NF-κB-mediated chemoresistance in breast cancer cells

被引:66
作者
Weldon, CB
Burow, ME
Rolfe, KW
Clayton, JL
Jaffe, BM
Beckman, BS
机构
[1] Tulane Univ, Sch Med, Sch Publ Hlth & Trop Med,Hlth Sci Ctr, Tulane Xavier Ctr Bioenvironm Res,Dept Surg, New Orleans, LA 70112 USA
[2] Tulane Univ, Sch Med, Sch Publ Hlth & Trop Med,Hlth Sci Ctr, Tulane Xavier Ctr Bioenvironm Res,Dept Pharmacol, New Orleans, LA 70112 USA
[3] Tulane Univ, Sch Med, Sch Publ Hlth & Trop Med,Hlth Sci Ctr, Tulane Xavier Ctr Bioenvironm Res,Dept Epidemiol, New Orleans, LA 70112 USA
[4] Tulane Univ, Sch Med, Sch Publ Hlth & Trop Med, Hlth Sci Ctr,Tulane Canc Ctr, New Orleans, LA 70112 USA
[5] Tulane Univ, Sch Med, Sch Publ Hlth & Trop Med, Hlth Sci Ctr,Program Mol & Cellular Biol, New Orleans, LA 70112 USA
关键词
D O I
10.1067/msy.2001.115512
中图分类号
R61 [外科手术学];
学科分类号
摘要
Background. Nuclear factor-kappa B (NF-kappaB) is a known survival pathway, and it may explain differential sensitivity to tumor necrosis factor-alpha (TNF-alpha) and chemotherapeutic-induced apoptosis in apoptotically sensitive (APO+) and apoptotically resistant (APO-) Michigan Cancer Foundation-7 breast cancer cells. Methods. Crystal violet viability and luciferase reporter gene assays were used to determine the inhibitory concentration of viability at 50% (IC50) and the inhibitory concentration of activity at 50% (EC50) values in APO- and APO+ cells with the selective NF-kappaB inhibitor, BAY 11-7082 (BAY). The apoptotic reporter assay was used to determine the effects of the transfection of the inhibitory kappa B-dominant negative (I kappaB-DN) construct in conjunction with TNF, paclitaxel, or doxorubicin treatments in these cells. Results. The concentrations at which 50% of cell viability is inhibited (IC50) and at which 50% of NF-kappaB activity is inhibited (EC50)for BAY in APO- and APO+ cells were 95.24 mu mol/L and 1.53 mu mol/L, respectively, and 7.62 mu mol/L and 2.64 mu mol/L, respectively. The IC50 and the EC50 values were equivalent for the APO+ cells (P =.665), but not for the APO- cells (P =.025). I kappaB-DN-transfection alone, or with TNF, doxorubicin, or paclitaxel treatments resulted in cell death of both APO- and APO+ cells as compared with vector-control; however, greater cytotoxicity was seen in the APO+ cells. Direct comparison of the APO+ cells versus the APO- cells revealed that these differences were significant (P =.05). Conclusions. Pharmacologic or molecular inhibition of the NF-kappaB pathway blocked cell survival in MCF-7 APO+ cells, while only molecular inhibition induced cytotoxicity in the APO- cells. Selective manipulation of the NF-kappaB pathway in combination with standard chemotherapeutic agents may lead to an increased potency and efficacy of these agents.
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页码:143 / 150
页数:8
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