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

•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 80–100 mm3 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.