TY - JOUR
T1 - Effect of interleukin-8 gene silencing with liposome-encapsulated small interfering RNA on ovarian cancer cell growth
AU - Merritt, William M.
AU - Lin, Yvonne G.
AU - Spannuth, Whitney A.
AU - Fletcher, Mavis S.
AU - Kamat, Aparna A.
AU - Han, Liz Y.
AU - Landen, Charles N.
AU - Jennings, Nicholas
AU - De Geest, Koen
AU - Langley, Robert R.
AU - Villares, Gabriel
AU - Sanguino, Angela
AU - Lutgendorf, Susan K.
AU - Lopez-Berestein, Gabriel
AU - Bar-Eli, Menashe M.
AU - Sood, Anil K.
N1 - Funding Information:
National Institutes of Health (NIH; CA110793 and CA199298); the University of Texas M. D. Anderson Ovarian Cancer Spore (P50 CA083639); Ovarian Cancer Research Fund, Inc. (Program Project Development Grant); Zarrow Foundation (to A.K.S.); National Cancer Institute — DHHS — NIH T32 Training Grant (T32 CA101642 to W.M.M., Y.G.L., and W.A.S.).
PY - 2008/3
Y1 - 2008/3
N2 - 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.
AB - 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.
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U2 - 10.1093/jnci/djn024
DO - 10.1093/jnci/djn024
M3 - Article
C2 - 18314475
AN - SCOPUS:40949126550
VL - 100
SP - 359
EP - 372
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
SN - 0027-8874
IS - 5
ER -