Effects of Nonselective Cyclooxygenase Inhibition with Low-Dose Ibuprofen on Tumor Growth, Angiogenesis, Metastasis, and Survival in a Mouse Model of Colorectal Cancer

Section of Gastroenterology, Boston University, Boston, Massachusetts, United States
Clinical Cancer Research (Impact Factor: 8.72). 03/2005; 11(4):1618-28. DOI: 10.1158/1078-0432.CCR-04-1696
Source: PubMed


To determine whether the nonselective and relatively inexpensive nonsteroidal anti-inflammatory drug ibuprofen would be effective in inhibiting colorectal cancer and might improve mortality in a mouse model.
The effects of ibuprofen on tumor growth inhibition and animal survival have been examined in both mouse and human colorectal cancer tumor models. Angiogenesis was measured by in vitro endothelial cell tube formation and immunohistochemistry.
Ibuprofen significantly inhibited cell proliferation in mouse (MC-26) and human (HT-29) colorectal cancer cell lines. In vitro angiogenesis assays also indicated that ibuprofen decreased both cell proliferation and tube formation. The administration of chow containing 1,360 ppm ibuprofen, which achieved an average plasma concentration of ibuprofen lower than the peak level achieved in humans at therapeutic doses, inhibited tumor growth by 40% to 82%. Fewer liver metastases were found in the ibuprofen group compared with the control group. In combination therapy with the standard antineoplastic agents, 5-fluorouracil, or irinotecan (CPT-11), tumor volumes in the groups with ibuprofen +/- CPT-11 or 5-fluorouracil were smaller than in the control group. Ibuprofen was similar to the cyclooxygenase-2 selective inhibitor rofecoxib in its ability to suppress tumor growth and improve overall survival.
Ibuprofen, in part by modulating tumor angiogenesis, decreases both tumor growth and metastatic potential in mice. The ibuprofen doses were in the low range of therapeutic human plasma concentrations. Ibuprofen potentiates the antitumor properties of CPT-11 and improves survival of mice without increasing gastrointestinal toxicity.

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    • "Treatment of SCI With Ghrelin, IBU, C16, and KD 879 anti-inflammatory therapy, ibuprofen has antiangiogenic properties, as demonstrated in both in vitro and in vivo models (Farrell et al., 1988; Palayoor et al., 2003; Yao et al., 2005). Thus, ibuprofen may override any influence that C16 or KD might have on angiogenesis and in this regard might not be advisable to administer simultaneously . "
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    ABSTRACT: Because of the complex, multifaceted nature of spinal cord injury (SCI), it is widely believed that a combination of approaches will be superior to individual treatments. Therefore, we employed a rat model of cervical SCI to evaluate the combination of four noninvasive treatments that individually have been reported to be effective for acute SCI during clinically relevant therapeutic time windows. These treatments included ghrelin, ibuprofen, C16, and ketogenic diet (KD). These were selected not only because of their previously reported efficacy in SCI models but also for their potentially different mechanisms of action. The administration of ghrelin, ibuprofen, C16, and KD several hours to days postinjury was based on previous observations by others that each treatment had profound effects on the pathophysiology and functional outcome following SCI. Here we showed that, with the exception of a modest improvement in performance on the Montoya staircase test at 8–10 weeks postinjury, the combinatorial treatment with ghrelin, ibuprofen, C16, and KD did not result in any significant improvements in the rearing test, grooming test, or horizontal ladder. Histologic analysis of the spinal cords did not reveal any significant differences in tissue sparing between treatment and control groups. Although single approaches of ghrelin, ibuprofen, C16, and KD have been reported to be beneficial after SCI, our results show that the combination of the four interventions did not confer significant functional or histological improvements in a cervical model of SCI. Possible interactions among the treatments may have negated their beneficial effects, emphasizing the challenges that have to be addressed when considering combinatorial drug therapies for SCI. © 2014 Wiley Periodicals, Inc.
    Journal of Neuroscience Research 07/2014; 92(7). DOI:10.1002/jnr.23372 · 2.59 Impact Factor
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    • "VEGF-targeted therapy Bevacizumab VEGF-A Hsu and Wakelee, 2009 VEGF-Trap VEGF-A, VEGF-B and PlGF Rudge et al., 2007 Sunitinib VEGFR1–3, PDGFR-α, PDGFR-β, c-Kit, CSF-1R and Flt-3 Huang et al., 2010 Sorafenib VEGFR1–3, PDGFR-β, Raf-1, B-Raf Huang et al., 2010 Vatalanib VEGFR1–3, PDGFR-β and c-Kit Qian et al., 2004; Jubb et al., 2006 Axitinib VEGFRs, PDGFR-β and c-Kit Jubb et al., 2006; Ma and Waxman, 2009 SU6668 VEGFR2, FGFR1 and PDGF-β Klenke et al., 2007 FGF-targeted therapy AZD4547 FGFR1–3 Gavine et al., 2012 Ponatinib FGFR1–4 Gozgit et al., 2012 SSR FGFRs Bono et al., 2013 Brivanib VEGFRs and FGFRs Allen et al., 2011 Dovitinib FEGFRs, VEGFRs and PDGFR Chen et al., 2012 Nintedanib VEGFRs, FGFRs and PDGFR Hilberg et al., 2008 Oncogene-targeted therapy/signalling transduction-targeted therapy Dasatinib Src and indirectly VEGF, IL-8 Summy et al., 2005; Han et al., 2006; Haura et al., 2010 Tipifarnib MMP-1 Izbicka et al., 2005 NVP-AUY922 Hsp90 Eccles et al., 2008; Moser et al., 2012 Bortezomib NF-κB-dependent release of VEGF and IL-8 Sunwoo et al., 2001 Gossypol VEGF and IL-8 release Pang et al., 2011 Dacinostat Histone deacetylase Qian et al., 2004 Matrix degrading and remodelling-targeted therapy DX-2400 MMP-14 Devy et al., 2009 PI-88 Heparanase Liu et al., 2009 Tumour-associated stromal cell-targeted therapy JNJ-28312141 CSF-1R Manthey et al., 2009 Zoledronic acid TAM-associated production of VEGF Coscia et al., 2010; Veltman et al., 2010 Anti-BV8 antibody Neutrophils recruitment Shojaei et al., 2008 CAMs-targeted therapy Cilengitide αvβ3 and αvβ5 integrins ligation to matrix proteins Hariharan et al., 2007 Volociximab αvβ1 integrin interaction with fibronectin Evans et al., 2007; Besse et al., 2013 ADH-1 N-cadherin Blaschuk et al., 2005; Blaschuk, 2012 Inflammatory angiogenesistargeted therapy Ibuprofen COX1/2 Yao et al., 2005 Celecoxib COX-2 Wei et al., 2004 Repertaxin CXCR1 and CXCR2 Ijichi et al., 2011 EC, endothelial cells; EPC, endothelial progenitor cells; Hsp90, heat shock protein 90; PlGF, placental growth factor; Src, sarcoma. "
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    British Journal of Pharmacology 08/2013; 170(4). DOI:10.1111/bph.12344 · 4.84 Impact Factor
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    • "Based on the pharmacokinetic profile of the drugs, which exhibit a similar elimination half life, the combination therapy used was: rosiglitazone as ACSL4 inhibitor [28], zileuton as LOX-5 inhibitor [29], [30] and ibuprofen as a non-selective COX-2 inhibitor [31], [32]. We assayed the effectiveness of therapy based on a combination of sub-effective doses of the different inhibitors. "
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