This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted 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 Yu, C. Articles by Grant, S. Search for Related Content PubMed PubMed Citation Articles by Yu, C. Articles by Grant, S.

The Lethal Effects of Pharmacological Cyclin-dependent Kinase Inhibitors in Human Leukemia Cells Proceed through a Phosphatidylinositol 3-Kinase/Akt-dependent Process¹

Departments of Medicine [C. Y., M. R., Y. D., G. K., S. G.], Biochemistry [S. G.], Pharmacology [S. G.], Microbiology [S. G., D. C.], and Radiation Oncology [P. D.], Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298

The impact of disruption of the PI3K (phosphatidylinositol 3-kinase) pathway on the response of human leukemia cells to pharmacological cyclin-dependent kinase (CDK) inhibitors has been examined. Exposure of U937 monocytic leukemia cells to minimally toxic concentrations of flavopiridol (FP), roscovitine, or CGP74514A for 3 h in conjunction with the PI3K inhibitor LY294002 (abbreviated LY in the article) resulted in a marked decrease in Akt phosphorylation. Coexposure of cells to LY and CDK inhibitors also resulted in an early (i.e., within 3 h) and striking increase in mitochondrial damage [e.g., cytochrome c, second mitochondria-derived activator of caspases/direct inhibitor of apoptosis (IAP)-binding protein with low isoelectric point (Smac/DIABLO), and apoptosis-initiating factor (AIF) release], caspase activation, and apoptosis. Similar interactions were observed in a variety of other leukemia cell types (e.g., HL-60, Jurkat, Raji, and NB4). Apoptosis, induced by FP/LY, was substantially blocked by ectopic expression of Bcl-2, but to a considerably lesser extent by dominant-negative caspase-8. FP-induced apoptosis was not enhanced by agents that inhibited protein kinase (PK) A (H89), PKC (GFX), mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK1/2; U0126), p38 MAP kinase (MAPK; SB202190), m-target of rapamycin (TOR; rapamycin), or ataxia-telangiectasia mutation (ATM; caffeine), whereas the PI3K inhibitor wortmannin exerted effects similar to those of LY. The dramatic potentiation of CDK inhibitor-induced apoptosis by LY was accompanied by diminished Bad phosphorylation, induction of Bcl-2 cleavage, and down-regulation of X-linked IAP (XIAP) and Mcl-1. Cells exposed to CDK inhibitors + LY also exhibited reduced phosphorylation of glycogen synthase kinase (GSK)-3, forkhead transcription factor (FKHR), p70^S6K, and ERK, but increased activation of p34^cdc2 and p38 MAPK. LY/CDK inhibitor-treated cells also displayed diminished pRb dephosphorylation on CDK2- and CDK4-specific sites, retinoblastoma protein cleavage, and down-regulation of cyclin D₁. Inducible expression of constitutively active (myristolated) Akt significantly, albeit partially, attenuated apoptosis in Jurkat leukemia cells treated with either FP alone or the combination of FP and LY. Finally, cotreatment with LY and FP resulted in a dramatic increase in apoptosis in primary leukemic blasts obtained from a patient with acute myeloblastic leukemia. Together, these findings suggest that the PI3K/Akt pathway plays a major role in regulating the apoptotic response of human leukemia cells to pharmacological CDK inhibitors and raise the possibility that combined interruption of CDK- and PI3K-related pathways may represent a novel therapeutic strategy in hematological malignancies.

This article has been cited by other articles:

				H. H. Kim, K. Abdelmohsen, A. Lal, R. Pullmann Jr., X. Yang, S. Galban, S. Srikantan, J. L. Martindale, J. Blethrow, K. M. Shokat, et al. Nuclear HuR accumulation through phosphorylation by Cdk1 Genes & Dev., July 1, 2008; 22(13): 1804 - 1815. [Abstract] [Full Text] [PDF]

				H. Hamed, W. Hawkins, C. Mitchell, D. Gilfor, G. Zhang, X.-Y. Pei, Y. Dai, M. P. Hagan, J. D. Roberts, A. Yacoub, et al. Transient exposure of carcinoma cells to RAS/MEK inhibitors and UCN-01 causes cell death in vitro and in vivo Mol. Cancer Ther., March 1, 2008; 7(3): 616 - 629. [Abstract] [Full Text] [PDF]

				S.-W. Wang, S.-L. Pan, Y.-C. Huang, J.-H. Guh, P.-C. Chiang, D.-Y. Huang, S.-C. Kuo, K.-H. Lee, and C.-M. Teng CHM-1, a novel synthetic quinolone with potent and selective antimitotic antitumor activity against human hepatocellular carcinoma in vitro and in vivo Mol. Cancer Ther., February 1, 2008; 7(2): 350 - 360. [Abstract] [Full Text] [PDF]

				R. T. Woodland, C. J. Fox, M. R. Schmidt, P. S. Hammerman, J. T. Opferman, S. J. Korsmeyer, D. M. Hilbert, and C. B. Thompson Multiple signaling pathways promote B lymphocyte stimulator dependent B-cell growth and survival Blood, January 15, 2008; 111(2): 750 - 760. [Abstract] [Full Text] [PDF]

				W. Li, C.-L. Wu, P. G. Febbo, and A. F. Olumi Stromally Expressed c-Jun Regulates Proliferation of Prostate Epithelial Cells Am. J. Pathol., October 1, 2007; 171(4): 1189 - 1198. [Abstract] [Full Text] [PDF]

				J. E. Karp, B. D. Smith, M. J. Levis, S. D. Gore, J. Greer, C. Hattenburg, J. Briel, R. J. Jones, J. J. Wright, and A. D. Colevas Sequential Flavopiridol, Cytosine Arabinoside, and Mitoxantrone: A Phase II Trial in Adults with Poor-Risk Acute Myelogenous Leukemia Clin. Cancer Res., August 1, 2007; 13(15): 4467 - 4473. [Abstract] [Full Text] [PDF]

				D. Sohn, F. Essmann, K. Schulze-Osthoff, and R. U. Janicke p21 Blocks Irradiation-Induced Apoptosis Downstream of Mitochondria by Inhibition of Cyclin-Dependent Kinase-Mediated Caspase-9 Activation Cancer Res., December 1, 2006; 66(23): 11254 - 11262. [Abstract] [Full Text] [PDF]

				Y. Ma, W.-D. Yu, R.-X. Kong, D. L. Trump, and C. S. Johnson Role of Nongenomic Activation of Phosphatidylinositol 3-Kinase/Akt and Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase/Extracellular Signal-Regulated Kinase 1/2 Pathways in 1,25D3-Mediated Apoptosis in Squamous Cell Carcinoma Cells Cancer Res., August 15, 2006; 66(16): 8131 - 8138. [Abstract] [Full Text] [PDF]

				T. Stromberg, S. Ekman, L. Girnita, L. Y. Dimberg, O. Larsson, M. Axelson, J. Lennartsson, U. Hellman, K. Carlson, A. Osterborg, et al. IGF-1 receptor tyrosine kinase inhibition by the cyclolignan PPP induces G2/M-phase accumulation and apoptosis in multiple myeloma cells Blood, January 15, 2006; 107(2): 669 - 678. [Abstract] [Full Text] [PDF]

				J. E. Karp, A. Passaniti, I. Gojo, S. Kaufmann, K. Bible, T. S. Garimella, J. Greer, J. Briel, B. D. Smith, S. D. Gore, et al. Phase I and Pharmacokinetic Study of Flavopiridol followed by 1-{beta}-D-Arabinofuranosylcytosine and Mitoxantrone in Relapsed and Refractory Adult Acute Leukemias Clin. Cancer Res., December 1, 2005; 11(23): 8403 - 8412. [Abstract] [Full Text] [PDF]

				S. Mishra, J. P. Mishra, K. Gee, D. C. McManus, E. C. LaCasse, and A. Kumar Distinct Role of Calmodulin and Calmodulin-dependent Protein Kinase-II in Lipopolysaccharide and Tumor Necrosis Factor-{alpha}-mediated Suppression of Apoptosis and Antiapoptotic c-IAP2 Gene Expression in Human Monocytic Cells J. Biol. Chem., November 11, 2005; 280(45): 37536 - 37546. [Abstract] [Full Text] [PDF]

				T. W. Poh and S. Pervaiz LY294002 and LY303511 Sensitize Tumor Cells to Drug-Induced Apoptosis via Intracellular Hydrogen Peroxide Production Independent of the Phosphoinositide 3-Kinase-Akt Pathway Cancer Res., July 15, 2005; 65(14): 6264 - 6274. [Abstract] [Full Text] [PDF]

				K. Lacrima, A. Valentini, C. Lambertini, M. Taborelli, A. Rinaldi, E. Zucca, C. Catapano, F. Cavalli, A. Gianella-Borradori, D. E. MacCallum, et al. In vitro activity of cyclin-dependent kinase inhibitor CYC202 (Seliciclib, R-roscovitine) in mantle cell lymphomas Ann. Onc., July 1, 2005; 16(7): 1169 - 1176. [Abstract] [Full Text] [PDF]

				Y. Dai, M. Rahmani, X.-Y. Pei, P. Dent, and S. Grant Bortezomib and flavopiridol interact synergistically to induce apoptosis in chronic myeloid leukemia cells resistant to imatinib mesylate through both Bcr/Abl-dependent and -independent mechanisms Blood, July 15, 2004; 104(2): 509 - 518. [Abstract] [Full Text] [PDF]

				S. Grant and P. Dent Gene profiling and the cyclin-dependent kinase inhibitor flavopiridol: What's in a name? Mol. Cancer Ther., July 1, 2004; 3(7): 873 - 875. [Full Text] [PDF]

				S. C. Maggio, R. R. Rosato, L. B. Kramer, Y. Dai, M. Rahmani, D. S. Paik, A. C. Czarnik, S. G. Payne, S. Spiegel, and S. Grant The Histone Deacetylase Inhibitor MS-275 Interacts Synergistically with Fludarabine to Induce Apoptosis in Human Leukemia Cells Cancer Res., April 1, 2004; 64(7): 2590 - 2600. [Abstract] [Full Text] [PDF]

				M. M. Simile, M. R. De Miglio, M. R. Muroni, M. Frau, G. Asara, S. Serra, M. D. Muntoni, M. A. Seddaiu, L. Daino, F. Feo, et al. Down-regulation of c-myc and Cyclin D1 genes by antisense oligodeoxy nucleotides inhibits the expression of E2F1 and in vitro growth of HepG2 and Morris 5123 liver cancer cells Carcinogenesis, March 1, 2004; 25(3): 333 - 341. [Abstract] [Full Text] [PDF]

				L. Canaple, T. Kakizawa, and V. Laudet The Days and Nights of Cancer Cells Cancer Res., November 15, 2003; 63(22): 7545 - 7552. [Abstract] [Full Text] [PDF]