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

Yi Zhang, MD Nasrul Hoda, Xuan Zheng, Weiguo Li, Pengcheng Luo, Krishna Rao Maddipati, Tsugio Seki, Adviye Ergul, Mong-Heng Wang

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

20-Hy-droxyeicosatetraenoic 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.

Original languageEnglish (US)
Pages (from-to)R693-R703
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume307
Issue number6
DOIs
StatePublished - Sep 15 2014

Fingerprint

Cyclooxygenase 2 Inhibitors
Cyclooxygenase 2
Colon
Stroke
Acids
Growth
Neoplasms
Therapeutics
Dinoprostone
rofecoxib
Cerebrovascular Circulation
Cell Proliferation
Growth Inhibitors
Eicosanoids

Keywords

  • HET0016
  • Rofecoxib
  • Stroke
  • Tumor growth

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

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. / Zhang, Yi; Hoda, MD Nasrul; Zheng, Xuan; Li, Weiguo; Luo, Pengcheng; Maddipati, Krishna Rao; Seki, Tsugio; Ergul, Adviye; Wang, Mong-Heng.

In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology, Vol. 307, No. 6, 15.09.2014, p. R693-R703.

Research output: Contribution to journalArticle

Zhang, Yi ; Hoda, MD Nasrul ; Zheng, Xuan ; Li, Weiguo ; Luo, Pengcheng ; Maddipati, Krishna Rao ; Seki, Tsugio ; Ergul, Adviye ; Wang, Mong-Heng. / 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. In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology. 2014 ; Vol. 307, No. 6. pp. R693-R703.
@article{d00550689f64445090c9c9b5099fc241,
title = "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-Hy-droxyeicosatetraenoic 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.",
keywords = "HET0016, Rofecoxib, Stroke, Tumor growth",
author = "Yi Zhang and Hoda, {MD Nasrul} and Xuan Zheng and Weiguo Li and Pengcheng Luo and Maddipati, {Krishna Rao} and Tsugio Seki and Adviye Ergul and Mong-Heng Wang",
year = "2014",
month = "9",
day = "15",
doi = "10.1152/ajpregu.00422.2013",
language = "English (US)",
volume = "307",
pages = "R693--R703",
journal = "American Journal of Physiology - Heart and Circulatory Physiology",
issn = "0363-6135",
publisher = "American Physiological Society",
number = "6",

}

TY - JOUR

T1 - 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

AU - Zhang, Yi

AU - Hoda, MD Nasrul

AU - Zheng, Xuan

AU - Li, Weiguo

AU - Luo, Pengcheng

AU - Maddipati, Krishna Rao

AU - Seki, Tsugio

AU - Ergul, Adviye

AU - Wang, Mong-Heng

PY - 2014/9/15

Y1 - 2014/9/15

N2 - 20-Hy-droxyeicosatetraenoic 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.

AB - 20-Hy-droxyeicosatetraenoic 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.

KW - HET0016

KW - Rofecoxib

KW - Stroke

KW - Tumor growth

UR - http://www.scopus.com/inward/record.url?scp=84907141827&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84907141827&partnerID=8YFLogxK

U2 - 10.1152/ajpregu.00422.2013

DO - 10.1152/ajpregu.00422.2013

M3 - Article

C2 - 24990856

AN - SCOPUS:84907141827

VL - 307

SP - R693-R703

JO - American Journal of Physiology - Heart and Circulatory Physiology

JF - American Journal of Physiology - Heart and Circulatory Physiology

SN - 0363-6135

IS - 6

ER -