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.
Footnotes
- Received March 13, 2014.
- Accepted March 31, 2014.
This work was supported by National Institutes of Health National Institute of Neurologic Disorders and Stroke [Grants U01-NS052465, U01-NS052465-S1, R01-NS074387, R01-NS057711, MICHR Pilot R14 U040007]; BioInterfaces Institute, University of Michigan [Grant U042841] (to M.G.C.); the National Institutes of Health National Institute of Neurologic Disorders and Stroke [Grants R01-NS054193, R01-NS061107, R01-NS082311, R21-NS084275] and University of Michgan [Grant M-Cube U036756] (to P.R.L.); the National Institutes of Health [Grant UL1-TR000433]; the National Institutes of Health National Cancer Institute [Training Grant T32-CA009676]; the National Institutes of Health National Institute of Neurologic Disorders and Stroke [Grant T32-NS007222]; the National Institutes of Health National Institute of General Medicine Sciences [Grant T32-GM007863]; and the National Institutes of Health through University of Michigan Cancer Center Support [Grant P30-CA046592].
↵This article has supplemental material available at jpet.aspetjournals.org.
- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|