QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jpet.105.083550v2 314/3/1134    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kristof, A. S. Articles by Moss, J. Search for Related Content PubMed PubMed Citation Articles by Kristof, A. S. Articles by Moss, J.

CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

LY303511 (2-Piperazinyl-8-phenyl-4H-1-benzopyran-4-one) Acts via Phosphatidylinositol 3-Kinase-Independent Pathways to Inhibit Cell Proliferation via Mammalian Target of Rapamycin (mTOR)- and Non-mTOR-Dependent Mechanisms

Pulmonary-Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland

Mammalian target of rapamycin (mTOR), a serine/threonine kinase, regulates cell growth and proliferation in part via the activation of p70 S6 kinase (S6K). Rapamycin is an antineo-plastic agent that, in complex with FKBP12, is a specific inhibitor of mTOR through interaction with its FKBP12-rapamycin binding domain, thereby causing G₁ cell cycle arrest. However, cancer cells often develop resistance to rapamycin, and alternative inhibitors of mTOR are desired. 2-(4-Morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) blocks mTOR kinase activity, but it also inhibits phosphatidylinositol 3-kinase (PI3K), an enzyme that regulates cellular functions other than proliferation. We hypothesized that a close structural analog, 2-piperazinyl-8-phenyl-4H-1-benzopyran-4-one (LY303511) might inhibit mTOR-dependent cell proliferation without unwanted effects on PI3K. In human lung epithelial adenocarcinoma (A549) cells, LY303511, like rapamycin, inhibited mTOR-dependent phosphorylation of S6K, but not PI3K-dependent phosphorylation of Akt. LY303511 blocked proliferation in A549 as well as in primary pulmonary artery smooth muscle cells, without causing apoptosis. In contrast to rapamycin, LY303511 reduced G₂/M progression as well as G₂/M-specific cyclins in A549 cells. Consistent with an additional mTOR-independent kinase target, LY303511 inhibited casein kinase 2 activity, a known regulator of G₁ and G₂/M progression. In addition to its antiproliferative effect in vitro, LY303511 inhibited the growth of human prostate adenocarcinoma tumor implants in athymic mice. Given its inhibition of cell proliferation via mTOR-dependent and independent mechanisms, LY303511 has therapeutic potential with antineoplastic actions that are independent of PI3K inhibition.

Address correspondence to: Dr. Arnold S. Kristof, McGill University, Royal Victoria Hospital, 687 Pine Ave. W., Room L3.05, Montreal, QC H3A 1A1, Canada. E-mail: arnold.kristof{at}muhc.mcgill.ca

This article has been cited by other articles:

				K. Shenoy, Y. Wu, and S. Pervaiz LY303511 Enhances TRAIL Sensitivity of SHEP-1 Neuroblastoma Cells via Hydrogen Peroxide-Mediated Mitogen-Activated Protein Kinase Activation and Up-regulation of Death Receptors Cancer Res., March 1, 2009; 69(5): 1941 - 1950. [Abstract] [Full Text] [PDF]

				C. Festuccia, G. L. Gravina, P. Muzi, R. Pomante, L. Ventura, R. L Vessella, C. Vicentini, and M. Bologna Bicalutamide increases phospho-Akt levels through Her2 in patients with prostate cancer Endocr. Relat. Cancer, September 1, 2007; 14(3): 601 - 611. [Abstract] [Full Text] [PDF]

				P. Mandal and T. Hamilton Signaling in Lipopolysaccharide-Induced Stabilization of Formyl Peptide Receptor 1 mRNA in Mouse Peritoneal Macrophages J. Immunol., February 15, 2007; 178(4): 2542 - 2548. [Abstract] [Full Text] [PDF]