Journal article
Effect of Interleukin-8 Gene Silencing With Liposome-Encapsulated Small Interfering RNA on Ovarian Cancer Cell Growth
JNCI : Journal of the National Cancer Institute, Vol.100(5), pp.359-372
2008
DOI: 10.1093/jnci/djn024
PMCID: PMC2770251
PMID: 18314475
Abstract
Background Interleukin-8 (IL-8) is a proangiogenic cytokine that is overexpressed in many human cancers. We investigated the clinical and biologic significance of IL-8 in ovarian carcinoma using human samples and orthotopic mouse models. Methods Tumor expression of IL-8 was assessed by immunohistochemistry among ovarian cancer patients (n = 102) with available clinical and survival data. We examined the effect of IL-8 gene silencing with small interfering RNAs incorporated into neutral liposomes (siRNA-DOPCs), alone and in combination with docetaxel, on in vivo tumor growth, angiogenesis (microvessel density), and tumor cell proliferation in mice (n = 10 per treatment group) bearing orthotopic taxane-sensitive (HeyA8 and SKOV3ip1) and taxane-resistant (SKOV3ip2.TR) ovarian tumors. All statistical tests were two-sided. Results Of the 102 cancer specimens, 43 (42%) had high IL-8 expression and 59 (58%) had low or no IL-8 expression; high IL-8 expression was associated with advanced tumor stage (P = .019), high tumor grade (P = .031), and worse survival (median survival for patients with high vs low IL-8 expression: 1.62 vs 3.79 years; P < .001). Compared with empty liposomes, IL-8 siRNA-DOPC reduced the mean tumor weight by 32% (95% confidence interval [CI] = 14% to 50%; P = .03) and 52% (95% CI = 27% to 78%; P = .03) in the HeyA8 and SKOV3ip1 mouse models, respectively. In all three mouse models, treatment with IL-8 siRNA-DOPC plus the taxane docetaxel reduced tumor growth the most compared with empty liposomes (77% to 98% reduction in tumor growth; P < .01 for all). In the HeyA8 and SKOV3ip1 models, tumors from mice treated with IL-8 siRNA-DOPC alone had lower microvessel density than tumors from mice treated with empty liposomes (HeyA8: 34% lower, 95% CI = 32% to 36% lower [P = .002]; SKOV3ip1: 39% lower, 95% CI = 34% to 44% lower [P = .007]). Compared with empty liposomes, IL-8 siRNA-DOPC plus docetaxel reduced tumor cell proliferation by 35% (95% CI = 25% to 44%; P < .001) and 38% (95% CI = 28% to 48%; P < .001) in the HeyA8 and SKOV3ip1 models, respectively. Conclusions Increased IL-8 expression is associated with poor clinical outcome in human ovarian carcinoma, and IL-8 gene silencing decreases tumor growth through antiangiogenic mechanisms.
Details
- Title: Subtitle
- Effect of Interleukin-8 Gene Silencing With Liposome-Encapsulated Small Interfering RNA on Ovarian Cancer Cell Growth
- Creators
- William M. MerrittYvonne G. LinWhitney A. SpannuthMavis S. FletcherAparna A. KamatLiz Y. HanCharles N. LandenNicholas JenningsKoen De Geest - Oregon Health & Science UniversityRobert R. LangleyGabriel VillaresAngela SanguinoSusan K. Lutgendorf - University of Iowa, Iowa Neuroscience InstituteGabriel Lopez-Berestein - The University of Texas MD Anderson Cancer CenterMenashe M. Bar-EliAnil K. Sood - The University of Texas MD Anderson Cancer Center
- Resource Type
- Journal article
- Publication Details
- JNCI : Journal of the National Cancer Institute, Vol.100(5), pp.359-372
- Publisher
- Oxford University Press
- DOI
- 10.1093/jnci/djn024
- PMID
- 18314475
- PMCID
- PMC2770251
- ISSN
- 0027-8874
- eISSN
- 1460-2105
- Language
- English
- Date published
- 2008
- Academic Unit
- Psychological and Brain Sciences; Iowa Neuroscience Institute; Obstetrics and Gynecology; Urology
- Record Identifier
- 9983557774802771
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