title: Cyclin-dependent kinase 1 inhibitor RO-3306 enhances p53-mediated Bax activation and mitochondrial apoptosis in AML.
abstract: Cyclin-dependent kinase (CDK) 1 and the murine double minute 2 homolog (MDM2)-p53 interaction are potential therapeutic targets in cancer, and their inhibition has been reported to be more proapoptotic in malignant cells compared to normal cells. We investigated the effect of CDK1 inhibition on p53 signaling after simultaneous dual blockade using the CDK1 inhibitor RO-3306 and the MDM2 inhibitor Nutlin-3 in AML. Treatment of growing AML cells with RO-3306 induced G2/M-phase cell cycle arrest and apoptosis in a dose- and time-dependent manner. We found that RO-3306 acts cooperatively with Nutlin-3 to induce mitochondrial apoptosis in a cell cycle-independent fashion. RO-3306 downregulated expression of the antiapoptotic proteins Bcl-2 and survivin and blocked p53-mediated induction of p21 and MDM2. CDK1 siRNA experiments showed that reduced CDK1 expression affects p53-induced p21 transactivation. We suggest that RO-3306 actively enhances downstream p53 signaling to promote apoptosis and that a combination strategy aimed at both inhibiting CDK1 and activating p53 signaling is potentially effective in AML, where TP53 mutations are rare and downstream p53 signaling is intact.
authors.affiliation: Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan. k-koji@wakayama-med.ac.jp
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kojima
authors.forename: Masaya
authors.initials: M
authors.lastname: Shimanuki
authors.forename: Masato
authors.initials: M
authors.lastname: Shikami
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakakuma
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D018922:HL-60 Cells / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D013844:Thiazoles / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000187:drug effects / Q000378:metabolism*
chemical_list: D011804:Quinolines; D034741:RNA, Small Interfering; C512984:RO 3306; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051736:Proto-Oncogene Proteins c-mdm2; D016203:CDC2 Protein Kinase