Alterations in eicosanoid levels during U937 bcl-xL tumour growth suppression and recovery in NU/NU mice in vivo—Involvement of phospholipase A2

• Published in: Prostaglandins & other lipid mediators 2013-12, Vol.107, p.43-47
• Main Authors: Pace-Asciak, Cecil R., Li, Xiang, Reynaud, Denis, Qiao, Na, Demin, Peter, Abdelhaleem, Mohamed
• Format: Article
• Language: English
• Subjects: 8,11,14-Eicosatrienoic Acid - analogs & derivatives; 8,11,14-Eicosatrienoic Acid - pharmacology; Animals; Antagonists; Antineoplastic Agents - pharmacology; Arachidonic Acid - metabolism; bcl-X Protein - metabolism; Cell Line, Tumor; Eicosanoids; Female; Hepoxilins; Humans; LCMSMS; Mice; Mice, Nude; Phospholipase; Phospholipases A2 - metabolism; Tumor Burden - drug effects; Tumours; Xenograft Model Antitumor Assays
• ISSN: 1098-8823
• DOI: 10.1016/j.prostaglandins.2013.03.004

•We report for the first time that the HX Analog, PBT-4, blocks AA release in vivo.•PBT-4, blocks growth of leukaemic U937 derived tumours in vivo.•During tumour growth blockade, AA release and 12-HETE formation was inhibited – other eicosanoids were blocked as well.•2–3 weeks after stopping PBT-4 treatment, AA and 12-HETE levels increased associated with tumour growth.•This data shows that the anti-cancer effects of PBT may be through inhibition of PLAse A2 in this cancer model in vivo. We report the effects of two anti-cancer drugs, PBT-4, an experimental antagonist to the pro-inflammatory hepoxilins, and Gleevec (STI-571), an anti-leukaemic drug, on eicosanoid tumour levels in immunodeficient mice (NU/NU) xenografted with the leukaemic cell line, U937 bcl-xL. After the tumours had grown to 80–100mm3 volume, an 8-day treatment with the drugs was initiated and the animals were monitored for 28 days. On various days, tumours were removed for measurement of 24 omega-6 eicosanoids. The data show remarkable direct correlation between inhibition of tumour AA release and 12-LOX products (including 12-HETE and hepoxilins) during PBT or STI treatment with tumour growth suppression. These findings suggest that inhibition of AA release may represent a novel underlying mechanism of action of PBT-4 (and STI) in vivo in suppressing tumour growth. As the PBT wears off, AA and 12-LOX products rise rapidly (Day 18) leading to the observed tumour growth spurt.