Aurora B kinase as a novel molecular target for inhibition the growth of osteosarcoma.

Abstract

Osteosarcoma is the primary human malignant tumor affecting bone. This cancer most frequently arises in children and adolescents, with a second peak in those over the age of 50. Currently, surgery followed by radiotherapy and chemotherapy are the main treatments, but long-term positive effects are very poor. Aurora B kinase is a serine/threonine kinase that is a key regulator of cell cycle and mitosis. Tissue array analysis revealed that Aurora B kinase is overexpressed in osteosarcoma compared with normal bone tissue. We developed a compound, HOI-07 (i.e., (E)-3-((E)-4-(benzo[d] [1,3]dioxol-5-yl)-2-oxobut-3-en-1-ylidene)indolin-2-one), as a specific Aurora B kinase inhibitor and examined its effectiveness against osteosarcoma cell growth in this study. This compound inhibited Aurora B kinase activity in osteosarcoma and induced apoptosis, caused G2-M phase arrest, and attenuated osteosarcoma anchorage-independent cell growth. Moreover, knocking down the expression of Aurora B effectively reduced the sensitivity of osteosarcoma to HOI-07. Results of a xenograft mouse study indicated that HOI-07 treatment effectively suppressed the growth of 143B and KHOS xenografts, without affecting the body weight of mice. The expression of phosphorylated histone H3 (Ser10) was reduced in mice treated with HOI-07. Overall, we identified HOI-07 as a specific Aurora B kinase inhibitor for osteosarcoma treatment and this compound warrants further investigation.