Abstract | PURPOSE: METHODS: Eleven lung cancer cell lines were studied. Growth inhibition by MK-5108 was assessed with short- and long-term MTT assays. Cell cycling was measured by flow cytometry. Immunoblotting was used to determine targeted activity of MK-5108 on Aurora A and downstream effects (TACC3 and Plk1). Efficacy of combination studies performed with cisplatin and docetaxel was evaluated by median effect analysis. RESULTS: All cell lines demonstrated sustained growth inhibition following MK-5108 at varying nanomolar concentrations. MK-5108 induced G2/M accumulation, polyploidy, and apoptosis (increased sub-G1/PARP cleavage). Levels of Aurora A, TACC3, and Plk1 diminished. Concurrent treatment of MK-5108 with cisplatin or docetaxel synergistically inhibited cell growth with the docetaxel combination performing better. When administered sequentially, treatment with docetaxel first followed by MK-5108 exhibited greater growth inhibition than the inverse; yet concurrent treatment remained superior. CONCLUSIONS:
MK-5108 has potent anti-proliferative activity in lung cancer cell lines alone and in combination with chemotherapies. Determining how best to integrate Aurora inhibitors into current lung cancer treatment regimens would be beneficial.
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Authors | Danielle C Chinn, William S Holland, Philip C Mack |
Journal | Journal of cancer research and clinical oncology
(J Cancer Res Clin Oncol)
Vol. 140
Issue 7
Pg. 1137-49
(Jul 2014)
ISSN: 1432-1335 [Electronic] Germany |
PMID | 24756365
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- 4-(3-chloro-2-fluorophenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridin to 2-yl)methyl) cyclohexanecarboxylic acid
- Cyclohexanecarboxylic Acids
- Protein Kinase Inhibitors
- Taxoids
- Thiazoles
- Docetaxel
- Aurora Kinase A
- Cisplatin
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Topics |
- Antineoplastic Combined Chemotherapy Protocols
(therapeutic use)
- Aurora Kinase A
(antagonists & inhibitors)
- Carcinoma, Non-Small-Cell Lung
(drug therapy, pathology)
- Cell Cycle
(drug effects)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Cisplatin
(administration & dosage)
- Cyclohexanecarboxylic Acids
(administration & dosage)
- Docetaxel
- Humans
- Lung Neoplasms
(drug therapy, pathology)
- Protein Kinase Inhibitors
(administration & dosage)
- Taxoids
(administration & dosage)
- Thiazoles
(administration & dosage)
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