Journal Article

KSP inhibitor ARRY-520 as a substitute for Paclitaxel in Type I ovarian cancer cells

Kim, Ki Hyung, Woessner, Richard, Alvero, Ayesha B, Mor, Gil, Xie, Yanhua, Tytler, Ewan M

2009

Overview

Background We previously described a sub-population of epithelial ovarian cancer (EOC) cells with a functional TLR-4/MyD88/NF-κB pathway (Type I EOC cells), which confers the capacity to respond to Paclitaxel, a known TLR-4 ligand, by enhancing NF-κB activity and upregulating cytokine secretion – events that are known to promote tumor progression. It is therefore important to distinguish those patients that should not receive Paclitaxel; it is also important to identify alternative chemotherapy options that would benefit this sub-group of patients. The objective of this study is to determine if the KSP inhibitor, ARRY-520, can be a substitute for Paclitaxel in patients with Type I EOC. Methods EOC cells isolated from either ascites or tumor tissue were treated with increasing concentrations of ARRY-520 or Paclitaxel and cell viability determined. Activation of the apoptotic pathway was determined using Western blot analysis. Mitochondrial integrity was quantified using JC1 dye. Cytokine profiling was performed from supernatants using xMAP technology. NF-κB activity was measured using a Luciferase reporter system. In vivo activity was determined using a subcutaneous xenograft mouse model. Results ARRY-520 and Paclitaxel exhibited the same cytotoxic effect on Type I and II cells. The GI 50 at 48 h for Type II EOC cells was 0.0015 μM and 0.2 μM for ARRY-520 and Paclitaxel, respectively. For Type I EOC cells, the GI 50 at 48 h was > 3 μM and >20 μM for ARRY-520 and Paclitaxel, respectively. Decrease in the number of viable cells was accompanied by mitochondrial depolarization and caspase activation. Unlike Paclitaxel, ARRY-520 did not induce NF-κB activation, did not enhance cytokine secretion, nor induce ERK phosphorylation in Type I EOC cells. Conclusion Administration of Paclitaxel to patients with high percentage Type I cancer cells could have detrimental effects due to Paclitaxel-induced enhancement of NF-κB and ERK activities, and cytokine production (e.g. IL-6), which promote chemoresistance and tumor progression. ARRY-520 has similar anti-tumor activity in EOC cells as that of Paclitaxel. However, unlike Paclitaxel, it does not induce these pro-tumor effects in Type I cells. Therefore, the KSP inhibitor ARRY-520 may represent an alternative to Paclitaxel in this subgroup of EOC patients.

• Publisher: BioMed Central,BioMed Central Ltd,BMC
• Subject: Antineoplastic Agents, Phytogenic - therapeutic use / Apoptosis - drug effects / Ascites - pathology / Biomedical and Life Sciences / Biomedicine / Caspase 3 - analysis / Caspase 3 - metabolism / Caspase 7 - analysis / Caspase 7 - metabolism / Caspase 9 - analysis / Caspase 9 - metabolism / Cell Line, Tumor / Cell Survival - drug effects / Development and progression / Diagnosis / Dosage and administration / Dose-Response Relationship, Drug / Drug therapy / Enzyme Activation - drug effects / Enzyme inhibitors / Enzyme Inhibitors - pharmacology / Female / Genes, Reporter / Humans / Inhibitory Concentration 50 / Kinesins - antagonists & inhibitors / Luciferases - metabolism / Medicine/Public Health / Organ Culture Techniques / Ovarian cancer / Ovarian Neoplasms - drug therapy / Ovarian Neoplasms - pathology / Paclitaxel / Paclitaxel - therapeutic use / Thiadiazoles - antagonists & inhibitors / Time Factors / Transfection