Effect of interleukin-8 gene silencing with liposome-encapsulated small interfering RNA on ovarian cancer cell growth

William M. Merritt, Yvonne G. Lin, Whitney A. Spannuth, Mavis S. Fletcher, Aparna A. Kamat, Liz Y. Han, Charles N. Landen, Nicholas Jennings, Koen De Geest, Robert R. Langley, Gabriel Villares, Angela Sanguino, Susan K. Lutgendorf, Gabriel Lopez-Berestein, Menashe M. Bar-Eli, Anil K. Sood

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198 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)359-372
Number of pages14
JournalJournal of the National Cancer Institute
Volume100
Issue number5
DOIs
StatePublished - Mar 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Merritt, W. M., Lin, Y. G., Spannuth, W. A., Fletcher, M. S., Kamat, A. A., Han, L. Y., Landen, C. N., Jennings, N., De Geest, K., Langley, R. R., Villares, G., Sanguino, A., Lutgendorf, S. K., Lopez-Berestein, G., Bar-Eli, M. M., & Sood, A. K. (2008). Effect of interleukin-8 gene silencing with liposome-encapsulated small interfering RNA on ovarian cancer cell growth. Journal of the National Cancer Institute, 100(5), 359-372. https://doi.org/10.1093/jnci/djn024