期刊
INVESTIGATIONAL NEW DRUGS
卷 40, 期 3, 页码 556-564出版社
SPRINGER
DOI: 10.1007/s10637-022-01238-2
关键词
Kinesin Eg5; K858; Head and neck cancer; Kinesin KIF11
资金
- Ateneo grant of Sapienza University
K858, an inhibitor of motor kinesin Eg5, exerts significant antiproliferative and apoptotic effects on breast cancer, prostatic cancer, melanoma, and glioblastoma cells. It has been demonstrated that high levels of kinesin Eg5 expression are associated with poor prognosis in laryngeal carcinoma. This study investigated the anticancer activity of K858 on head and neck squamous cell carcinomas (HNSCCs), which are known to be unresponsive to therapy. The findings suggest that K858 inhibits cell replication, blocks the cell cycle in the G2 phase, induces apoptosis, and attenuates the malignant phenotype, making it a potential therapeutic option for HNSCCs.
Our group recently demonstrated that K858, an inhibitor of motor kinesin Eg5, has important antiproliferative and apoptotic effects on breast cancer, prostatic cancer, melanoma and glioblastoma cells. Since high levels of kinesin Eg5 expression have been correlated with a poor prognosis in laryngeal carcinoma, we decided to test the anticancer activity of K858 toward this tumor, which belongs to the group of head and neck squamous cell carcinomas (HNSCCs). These cancers are characterized by low responsiveness to therapy. The effects of K858 on the proliferation and assembly of mitotic spindles of three human HNSCC cell lines were studied using cytotoxicity assays and immunofluorescence for tubulin. The effect of K858 on the cell cycle was analyzed by FACS. The expression levels of cyclin B1 and several markers of apoptosis and invasion were studied by Western blot. Finally, the negative regulation of the malignant phenotype by K858 was evaluated by an invasion assay. K858 inhibited cell replication by rendering cells incapable of developing normal bipolar mitotic spindles. At the same time, K858 blocked the cell cycle in the G2 phase and induced the accumulation of cytoplasmic cyclin B and, eventually, apoptosis. Additionally, K858 inhibited cell migration and attenuated the malignant phenotype. The data described confirm that kinesin Eg5 is an interesting target for new anticancer strategies and suggest that this compound may be a powerful tool for an alternative therapeutic approach to HNSCCs.
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