Clinical cancer research, 2012-08, Vol.18 (15), p.4104-4113
2012
Details
- Autor(en) / Beteiligte
- Titel
- Cancer Network Disruption by a Single Molecule Inhibitor Targeting Both Histone Deacetylase Activity and Phosphatidylinositol 3-Kinase Signaling
- Ist Teil von
- Clinical cancer research, 2012-08, Vol.18 (15), p.4104-4113
- Ort / Verlag
- Philadelphia, PA: American Association for Cancer Research
- Erscheinungsjahr
- 2012
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Given that histone deacetylase (HDAC) inhibitors are known to induce multiple epigenetic modifications affecting signaling networks and act synergistically with phosphatidylinositol 3-kinase (PI3K) inhibitors, we developed a strategy to simultaneously inhibit HDACs and PI3K in cancer cells. We constructed dual-acting inhibitors by incorporating HDAC inhibitory functionality into a PI3K inhibitor pharmacophore. CUDC-907, a development candidate selected from these dual inhibitors, was evaluated in vitro and in vivo to determine its pharmacologic properties, anticancer activity, and mechanism of action. CUDC-907 potently inhibits class I PI3Ks as well as classes I and II HDAC enzymes. Through its integrated HDAC inhibitory activity, CUDC-907 durably inhibits the PI3K-AKT-mTOR pathway and compensatory signaling molecules such as RAF, MEK, MAPK, and STAT-3, as well as upstream receptor tyrosine kinases. CUDC-907 shows greater growth inhibition and proapoptotic activity than single-target PI3K or HDAC inhibitors in both cultured and implanted cancer cells. CUDC-907 may offer improved therapeutic benefits through simultaneous, sustained disruption of multiple oncogenic signaling networks.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1078-0432eISSN: 1557-3265DOI: 10.1158/1078-0432.ccr-12-0055Titel-ID: cdi_proquest_miscellaneous_1030874255
- Format
- –
- Schlagworte
- Animals, Antineoplastic agents, Apoptosis - drug effects, Biological and medical sciences, Blotting, Western, Caspase 3 - metabolism, Cell Cycle - drug effects, Cell Line, Tumor, Cell Proliferation - drug effects, Enzyme Activation - drug effects, Enzyme Inhibitors - pharmacology, Female, HCT116 Cells, Histone Deacetylase Inhibitors - pharmacology, Histone Deacetylases - metabolism, Humans, Hydroxamic Acids - pharmacology, Medical sciences, Mice, Mice, Nude, Mice, SCID, Morpholines - pharmacology, Neoplasms - drug therapy, Neoplasms - metabolism, Neoplasms - pathology, Pharmacology. Drug treatments, Phosphatidylinositol 3-Kinase - antagonists & inhibitors, Phosphatidylinositol 3-Kinase - metabolism, Pyrimidines - pharmacology, Quinazolines - pharmacology, Sf9 Cells, Signal Transduction - drug effects, Tumor Burden - drug effects, Xenograft Model Antitumor Assays