Overcoming Hypoxia-Induced Apoptotic Resistance through Combinatorial Inhibition of GSK-3β and CDK1

被引：29

作者：

Mayes, Patrick A. ^{[2
,3
,4
,5
]}

Dolloff, Nathan G. ^{[1
,2
,3
,4
,5
]}

Daniel, Colin J. ^{[10
]}

Liu, J. Judy ^{[2
,3
,4
,5
]}

Hart, Lori S. ^{[2
,3
,4
,5
]}

Kuribayashi, Kageaki ^{[2
,3
,4
,5
]}

Allen, Joshua E. ^{[1
,2
,3
,4
,5
]}

Jee, David I. H. ^{[2
,3
,4
,5
]}

Dorsey, Jay F. ^{[2
,3
,4
,5
]}

Liu, Yingqiu Y. ^{[1
,2
,3
,4
,5
]}

Dicker, David T. ^{[1
,2
,3
,4
,5
]}

Brown, J. Martin ^{[9
]}

Furth, Emma E.

Klein, Peter S. ^{[6
,7
,8
]}

Sears, Rosalie C. ^{[10
]}

El-Deiry, Wafik S. ^{[1
,2
,3
,4
,5
,11
]}

机构：

[1] Penn State Hershey Med Ctr, Penn State Hershey Canc Inst, Lab Translat Oncol & Expt Canc Therapeut, Dept Med Hematol Oncol,Penn State Coll Med, Hershey, PA 17033 USA

[2] Univ Penn, Dept Med Hematol Oncol, Lab Mol Oncol & Cell Cycle Regulat, Inst Translat Med & Therapeut,Sch Med, Philadelphia, PA 19104 USA

[3] Univ Penn, Dept Pharmacol, Lab Mol Oncol & Cell Cycle Regulat, Inst Translat Med & Therapeut,Sch Med, Philadelphia, PA 19104 USA

[4] Univ Penn, Dept Genet, Lab Mol Oncol & Cell Cycle Regulat, Inst Translat Med & Therapeut,Sch Med, Philadelphia, PA 19104 USA

[5] Univ Penn, Sch Med, Abramson Comprehens Canc Ctr, Philadelphia, PA 19104 USA

[6] Univ Penn, Sch Med, Dept Med Hematol Oncol, Philadelphia, PA 19104 USA

[7] Univ Penn, Sch Med, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA

[8] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[9] Stanford Univ, Sch Med, Dept Radiat Oncol, Stanford, CA 94305 USA

[10] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97201 USA

[11] Amer Canc Soc, Atlanta, GA 30329 USA

来源：

CANCER RESEARCH | 2011年 / 71卷 / 15期

关键词：

C-MYC; IN-VIVO; CELL APOPTOSIS; GLIOMA-CELLS; SOLID TUMORS; KAPPA-B; CANCER; THERAPY; PHOSPHORYLATION; ACTIVATION;

D O I：

10.1158/0008-5472.CAN-11-1383

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Tumor hypoxia is an inherent impediment to cancer treatment that is both clinically significant and problematic. In this study, we conducted a cell-based screen to identify small molecules that could reverse the apoptotic resistance of hypoxic cancer cells. Among the compounds, we identified were a structurally related group that sensitized hypoxic cancer cells to apoptosis by inhibiting the kinases GSK-3 beta and cyclin-dependent kinase (CDK) 1. Combinatorial inhibition of these proteins in hypoxic cancer cells and tumors increased levels of c-Myc and decreased expression of c-IAP2 and the central hypoxia response regulator hypoxia-inducible factor (HIF) 1 alpha. In mice, these compounds augmented the hypoxic tumor cell death induced by cytotoxic chemotherapy, blocking angiogenesis and tumor growth. Taken together, our findings suggest that combinatorial inhibition of GSK-3 beta and CDK1 augment the apoptotic sensitivity of hypoxic tumors, and they offer preclinical validation of a novel and readily translatable strategy to improve cancer therapy. Cancer Res; 71(15); 5265-75. (c) 2011 AACR.

引用

页码：5265 / U264

页数：26

共 42 条

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