Concomitant inhibition of Mdm2-p53 interaction and Aurora kinases activates the p53-dependent postmitotic checkpoints and synergistically induces p53-mediated mitochondrial apoptosis along with reduced endoreduplication in acute myelogenous leukemia.
Aberrant expression of Aurora kinases and inactivation of wild-type p53 by Mdm2 overexpression are frequent molecular events in acute myelogenous leukemia (AML), and preclinical data for inhibition of Aurora kinases or Mdm2 are promising. However, it remains largely unknown whether the viability of cells exposed to Aurora kinase inhibitors depends on the p53 status. We investigated the interaction of Aurora kinases and p53 pathways after their simultaneous blockades using a small-molecule pan-Aurora kinase inhibitor, MK-0457, and a selective small-molecule antagonist of Mdm2, Nutlin-3. We found that MK-0457, which itself activates p53 signaling, acts synergistically with Nutlin-3 to induce apoptosis in wild-type p53 AML cell lines OCI-AML-3 and MOLM-13 but not in p53-null HL-60 cells. MK-0457 and Nutlin-3 showed synergism in inducing p53, conformational change of Bax and Deltapsi(m) loss, suggesting an involvement of p53-mediated mitochondrial apoptosis. Nutlin-3 constrained endoreduplication after Aurora inhibition via activation of a p53-dependent postmitotic checkpoint and p21 induction in pseudo-G1 cells. Our findings provide the molecular rationale for concomitant targeting of Aurora kinases and Mdm2 in AML where TP53 mutations are rare and downstream p53 signaling is mostly intact.
Kojima
Kensuke
K
Department of Hematology, Wakayama Medical University, Wakayama, Japan.
Konopleva
Marina
M
Tsao
Twee
T
Nakakuma
Hideki
H
Andreeff
Michael
M
D017209:Apoptosis / Q000187:drug effects; D064127:Aurora Kinases; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004273:DNA, Neoplasm / Q000032:analysis; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D016193:G1 Phase / Q000187:drug effects; D020440:Gene Duplication / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D008938:Mitosis / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
D064127:Aurora Kinases; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004273:DNA, Neoplasm; D007093:Imidazoles; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; D051736:Proto-Oncogene Proteins c-mdm2; D016159:Tumor Suppressor Protein p53; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines; C482205:nutlin 3; C497206:MDM2 protein, human