IKK inhibition increases bortezomib effectiveness in ovarian cancer.

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.

• Authors: Bipradeb Singha, Himavanth Reddy Gatla, Sai Phyo, Atish Patel, Zhe-Sheng Chen, Ivana Vancurova
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 28 Pg. 26347-58 (Sep 22 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26267322 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• BAY 11-7085
• CXCL8 protein, human
• Interleukin-8
• Nitriles
• Proteasome Inhibitors
• Protein Kinase Inhibitors
• RELA protein, human
• Sulfones
• Transcription Factor RelA
• Bortezomib
• I-kappa B Kinase
• IKBKB protein, human

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Binding Sites
• Bortezomib (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Female
• Humans
• I-kappa B Kinase (antagonists & inhibitors, metabolism)
• Interleukin-8 (genetics, metabolism)
• Mice, Nude
• Nitriles (pharmacology)
• Ovarian Neoplasms (drug therapy, enzymology, genetics, pathology)
• Promoter Regions, Genetic
• Proteasome Inhibitors (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• RNA Interference
• Sulfones (pharmacology)
• Time Factors
• Transcription Factor RelA (metabolism)
• Transfection
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays