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Combined therapy with COX-2 inhibitor and 20-HETE inhibitor reduces colon tumor growth and the adverse effects of ischemic stroke associated with COX-2 inhibition.

Abstract
20-Hydroxyeicosatetraenoic acid (20-HETE), Cyp4a-derived eicosanoid, is a lipid mediator that promotes tumor growth, as well as causing detrimental effects in cerebral circulation. We determined whether concurrent inhibition of cyclooxygenase-2 (COX-2) and 20-HETE affects colon tumor growth and ischemic stroke outcomes. The expression of Cyp4a and COXs and production of 20-HETE and PGE2 were determined in murine colon carcinoma (MC38) cells. We then examined the effects of combined treatment with rofecoxib, a potent COX-2 inhibitor, and HET0016, a potent Cyp4a inhibitor, on the growth and proliferation of MC38 cells. Subsequently, we tested the effects of HET0016 plus rofecoxib in MC38 tumor and ischemic stroke models. Cyp4a and COXs are highly expressed in MC38 cells. Respectively, HET0016 and rofecoxib inhibited 20-HETE and PGE2 formation in MC38 cells. Moreover, rofecoxib combined with HET0016 had greater inhibitory effects on the growth and proliferation of MC38 cells than did rofecoxib alone. Importantly, rofecoxib combined with HET0016 provided greater inhibition on tumor growth than did rofecoxib alone in MC38 tumor-bearing mice. Prolonged treatment with rofecoxib selectively induced circulating 20-HETE levels and caused cerebrovascular damage after ischemic stroke, whereas therapy with rofecoxib and HET0016 attenuated 20-HETE levels and reduced rofecoxib-induced cerebrovascular damage and stroke outcomes during anti-tumor therapy. Thus these results demonstrate that combination therapy with rofecoxib and HET0016 provides a new treatment of colon tumor, which can not only enhance the anti-tumor efficacy of rofecoxib, but also reduce rofecoxib-induced cerebrovascular damage and stroke outcomes.
AuthorsYi Zhang, Md Nasrul Hoda, Xuan Zheng, Weiguo Li, Pengcheng Luo, Krishna Rao Maddipati, Tsugio Seki, Adviye Ergul, Mong-Heng Wang
JournalAmerican journal of physiology. Regulatory, integrative and comparative physiology (Am J Physiol Regul Integr Comp Physiol) Vol. 307 Issue 6 Pg. R693-703 (Sep 15 2014) ISSN: 1522-1490 [Electronic] United States
PMID24990856 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 the American Physiological Society.
Chemical References
  • Cyclooxygenase 2 Inhibitors
  • Hydroxyeicosatetraenoic Acids
  • Lactones
  • Sulfones
  • rofecoxib
  • 20-hydroxy-5,8,11,14-eicosatetraenoic acid
  • Cytochrome P-450 CYP4A
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • Dinoprostone
Topics
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols (pharmacology, toxicity)
  • Brain Ischemia (chemically induced, enzymology, prevention & control)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Colonic Neoplasms (drug therapy, enzymology, pathology)
  • Cyclooxygenase 2 (metabolism)
  • Cyclooxygenase 2 Inhibitors (administration & dosage, toxicity)
  • Cytochrome P-450 CYP4A (antagonists & inhibitors, metabolism)
  • Dinoprostone (metabolism)
  • Humans
  • Hydroxyeicosatetraenoic Acids (antagonists & inhibitors, metabolism)
  • Lactones (administration & dosage, toxicity)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Rats
  • Stroke (chemically induced, enzymology, prevention & control)
  • Sulfones (administration & dosage, toxicity)
  • Time Factors
  • Tumor Burden

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