| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Experimental Therapeutics, Preclinical Pharmacology |
1 Developmental Therapeutics Program, National Cancer Institute, and 2 Experimental Diabetes, National Institutes of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, Maryland
7-Hydroxystaurosporine (UCN-01) infused for 72 hours by continuous i.v. infusion induced insulin resistance during phase I clinical trials. To understand the mechanism for this observation, we examined the effect of UCN-01 on insulin-stimulated glucose transport activity with 3-O-methylglucose in isolated rat adipose cells. UCN-01 inhibits glucose transport activity in a dose-dependent manner at all insulin concentrations. At the clinically relevant concentration of 0.25 µmol/L UCN-01, glucose transport is inhibited 66, 29, and 26% at insulin concentrations of 10, 50, and 100,000 (100K) microunits/mL respectively, thus shifting the dose-response curve to the right. Increasing concentrations of UCN-01 up to 2.5 µmol/L progressively shift the insulin dose-response curve even further. As Akt is known to mediate in part action initiated at the insulin receptor, we also studied the effect of UCN-01 on Akt activation in whole-cell homogenates of these cells. Decreased glucose transport activity directly parallels decreased Akt Thr308 phosphorylation in both an insulin and UCN-01 dose-dependent manner, whereas Akt Ser473 phosphorylation is inhibited only at the lowest insulin concentration, and then, only modestly. UCN-01 also inhibits insulin-induced Thr308 but not Ser473 phosphorylation of Akt associated with the plasma membranes and low-density microsomes and inhibits translocation of GLUT4 from low-density microsomes to plasma membranes as expected from the glucose transport activity measurements. These data suggest that UCN-01 induces clinical insulin resistance by blocking Akt activation and subsequent GLUT4 translocation in response to insulin, and this effect appears to occur by inhibiting Thr308 phosphorylation even in the face of almost completely unaffected Ser473 phosphorylation.
This article has been cited by other articles:
|
|
 |
|
  S. Banerjee, K. Saito, M. Ait-Goughoulte, K. Meyer, R. B. Ray, and R. Ray Hepatitis C Virus Core Protein Upregulates Serine Phosphorylation of Insulin Receptor Substrate-1 and Impairs the Downstream Akt/Protein Kinase B Signaling Pathway for Insulin Resistance J. Virol., March 15, 2008; 82(6): 2606 - 2612. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Sargeant, R. D. Klein, R. C. Rengel, S. K. Clinton, S. K. Kulp, Y. Kashida, M. Yamaguchi, Xingya Wang, and C.-S. Chen Chemopreventive and Bioenergetic Signaling Effects of PDK1/Akt Pathway Inhibition in a Transgenic Mouse Model of Prostate Cancer Toxicol Pathol, June 1, 2007; 35(4): 549 - 561. [Abstract] [PDF]
|
|
|
|
 |
|
 M. J. Edelman, K. S. Bauer Jr., S. Wu, R. Smith, S. Bisacia, and J. Dancey Phase I and Pharmacokinetic Study of 7-Hydroxystaurosporine and Carboplatin in Advanced Solid Tumors Clin. Cancer Res., May 1, 2007; 13(9): 2667 - 2674. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. D. Wadley, N. Konstantopoulos, L. Macaulay, K. F. Howlett, A. Garnham, M. Hargreaves, and D. Cameron-Smith Increased insulin-stimulated Akt pSer473 and cytosolic SHP2 protein abundance in human skeletal muscle following acute exercise and short-term training J Appl Physiol, April 1, 2007; 102(4): 1624 - 1631. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Powis, N. Ihle, and D. L. Kirkpatrick Practicalities of drugging the phosphatidylinositol-3-kinase/akt cell survival signaling pathway. Clin. Cancer Res., May 15, 2006; 12(10): 2964 - 2966. [Full Text] [PDF]
|
|
|
|
 |
|
 D. Sampath, J. Cortes, Z. Estrov, M. Du, Z. Shi, M. Andreeff, V. Gandhi, and W. Plunkett Pharmacodynamics of cytarabine alone and in combination with 7-hydroxystaurosporine (UCN-01) in AML blasts in vitro and during a clinical trial Blood, March 15, 2006; 107(6): 2517 - 2524. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. K. Schwartz and M. A. Shah Targeting the Cell Cycle: A New Approach to Cancer Therapy J. Clin. Oncol., December 20, 2005; 23(36): 9408 - 9421. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. B. Okon, A. W.Y. Chung, P. Rauniyar, E. Padilla, T. Tejerina, B. M. McManus, H. Luo, and C. van Breemen Compromised Arterial Function in Human Type 2 Diabetic Patients Diabetes, August 1, 2005; 54(8): 2415 - 2423. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. K. Schwartz Development of Cell Cycle Active Drugs for the Treatment of Gastrointestinal Cancers: A New Approach to Cancer Therapy J. Clin. Oncol., July 10, 2005; 23(20): 4499 - 4508. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Tian Another Role for the Celebrity: Akt and Insulin Resistance Circ. Res., February 4, 2005; 96(2): 139 - 140. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Cell Growth & Differentiation |
