Preclinical characterization of signal transducer and activator of transcription 3 small molecule inhibitors for primary and metastatic brain cancer therapy.
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.
Department of Neurosurgery and Department of Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, Michigan (H.H.A., C.P., N.V., J.S., R.D., P.R.L., M.G.C.); Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California (H.H.A.); Department of Chemistry, Eastern Michigan University, Ypsilanti, Michigan (E.P., J.D.H.); Department of Pathology, University of Michigan School of Medicine, University Hospital, Ann Arbor, Michigan (H.A.); Department of Biomedical and Molecular Sciences, Queen's University School of Medicine, Kingston, Ontario, Canada (L.R.); and Department of Neurology, Henry Ford Hospital, Detroit, Michigan (T.M.).
Hikmat H
HH
Assi
Chris
C
Paran
Nathan
N
VanderVeen
Jonathan
J
Savakus
Robert
R
Doherty
Emanuele
E
Petruzzella
James D
JD
Hoeschele
Henry
H
Appelman
Leda
L
Raptis
Tom
T
Mikkelsen
Pedro R
PR
Lowenstein
Maria G
MG
Castro
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017606:Chlorine Compounds / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D004354:Drug Screening Assays, Antitumor; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006574:Heterocyclic Compounds, 2-Ring / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D051379:Mice; D010880:Piperidines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D017671:Platinum Compounds / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D054852:Small Molecule Libraries / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D014018:Tissue Distribution; D020032:Tyrphostins / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
C000589287:4-benzyl-1-(thieno(2,3-d)pyrimidin-4-yl)piperidine; D000970:Antineoplastic Agents; D017606:Chlorine Compounds; D006574:Heterocyclic Compounds, 2-Ring; D010880:Piperidines; D017671:Platinum Compounds; D011725:Pyridines; D050796:STAT3 Transcription Factor; D054852:Small Molecule Libraries; D020032:Tyrphostins; C519885:WP1066; C529200:trichloronitritodiammineplatinum(IV)