Inhibition of Aurora-A results in increased cell death in 3-dimensional culture microenvironment, reduced migration and is associated with enhanced radiosensitivity in human nasopharyngeal carcinoma.

Abstract

Mitosis related Aurora-A kinase is amplified in a variety of carcinomas. Overexpression of Aurora-A contributes to tumorigenesis and disease progression, and has emerged as an attractive molecular target for the design of anticancer drugs. In this study, we investigated the function of Aurora-A selectively small molecule inhibitor VX-680 in nasopharyngeal carcinoma (NPC) CNE-2 cells. We found that VX-680 suppressed proliferation and induced apoptosis of 2Dimensional (2D) cultured NPC CNE-2 cells. Moreover, CNE-2 cells formed a tumor-like cell mass in 3Dimensional (3D) matrix culture microenvironment, and the tumor mass formation could be impaired when pretreated with VX-680 for indicated time. Similarly, when adding VX-680 to preformed 3D CNE-2 tumor mass, the tight spatial tumor mass experienced apparent apoptotic cell death and consequently dissociated into individual dead cells, as detected by cleaved Caspase-3 immunofluorescence assay. The migration assay showed that VX-680 decreased NPC CNE-2 cell migration ability in a dose-dependent manner. Our further study revealed that X-ray irradiation and VX-680 upregulated p53 expression level as well as arrested cell cycle in G(2)/M, sensitized NPC CNE-2 cells to radiation and effectively resulted in cell death. In summary, our data indicated that Aurora-A small molecule inhibitor VX-680, potently destructed tumor formation and induced apoptosis, reduced cell migration and enhanced radiosensitivity, offering a promising therapeutic agent for human NPC.

• Authors: Xiang-Bo Wan, Xin-Juan Fan, Ming-Yuan Chen, Jie Xu, Zi-Jie Long, Yi-Jun Hua, Hong Ji, Li Liu, Ming-Huang Hong, Yi-Xin Zeng, Quentin Liu
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 8 Issue 15 Pg. 1500-6 (Aug 2009) ISSN: 1555-8576 [Electronic] United States
• PMID: 19502819 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Neoplasm Proteins
• Piperazines
• Protein Kinase Inhibitors
• tozasertib
• Aurora Kinases
• Protein Serine-Threonine Kinases

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Aurora Kinases
• Carcinoma (enzymology, pathology)
• Cell Cycle (drug effects)
• Cell Division (drug effects)
• Cell Movement (drug effects)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Gene Expression Regulation, Neoplastic (drug effects)
• Genes, p53
• Humans
• Nasopharyngeal Neoplasms (enzymology, pathology)
• Neoplasm Proteins (antagonists & inhibitors, physiology)
• Piperazines (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, physiology)
• Radiation Tolerance (drug effects)
• Tumor Cells, Cultured (drug effects, enzymology, radiation effects)