Preclinical validation of Aurora kinases-targeting drugs in osteosarcoma

Abstract

Background: Aurora kinases are key regulators of cell cycle and represent new promising therapeutic targets in several human tumours.

Alisertib (MLN8237), a selective Aurora-A kinase inhibitor, induces apoptosis in human tongue squamous cell carcinoma cell both in vitro and in vivo

“…Aurora-A kinases are observed at centrosomes and adjacent spindle fibers, and current evidence supports key roles in regulating protein localization and function at centrosomes, as well as regulation of the assembly, stability, and function of the mitotic spindle [3]. A number of experimental observations suggest Aurora-A kinases overexpression in many cancer tissues and cells [4][5][6]. Inhibition of Aurora-A kinases could inhibit proliferation, viability, migration, and invasion of gastric cancer cells [6].…”

Advances in emerging drugs for osteosarcoma

“…In human OS experimental models, we have recently provided evidence that inhibiting ABCB1 transport activity with CBT-1 (CBA Research Inc., Lexington, KY), a new generation of ABC transporter inhibitor, may open new therapeutic perspectives based on the use of this agent as potential adjuvant to standard chemotherapy in ABCB1-overexpressing OS patients [69,70].…”

Targeting polo-like kinase 1 by NMS-P937 in osteosarcoma cell lines inhibits tumor cell growth and partially overcomes drug resistance

“…Secondly, NMS-P937 can negatively interact with ABCB1-mediated drug transport and partially revert ABCB1-mediated drug resistance, which is the main mechanism responsible for treatment unresponsiveness of OS patients [22,24]. In this perspective, it is also worth noting that ABCB1 inhibitor CBT-1 confirmed its efficacy on drugresistant OS cells, as indicated in a recent study [18], further proposing itself as a new candidate agent for treatment of drug-unresponsive OS patients.…”

“…To define the type of interaction in terms of synergism, antagonism or additivity, the combination index (CI) of each two-drug combination was calculated with the equation of Chou-Talalay by using the CalcuSyn software (Biosoft, Stapleford, UK), as previously described [14,18]. By following the range of CI values indicated in the CalcuSyn software manual, we classified drug-drug interaction as synergistic when CI was lower than 0.90, as additive when 0.90≤CI≤ 1.10, or as antagonistic when CI was higher than 1.10.…”