinary Bladder Neoplasms
Neoplasms
Cell Death
Body Weight
Phosphorylation
Apoptosis
Staining and Labeling
Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

COX-2/sEH dual inhibitor PTUPB potentiates the antitumor efficacy of cisplatin. / Wang, Fuli; Zhang, Hongyong; Ma, Ai Hong; Yu, Weimin; Zimmermann, Maike; Yang, Jun; Hwang, Sung Hee; Zhu, Daniel; Lin, Tzu-Yin; Malfatti, Michael; Turteltaub, Ken W; Henderson, Paul; Airhart, Susan; Hammock, Bruce D.; Yuan, Jianlin; deVere White, Ralph W; Pan, Chong-Xian.

In: Molecular Cancer Therapeutics, Vol. 17, No. 2, 01.02.2018, p. 474-483.

Research output: Contribution to journalArticle

Wang, F, Zhang, H, Ma, AH, Yu, W, Zimmermann, M, Yang, J, Hwang, SH, Zhu, D, Lin, T-Y, Malfatti, M, Turteltaub, KW, Henderson, P, Airhart, S, Hammock, BD, Yuan, J, deVere White, RW & Pan, C-X 2018, 'COX-2/sEH dual inhibitor PTUPB potentiates the antitumor efficacy of cisplatin', Molecular Cancer Therapeutics, vol. 17, no. 2, pp. 474-483. https://doi.org/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, Ken W ; Henderson, Paul ; Airhart, Susan ; Hammock, Bruce D. ; Yuan, Jianlin ; deVere White, Ralph W ; Pan, Chong-Xian. / COX-2/sEH dual inhibitor PTUPB potentiates the antitumor efficacy of cisplatin. In: Molecular Cancer Therapeutics. 2018 ; Vol. 17, No. 2. pp. 474-483.
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AU - Yang, Jun

AU - Hwang, Sung Hee

AU - Zhu, Daniel

AU - Lin, Tzu-Yin

AU - Malfatti, Michael

AU - Turteltaub, Ken W

AU - Henderson, Paul

AU - Airhart, Susan

AU - Hammock, Bruce D.

AU - Yuan, Jianlin

AU - deVere White, Ralph W

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