Oncotarget

Research Papers:

IKK inhibition increases bortezomib effectiveness in ovarian cancer

Bipradeb Singha, Himavanth Reddy Gatla, Sai Phyo, Atish Patel, Zhe-Sheng Chen and Ivana Vancurova _

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Oncotarget. 2015; 6:26347-26358. https://doi.org/10.18632/oncotarget.4713

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Abstract

Bipradeb Singha1, Himavanth Reddy Gatla1, Sai Phyo1, Atish Patel2, Zhe-Sheng Chen2, Ivana Vancurova1

1Department of Biological Sciences, St. John's University, Queens, NY 11439, USA

2Department of Pharmaceutical Sciences, St. John's University, Queens, NY 11439, USA

Correspondence to:

Ivana Vancurova, e-mail: [email protected]

Keywords: bortezomib, IKK, interleukin-8, ovarian cancer, proteasome inhibition

Received: May 13, 2015     Accepted: July 08, 2015     Published: July 20, 2015

ABSTRACT

Ovarian cancer is associated with increased expression of the pro-angiogenic chemokine interleukin-8 (IL-8, CXCL8), which induces tumor cell proliferation, angiogenesis, and metastasis. Even though bortezomib (BZ) has shown remarkable anti-tumor activity in hematological malignancies, it has been less effective in ovarian cancer; however, the mechanisms are not understood. We have recently shown that BZ unexpectedly induces the expression of IL-8 in ovarian cancer cells in vitro, by IκB kinase (IKK)-dependent mechanism. Here, we tested the hypothesis that IKK inhibition reduces the IL-8 production and increases BZ effectiveness in reducing ovarian tumor growth in vivo. Our results demonstrate that the combination of BZ and the IKK inhibitor Bay 117085 significantly reduces the growth of ovarian tumor xenografts in nude mice when compared to either drug alone. Mice treated with the BZ/Bay 117085 combination exhibit smallest tumors, and lowest levels of IL-8. Furthermore, the reduced tumor growth in the combination group is associated with decreased tumor levels of S536P-p65 NFκB and its decreased recruitment to IL-8 promoter in tumor tissues. These data provide the first in vivo evidence that combining BZ with IKK inhibitor is effective, and suggest that using IKK inhibitors may increase BZ effectiveness in ovarian cancer treatment.


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