Prostaglandin E2, the major COX-2 product, acts via 4 functionally distinct
prostanoid receptors, EP(1-4). PGE-2, through its receptors, feeds back to positively increase COX-2 expression augmenting its own synthesis thereby driving angiogenesis, while suppressing apoptosis and innate immunity. In addition to the well characterized
PGE2/EP4/cAMP/PKA/CREB, EP4 activation increases GSK3 phosphorylation via PI3K and Akt consequently reducing β-
catenin phosphorylation. EP4 induces angiogenesis by enhancing
VEGF production via ERK activation. These effects of EP4 are asserted either directly or via EGFR transactivation depending on the type of
cancer. In view of the safety concerns regarding long term use of
COX-2 inhibitors and to find more effective alternatives, we evaluated the potential of
EP4 prostanoid receptor as a target for treating
cancer progression using a highly selective EP4 antagonist, 4-(4,9-diethoxy-1,3-dihydro-1-oxo-2H-benz[f]isoindol-2-yl)-
N-(phenylsulfonyl)-benzeneacetamide.
Oral administration of
GW627368X showed significant
tumor regression characterized by
tumor reduction and induction of apoptosis. Reduction in
prostaglandin E2 synthesis also led to reduced level of
VEGF in plasma. Regulation of multiple pathways downstream of EP4 was evident by down regulation of COX-2, p-Akt, p-MAPK and p-EGFR. Considering wide distribution of the
EP4 prostanoid receptor in major organs and the array of physiological processes it contributes to, the safety profile of the
drug was analyzed. No major organ toxicity, immunosupression, behavioral change or change in blood parameters attributable to the
drug was observed. The results assert the significance of
EP4 prostanoid receptor as a therapeutic target as well as the safety of EP4 blockade by
GW627368X.