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Preclinical characterization of signal transducer and activator of transcription 3 small molecule inhibitors for primary and metastatic brain cancer therapy.

Abstract
Signal transducer and activator of transcription 3 (STAT3) has been implicated as a hub for multiple oncogenic pathways. The constitutive activation of STAT3 is present in several cancers, including gliomas (GBMs), and is associated with poor therapeutic responses. Phosphorylation of STAT3 triggers its dimerization and nuclear transport, where it promotes the transcription of genes that stimulate tumor growth. In light of this role, inhibitors of the STAT3 pathway are attractive therapeutic targets for cancer. To this end, we evaluated the STAT3-inhibitory activities of three compounds (CPA-7 [trichloronitritodiammineplatinum(IV)], WP1066 [(S,E)-3-(6-bromopyridin-2-yl)-2-cyano-N-(1-phenylethyl)acrylamide, C17H14BrN3O], and ML116 [4-benzyl-1-{thieno[2,3-d]pyrimidin-4-yl}piperidine, C18H19N3S]) in cultured rodent and human glioma cells, including GBM cancer stem cells. Our results demonstrate a potent induction of growth arrest in GBM cells after drug treatment with a concomitant induction of cell death. Although these compounds were effective at inhibiting STAT3 phosphorylation, they also displayed variable dose-dependent inhibition of STAT1, STAT5, and nuclear factor κ light-chain enhancer of activated B cells. The therapeutic efficacy of these compounds was further evaluated in peripheral and intracranial mouse tumor models. Whereas CPA-7 elicited regression of peripheral tumors, both melanoma and GBM, its efficacy was not evident when the tumors were implanted within the brain. Our data suggest poor permeability of this compound to tumors located within the central nervous system. WP1066 and ML116 exhibited poor in vivo efficacy. In summary, CPA-7 constitutes a powerful anticancer agent in models of peripheral solid cancers. Our data strongly support further development of CPA-7-derived compounds with increased permeability to enhance their efficacy in primary and metastatic brain tumors.
AuthorsHikmat H Assi, Chris Paran, Nathan VanderVeen, Jonathan Savakus, Robert Doherty, Emanuele Petruzzella, James D Hoeschele, Henry Appelman, Leda Raptis, Tom Mikkelsen, Pedro R Lowenstein, Maria G Castro
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 349 Issue 3 Pg. 458-69 (Jun 2014) ISSN: 1521-0103 [Electronic] United States
PMID24696041 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • 4-benzyl-1-(thieno(2,3-d)pyrimidin-4-yl)piperidine
  • Antineoplastic Agents
  • Chlorine Compounds
  • Heterocyclic Compounds, 2-Ring
  • Piperidines
  • Platinum Compounds
  • Pyridines
  • STAT3 Transcription Factor
  • Small Molecule Libraries
  • Tyrphostins
  • WP1066
  • trichloronitritodiammineplatinum(IV)
Topics
  • Animals
  • Antineoplastic Agents (pharmacokinetics, pharmacology, therapeutic use)
  • Apoptosis (drug effects)
  • Blood-Brain Barrier (metabolism)
  • Brain Neoplasms (drug therapy, metabolism, pathology)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Chlorine Compounds (pharmacokinetics, pharmacology, therapeutic use)
  • Drug Screening Assays, Antitumor
  • Glioma (drug therapy, metabolism, pathology)
  • HEK293 Cells
  • Heterocyclic Compounds, 2-Ring (pharmacokinetics, pharmacology, therapeutic use)
  • Humans
  • Melanoma, Experimental (drug therapy, metabolism, pathology, secondary)
  • Mice
  • Piperidines (pharmacokinetics, pharmacology, therapeutic use)
  • Platinum Compounds (pharmacokinetics, pharmacology, therapeutic use)
  • Pyridines (pharmacokinetics, pharmacology, therapeutic use)
  • STAT3 Transcription Factor (antagonists & inhibitors, genetics)
  • Small Molecule Libraries (pharmacokinetics, pharmacology, therapeutic use)
  • Tissue Distribution
  • Tyrphostins (pharmacokinetics, pharmacology, therapeutic use)

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