PMCID string | Title string | Sentences string |
|---|---|---|
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | The PTX10 cell line exhibited little cell death in low doses of VE-465, but as the concentrations approached 100 nM the percentage of apoptotic cells increased 8-fold (Fig. 4A). |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | The presence of both drugs, paclitaxel and VE-465, did not act synergistically in the PTX10 or 1A9 cell lines at high concentrations as the levels of cell death were only slightly increased when treated with VE-465 in the presence of paclitaxel (Fig. 4C and 4D). |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Caspase 3/7 assays of PTX10 cells confirmed that there was no statistically significant difference in apoptosis induction between cells treated with VE-465 alone or in combination with 15 ng/mL paclitaxel (Fig. 4E). |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | VE-465 induces cell death in the presence of paclitaxel. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Cells were treated for 96 hours with differing doses of VE-465 in the presence of 15 ng/mL paclitaxel. ( |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | PTX10 cells (B) 1A9 cells. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Analysis was performed as described in Figure 3. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | The sub G0/G1 population represents apoptotic cells. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Each time point represents data from at least 3 independent experiments. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Paclitaxel and VE-465 did not synergize to cause apoptosis in PTX10 (C) or 1A9 (D) cells. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Percent of apoptotic cells are plotted for cells treated for 96 hrs with VE-465 alone or VE-465 and 15 ng/mL paclitaxel. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Triangles – cells treated with increasing concentrations of VE-465. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Squares – cells treated with increasing concentrations of VE-465 in the presence of 15 ng/mL paclitaxel. ( |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Caspase 3/7 assays of PTX10 cells treated with 10–100 nM of VE-465 alone or in combination with 15 ng/mL paclitaxel. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Confirming flow cytometry data, combination treatment with paclitaxel and VE-465 did not synergistically increase apoptosis in the PTX10 cell line. ( |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Caspase 3/7 assays of 1A9 cells treated with 1–3 nM of VE-465 alone, 15 ng/mL paclitaxel alone, or in combination with 15 ng/mL paclitaxel. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | A dose of 3 nM VE-465 alone induced 2-fold more apoptosis than 15 ng/mL paclitaxel, whereas combined 3 nM VE-465 and 15 ng/mL paclitaxel synergistically induced 4.5-fold more apoptosis than 15 ng/mL paclitaxel alone. (* |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | = p-value less than 0.0025 by students T-test.) ( |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Immunoblot of 1A9 cells treated with increasing concentrations of VE-465 for 96 hours. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | The kinase activity of Aurora-A and Aurora-B is suppressed in a dose-dependent manner consistent with the known Ki values of VE-465. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Phosphorylation of the Aurora-A target p53 (S315) is inhibited at doses of 1 nM and higher whereas auto-phosphorylation of Aurora-B (T232) is only inhibited at doses exceeding 25 nM. We observed increased apoptosis at low doses of VE-465 in combination with 15 ng/mL paclitaxel in the paclitaxel-sensitive 1A9 cells (Fig... |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Therefore, we tested if doses of VE-465 that were specific to Aurora-A (3 nM or less) could synergize with paclitaxel to induce apoptosis in the 1A9 cell line. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | VE-465 alone induced 2-fold more apoptosis than 15 ng/mL paclitaxel alone (Fig. 4F). |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Compared to 15 ng/mL paclitaxel alone, 3 nM VE-465 combined with 15 ng/mL paclitaxel to cause a roughly 4.5-fold increase in cell death as measured by caspase 3/7 activity assay (Fig. 4F). |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | To confirm the effects were due to Aurora-A specific inhibition, we treated 1A9 cells with both low and high doses of VE-465 for 96 hours and probed immunoblots for phospho-Aurora-B (T232) and phospho-p53 (S315) (Fig. 4G). |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | is phosphorylated by Aurora-A but not Aurora-B . |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Aurora B auto-phosphorylates threonine residue 232 (T232) upon activation . |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Following VE-465 treatment, phoshpo-p53 levels are reduced at doses of 1 nM and higher, indicating an inhibition of Aurora-A activity. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | As expected, Aurora-B kinase activity was inhibited only at doses of VE-465 that exceeded 25 nM. The level of inhibition we observed is in agreement with the Ki values for Aurora-A (1 nM) and Aurora-B (25 nM), respectively. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | These results show that VE-465 by itself can induce apoptosis, and can synergize with paclitaxel at Aurora-A specific concentrations (< 5 nM) to enhance cell killing. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Recently, we identified Aurora-A kinase to be significantly overexpressed in carcinoma patients compared to adenomas . |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Our data suggested that reduced p53 activity can lead to improved clinical outcome for ovarian cancer patients undergoing chemotherapy . |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | One mechanism that might contribute to this phenomenon is that Aurora-A renders cells resistant to paclitaxel-induced apoptosis and stimulates Akt1 and Akt2 activity in wild-type p53 but not p53-null ovarian cancer cells . |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Thus, p53-null tumors would be more responsive to chemotherapy regimens. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Here, we have shown that the mitotic kinase Aurora-A is overexpressed in ovarian carcinomas compared to adenomas. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Furthermore, we have demonstrated that the pan-Aurora inhibitor VE-465 can synergize with paclitaxel to induce apoptosis and is a potent killer of taxane-sensitive and resistant ovarian cancer cells. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Although other Aurora family members were not overexpressed, other genes known to interact with Aurora-A kinase were significantly increased. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | One of the most significantly overexpressed was TPX2, an activator and substrate of Aurora-A . |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Recently, a link between another Aurora-A substrate, BRCA1, and TPX2 has been demonstrated . |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Juokov et al. showed that loss of BRCA1 expression leads to mislocalization of TPX2 along microtubules instead of at the aster poles, suggesting a mechanism by which BRCA1 mutation could lead to chromosomal instability . |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | TPX2 was overexpressed 15-fold in carcinomas and provides a possible mechanism for increased activation of Aurora-A kinase. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | These observations have implications for ovarian cancer because overexpression of Aurora-A can induce resistance to the chemotherapeutic paclitaxel . |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | We predicted that ovarian cancer patients who overexpress Aurora-A would have a higher chance of becoming resistant to taxanes and possibly benefit from a different treatment strategy targeted at Aurora-A and other Aurora family members. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | To test this prediction, we evaluated the compound VE-465 as a pan-Aurora kinase inhibitor and inducer of apoptosis in ovarian cancer cell lines. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Although VE-465 is not specific to Aurora-A, it is highly selective and effective at inhibiting Aurora family kinases and offered a unique opportunity to evaluate the entire family of kinases as a therapeutic target. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Our results indicate that VE-465 is able to induce apoptosis in the paclitaxel resistant, ovarian cancer cell line PTX10 in a dose dependent manner and synergize with paclitaxel in the 1A9 paclitaxel-sensitive cell line. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | VE-465 and paclitaxel are both drugs that function by targeting mitotic cells, but induce apoptosis by different mechanisms. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Paclitaxel alters microtubule dynamics and induces the spindle checkpoint resulting in mitotic arrest and eventual apoptosis. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | VE-465, on the other hand, inhibits the activity of the Aurora kinase family and subsequent mitotic entry. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | We found that many PTX10 cells treated with VE-465 bypass the spindle checkpoint resulting in missegregation of chromosomes and aneuploidy, possibly due to the inhibition of other family members such as Aurora-B. Thus, in addition to inhibiting mitotic entry, VE-465 appears to induce apoptosis by causing catastrophic c... |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Intriguingly, 1A9 cells were more sensitive to VE-465 than PTX10 cells and this correlates with the roughly two fold higher expression of Aurora-A in the 1A9 cell line. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Significant cell death was observed at low concentrations in 1A9 cells such as 1–25 nM relative to 50–75 nM for PTX10 cells, suggesting that at low doses VE-465 synergizes with paclitaxel in taxol-sensitive ovarian cancer cells. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Interestingly, at low concentrations VE-465 has a Ki more specific to Aurora-A (1 nM) than Aurora-B (26 nM) or -C (9 nM). |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | This suggests the synergistic effects are due to the specific inhibition of Aurora-A and not other family members. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | However, at higher concentrations, we found no evidence that paclitaxel and VE-465 synergized to induce apoptosis in PTX10 cells. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | This could be because a very high percentage of cells are undergoing apoptosis at high doses, or possibly due to the inherent nature of the resistance of PTX0 cells. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | PTX10 cells harbor a point mutation in the M40 β-tubulin isotype resulting in a phenylalanine to valine mutation which may alter the binding of paclitaxel to microtubules. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | It is possible that this particular form of resistance does not coincide with the function of Aurora kinases and therefore no synergism is seen when treating with a combination of both drugs. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Tumors that exhibit other forms of taxane resistance such as Aurora-A overexpression, alternate point mutations, modulations in tubulin isotypes, decreased tubulin expression and changes in post-translational modifications may respond synergistically when treated with VE-465 and paclitaxel. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Alternatively, a synergistic effect may be observed prior to the acquisition of taxol resistance, or in combination with other drugs that target different cellular pathways such as tyrosine kinase receptor signals or apoptosis resistance pathways. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Aurora kinase inhibitors represent a promising alternative to taxane therapy, especially for patients who overexpress the mitotic kinase Aurora-A, or other family members, or whose disease continues to progress during taxane therapy . |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Treatment of patients with different drugs in a serial fashion allows for clones that are resistant to one therapy to arise by drug-resistance selection. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | However, combinatorial therapies may be more effective, as has been shown using cocktail therapies for the treatment of the rapidly evolving human immunodeficiency virus . |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Thus, initial combinatorial chemotherapy using Aurora-inhibitors, paclitaxel, and other chemotherapeutic agents could be an effective approach to prevent the development of chemo-resistant ovarian cancers. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | In summary, we have shown the mitotic kinase Aurora-A to be overexpressed in ovarian carcinomas compared to adenomas. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Furthermore, we demonstrated the pan-Aurora inhibitor VE-465 can synergize with paclitaxel to induce apoptosis and is a potent killer of taxane-sensitive and resistant ovarian cancer cells. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | Our results suggest that Aurora kinase inhibitors could be useful for treatment of taxane resistant ovarian tumors. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | The authors declare that they have no competing interests. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | CDS performed the flow cytometry, immunofluorescence, drug treatments, and immunoblotting experiments and wrote the initial draft. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | NL performed the caspase 3/7 and qPCR assays. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | AOO read and scored the TMA. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | SL generated the tissue microarray. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | JFM generated the microarray expression data. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | BBB provided the ovarian patient tissue samples. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | CSM directed the research, analyzed the microarray data, and co-wrote the manuscript. |
PMC2614415 | Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells | All authors read and approved the manuscript. |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.