Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/85687
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dc.contributor.author | Thomas, D. | - |
dc.contributor.author | Powell, J. | - |
dc.contributor.author | Vergez, F. | - |
dc.contributor.author | Segal, D. | - |
dc.contributor.author | Nguyen, N. | - |
dc.contributor.author | Baker, A. | - |
dc.contributor.author | Teh, T. | - |
dc.contributor.author | Barry, E. | - |
dc.contributor.author | Sarry, J. | - |
dc.contributor.author | Lee, E. | - |
dc.contributor.author | Nero, T. | - |
dc.contributor.author | Jabbour, A. | - |
dc.contributor.author | Giovanna, P. | - |
dc.contributor.author | Green, B. | - |
dc.contributor.author | Manenti, S. | - |
dc.contributor.author | Glaser, S. | - |
dc.contributor.author | Parker, M. | - |
dc.contributor.author | Lopez, A. | - |
dc.contributor.author | Ekert, P. | - |
dc.contributor.author | Lock, R. | - |
dc.contributor.author | et al. | - |
dc.date.issued | 2013 | - |
dc.identifier.citation | Blood, 2013; 122(5):738-748 | - |
dc.identifier.issn | 0006-4971 | - |
dc.identifier.issn | 1528-0020 | - |
dc.identifier.uri | http://hdl.handle.net/2440/85687 | - |
dc.description.abstract | Resistance to cell death is a hallmark of cancer and renders transformed cells resistant to multiple apoptotic triggers. The Bcl-2 family member, Mcl-1, is a key driver of cell survival in diverse cancers, including acute myeloid leukemia (AML). A screen for compounds that downregulate Mcl-1 identified the kinase inhibitor, PIK-75, which demonstrates marked proapoptotic activity against a panel of cytogenetically diverse primary human AML patient samples. We show that PIK-75 transiently blocks Cdk7/9, leading to transcriptional suppression of MCL-1, rapid loss of Mcl-1 protein, and alleviation of its inhibition of proapoptotic Bak. PIK-75 also targets the p110α isoform of PI3K, which leads to a loss of association between Bcl-xL and Bak. The simultaneous loss of Mcl-1 and Bcl-xL association with Bak leads to rapid apoptosis of AML cells. Concordantly, low Bak expression in AML confers resistance to PIK-75–mediated killing. On the other hand, the induction of apoptosis by PIK-75 did not require the expression of the BH3 proteins Bim, Bid, Bad, Noxa, or Puma. PIK-75 significantly reduced leukemia burden and increased the survival of mice engrafted with human AML without inducing overt toxicity. Future efforts to cotarget PI3K and Cdk9 with drugs such as PIK-75 in AML are warranted. | - |
dc.description.statementofresponsibility | Daniel Thomas, Jason A. Powell ... Angel F. Lopez ... Mark A. Guthridge | - |
dc.language.iso | en | - |
dc.publisher | American Society of Hematology | - |
dc.rights | © 2013 by The American Society of Hematology | - |
dc.source.uri | http://dx.doi.org/10.1182/blood-2012-08-447441 | - |
dc.subject | Cells, Cultured | - |
dc.subject | HL-60 Cells | - |
dc.subject | Animals | - |
dc.subject | Mice, Inbred NOD | - |
dc.subject | Mice, Knockout | - |
dc.subject | Humans | - |
dc.subject | Mice | - |
dc.subject | Mice, SCID | - |
dc.subject | Sulfonamides | - |
dc.subject | Hydrazones | - |
dc.subject | Proto-Oncogene Proteins c-bcl-2 | - |
dc.subject | Antineoplastic Agents | - |
dc.subject | Protein Kinase Inhibitors | - |
dc.subject | Xenograft Model Antitumor Assays | - |
dc.subject | Signal Transduction | - |
dc.subject | Transcription, Genetic | - |
dc.subject | Gene Expression Regulation, Leukemic | - |
dc.subject | Cyclin-Dependent Kinase 9 | - |
dc.subject | Leukemia, Myeloid, Acute | - |
dc.subject | HEK293 Cells | - |
dc.subject | Molecular Targeted Therapy | - |
dc.subject | Myeloid Cell Leukemia Sequence 1 Protein | - |
dc.subject | Phosphoinositide-3 Kinase Inhibitors | - |
dc.title | Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1182/blood-2012-08-447441 | - |
pubs.publication-status | Published | - |
dc.identifier.orcid | Lopez, A. [0000-0001-7430-0135] | - |
Appears in Collections: | Aurora harvest 7 Medicine publications |
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