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Chemoprevention of metastasis.

Emenaker NJ, Zudaire E, St Croix B - Oncotarget (2014)

View Article: PubMed Central - PubMed

Affiliation: Tumor Angiogenesis Section, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI) at Frederick, NIH, Frederick, MD, USA.

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Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is used clinically to prevent polyp formation in familial adenomatous polyposis (FAP) patients, a population at high risk for colorectal cancer development... However, recent preclinical studies suggest that chemopreventive agents like celecoxib may have effective anti-tumor and anti-metastatic properties against advanced stage disease... COX-2 played a key regulatory role in prostaglandin E2 (PGE2) biosynthesis, driving angiogenesis in CT26 VEGF inhibitor refractory colon tumors... Moreover, activation of the COX-2/PGE2 pathway also enhanced myeloid cell recruitment into tumors likely increasing production of additional pro-angiogenic factors and further fueling angiogenesis... Because tumor vessels provide an escape route for tumor cells, we hypothesized that simultaneous targeting of the VEGF and COX-2/PGE2 pathways may also aid in blocking metastases... Indeed, in both experimental and spontaneous colon and breast cancer models dual VEGF/ COX-2 pathway inhibition reduced metastasis... For example, six months post axitinib/celecoxib therapy 60% of the mice were cured by the combination compared to only 8% (axitinib) or 17% (celecoxib) in the monotherapy arms... Celecoxib is the only clinically approved chemoprevention agent used for high risk FAP patients... While potential cardiotoxicities prevent its chemopreventive use in the general population, as an adjuvant therapy for blocking recurrence of late stage disease the potential benefits may be worth the risk, at least for some patients... Another possibility may be to substitute COX inhibitors for other tumoricidal agents such as resveratrol, curcumin, vitamin D, naringenin or their synthetic derivatives, which are well tolerated and have been shown to block COX-2 expression... Although soluble epoxide hydrolase (sEH) inhibitors used as a monotherapy may promote angiogenesis, when combined with celecoxib they also appear to potently suppress angiogenesis, tumor growth, and metastasis... Similarly, COX-2/sEH dual pharmacological inhibitors have shown promising antitumor activity in preclinical studies... Importantly, combination COX-2/sEH therapy may circumvent the cardiotoxicities associated with COX-2 inhibition by maintaining cardioprotective prostacyclin (PGI2) to thromboxane A2 (TXA2) ratios..

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A model highlighting the independent nature of the VEGF/VEGFR and COX/PGE2 pathwaysDual inhibition of the pathways at the indicated junctures may result in the most effective inhibition of angiogenesis and metastasis.
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Figure 1: A model highlighting the independent nature of the VEGF/VEGFR and COX/PGE2 pathwaysDual inhibition of the pathways at the indicated junctures may result in the most effective inhibition of angiogenesis and metastasis.

Mentions: Recent preclinical tumor studies suggest that the effectiveness of celecoxib against late stage colon and breast cancers can be significantly enhanced when combined with an anti-angiogenic agent (i.e., bevacizumab, neutralizing anti-VEGF antibody) or a receptor tyrosine kinase inhibitor (i.e., axitinib, selectively targeting VEGF receptors) [2] (Figure 1). COX-2 played a key regulatory role in prostaglandin E2 (PGE2) biosynthesis, driving angiogenesis in CT26 VEGF inhibitor refractory colon tumors. Moreover, activation of the COX-2/PGE2 pathway also enhanced myeloid cell recruitment into tumors likely increasing production of additional pro-angiogenic factors and further fueling angiogenesis. PGE2 has also been found to promote tumor cell growth, and prevent apoptosis and immune suppression. Thus, PGE2 likely promotes tumor growth through multiple mechanisms.


Chemoprevention of metastasis.

Emenaker NJ, Zudaire E, St Croix B - Oncotarget (2014)

A model highlighting the independent nature of the VEGF/VEGFR and COX/PGE2 pathwaysDual inhibition of the pathways at the indicated junctures may result in the most effective inhibition of angiogenesis and metastasis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4196143&req=5

Figure 1: A model highlighting the independent nature of the VEGF/VEGFR and COX/PGE2 pathwaysDual inhibition of the pathways at the indicated junctures may result in the most effective inhibition of angiogenesis and metastasis.
Mentions: Recent preclinical tumor studies suggest that the effectiveness of celecoxib against late stage colon and breast cancers can be significantly enhanced when combined with an anti-angiogenic agent (i.e., bevacizumab, neutralizing anti-VEGF antibody) or a receptor tyrosine kinase inhibitor (i.e., axitinib, selectively targeting VEGF receptors) [2] (Figure 1). COX-2 played a key regulatory role in prostaglandin E2 (PGE2) biosynthesis, driving angiogenesis in CT26 VEGF inhibitor refractory colon tumors. Moreover, activation of the COX-2/PGE2 pathway also enhanced myeloid cell recruitment into tumors likely increasing production of additional pro-angiogenic factors and further fueling angiogenesis. PGE2 has also been found to promote tumor cell growth, and prevent apoptosis and immune suppression. Thus, PGE2 likely promotes tumor growth through multiple mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Tumor Angiogenesis Section, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI) at Frederick, NIH, Frederick, MD, USA.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is used clinically to prevent polyp formation in familial adenomatous polyposis (FAP) patients, a population at high risk for colorectal cancer development... However, recent preclinical studies suggest that chemopreventive agents like celecoxib may have effective anti-tumor and anti-metastatic properties against advanced stage disease... COX-2 played a key regulatory role in prostaglandin E2 (PGE2) biosynthesis, driving angiogenesis in CT26 VEGF inhibitor refractory colon tumors... Moreover, activation of the COX-2/PGE2 pathway also enhanced myeloid cell recruitment into tumors likely increasing production of additional pro-angiogenic factors and further fueling angiogenesis... Because tumor vessels provide an escape route for tumor cells, we hypothesized that simultaneous targeting of the VEGF and COX-2/PGE2 pathways may also aid in blocking metastases... Indeed, in both experimental and spontaneous colon and breast cancer models dual VEGF/ COX-2 pathway inhibition reduced metastasis... For example, six months post axitinib/celecoxib therapy 60% of the mice were cured by the combination compared to only 8% (axitinib) or 17% (celecoxib) in the monotherapy arms... Celecoxib is the only clinically approved chemoprevention agent used for high risk FAP patients... While potential cardiotoxicities prevent its chemopreventive use in the general population, as an adjuvant therapy for blocking recurrence of late stage disease the potential benefits may be worth the risk, at least for some patients... Another possibility may be to substitute COX inhibitors for other tumoricidal agents such as resveratrol, curcumin, vitamin D, naringenin or their synthetic derivatives, which are well tolerated and have been shown to block COX-2 expression... Although soluble epoxide hydrolase (sEH) inhibitors used as a monotherapy may promote angiogenesis, when combined with celecoxib they also appear to potently suppress angiogenesis, tumor growth, and metastasis... Similarly, COX-2/sEH dual pharmacological inhibitors have shown promising antitumor activity in preclinical studies... Importantly, combination COX-2/sEH therapy may circumvent the cardiotoxicities associated with COX-2 inhibition by maintaining cardioprotective prostacyclin (PGI2) to thromboxane A2 (TXA2) ratios..

Show MeSH
Related in: MedlinePlus