![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Departments of Surgery (X.-H.P., P.K., W.C.W., L.Y.) and Hematology and Oncology (R.M.O., X.L., L.Y.), Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia; Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois (R.N., R.M.M.); Department of Thoracic/Head and Neck Medical Oncology (H.-Y.L.), the University of Texas M. D. Anderson Cancer Center, Houston, Texas
The identification of differentially regulated apoptotic signals in normal and tumor cells allows the development of cancer cell-selective therapies. Increasing evidence shows that the inhibitor of apoptosis (IAP) proteins survivin and XIAP are highly expressed in tumor cells but are absent or have very low levels of expression in normal adult tissues. We found that inhibiting AKT activity with 10 to 100 nM deguelin, a small molecule derived from natural products, markedly reduced the levels of both survivin and XIAP, inducing apoptosis in human breast cancer cells but not in normal cells. It is noteworthy that we detected an elevated level of cleaved poly(ADP-ribose) polymerase, a signature of caspase activation, without a significant increase in caspase activity in deguelin-treated cancer cells. Our results suggest that severe down-regulation of the IAPs by deguelin releases their inhibitory activity over pre-existing active caspases present in cancer cells, inducing apoptosis without the need for further caspase activation. Because normal cells have very low levels of p-AKT, XIAP, survivin, and pre-existing caspase activity, deguelin had little effect on those cells. In addition, we found that combining deguelin with chemotherapy drugs enhanced drug-induced apoptosis selectively in human tumor cells, which suggests that deguelin has great potential for chemosensitization and could represent a new therapeutic agent for treatment of breast cancer.
Address correspondence to: Lily Yang, Department of Surgery and Winship Cancer Institute; Emory University School of Medicine, Clinic C, Room C-4088, 1365 C Clifton Road, N.E. Atlanta, GA 30322. E-mail: lyang02{at}emory.edu
This article has been cited by other articles:
|
|
 |
|
  J. K. Woo, D. S. Choi, H. T. Tran, B. E. Gilbert, W. K. Hong, and H.-Y. Lee Liposomal Encapsulation of Deguelin: Evidence for Enhanced Antitumor Activity in Tobacco Carcinogen-Induced and Oncogenic K-ras-Induced Lung Tumorigenesis Cancer Prevention Research, April 1, 2009; 2(4): 361 - 369. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Goodell, J. Waisman, L. G. Salazar, C. dela Rosa, J. Link, A. L. Coveler, J. S. Childs, P. A. Fintak, D. M. Higgins, and M. L. Disis Level of HER-2/neu protein expression in breast cancer may affect the development of endogenous HER-2/neu-specific immunity Mol. Cancer Ther., March 1, 2008; 7(3): 449 - 454. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Jin, L. Feng, C. Behrens, B. N. Bekele, I. I. Wistuba, W.-K. Hong, and H.-Y. Lee Implication of AMP-Activated Protein Kinase and Akt-Regulated Survivin in Lung Cancer Chemopreventive Activities of Deguelin Cancer Res., December 15, 2007; 67(24): 11630 - 11639. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Crowell, V. E. Steele, and J. R. Fay Targeting the AKT protein kinase for cancer chemoprevention Mol. Cancer Ther., August 1, 2007; 6(8): 2139 - 2148. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
