Short and long-term tumor cell responses to Aurora kinase inhibitors.
Aurora kinases are essential for mitosis and are candidate targets of novel chemotherapeutic agents. The inhibitors ZM447439, MK-0457 (VX-680) as well as Hesperadin have been used to dissect the roles of Aurora kinases in the cell cycle and have been tested clinically for the treatment of cancer. Here we have carried out a detailed kinetic analysis of two isogenic cell lines differing in p53 function and have compared the effects of ZM447439 and VE-465 (related to MK-0457). We find that p53 is needed for efficient cell cycle arrest when Aurora kinases are inhibited by either ZM447439 or VE-465. However, the p53-induced cell cycle block is neither immediate nor absolute. ZM447439 induced the localized accumulation of gammaH2A.X indicating that p53 induction by this drug occurs in response to DNA damage. Our analysis of the long-term effects of ZM447439 indicates that cells can evade killing by the drug, but not via a classical drug-resistance mechanism. Several mechanisms to explain how cells may evade killing by Aurora kinase inhibitors are described.
Dreier
Megan R
MR
Department of Biological Sciences, University of Toledo, Toledo, OH 43606, USA. megan.dreier@utoledo.edu
Grabovich
Aaron Z
AZ
Katusin
Jamie D
JD
Taylor
William R
WR
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D064127:Aurora Kinases; D001549:Benzamides / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects*; D004249:DNA Damage; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D010879:Piperazines / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
D000972:Antineoplastic Agents, Phytogenic; D064127:Aurora Kinases; D001549:Benzamides; D004791:Enzyme Inhibitors; D005047:Etoposide; D006657:Histones; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; D011799:Quinazolines; D016159:Tumor Suppressor Protein p53; C474722:4-(4-(N-benzoylamino)anilino)-6-methoxy-7-(3-(1-morpholino)propoxy)quinazoline; C468783:H2AX protein, human; C495901:TP53 protein, human; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines