TY - JOUR
T1 - Molecular inhibition of prostaglandin E2 with GW627368X
T2 - Therapeutic potential and preclinical safety assessment in mouse sarcoma model
AU - Parida, Sheetal
AU - Parekh, Aditya
AU - Dey, Goutam
AU - Ghosh, Sukhen C.
AU - Mandal, Mahitosh
N1 - Funding Information:
University Grants Commission (UGC), India; Council of Scientific and Industrial Research (CSIR), India; Department of Biotechnology (DBT), India.
Funding Information:
The authors are thankful to all members of Cancer Biology lab, School of Medical Science and Technology, IIT Kharagpur, Colleagues from Dept. of Biotechnology, The Institutional Animal Ethical Committee, IIT Kharagpur, University grants commission (UGC), India, Council of Scientific and Industrial Research (CSIR), India and Department of Biotechnology DBT, India.
Publisher Copyright:
© 2015 Taylor & Francis Group, LLC.
PY - 2015/1/1
Y1 - 2015/1/1
N2 - 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.
AB - 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.
KW - COX-2
KW - GW627368X
KW - Prostaglandins
KW - Prostanoid receptors
KW - VEGF
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U2 - 10.1080/15384047.2015.1040953
DO - 10.1080/15384047.2015.1040953
M3 - Article
C2 - 25894216
AN - SCOPUS:84943742403
SN - 1538-4047
VL - 16
SP - 922
EP - 932
JO - Cancer Biology and Therapy
JF - Cancer Biology and Therapy
IS - 6
ER -