NF-kappa B-mediated chemoresistance in breast cancer cells.

Abstract

BACKGROUND:

Nuclear factor-kappa B (NF-kappa B) 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% (IC(50)) and the inhibitory concentration of activity at 50% (EC(50)) values in APO- and APO+ cells with the selective NF-kappa B 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 kappa B-DN) construct in conjunction with TNF, paclitaxel, or doxorubicin treatments in these cells.

RESULTS:

The concentrations at which 50% of cell viability is inhibited (IC(50)) and at which 50% of NF-kappa B activity is inhibited (EC(50)) for BAY in APO- and APO+ cells were 95.24 micromol/L and 1.53 micromol/L, respectively, and 7.62 micromol/L and 2.64 micromol/L, respectively. The IC(50) and the EC(50) values were equivalent for the APO+ cells (P =.665), but not for the APO- cells (P =.025). I kappa B-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-kappa B pathway blocked cell survival in MCF-7 APO+ cells, while only molecular inhibition induced cytotoxicity in the APO- cells. Selective manipulation of the NF-kappa B pathway in combination with standard chemotherapeutic agents may lead to an increased potency and efficacy of these agents.

• Authors: C B Weldon, M E Burow, K W Rolfe, J L Clayton, B M Jaffe, B S Beckman
• Journal: Surgery (Surgery) Vol. 130 Issue 2 Pg. 143-50 (Aug 2001) ISSN: 0039-6060 [Print] United States
• PMID: 11490342 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 3-(4-methylphenylsulfonyl)-2-propenenitrile
• Antineoplastic Agents
• Antineoplastic Agents, Phytogenic
• NF-kappa B
• Nitriles
• Organic Chemicals
• Sulfones
• Doxorubicin
• Luciferases
• Paclitaxel

Topics

• Antineoplastic Agents (pharmacology)
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects, physiology)
• Breast Neoplasms
• Doxorubicin (pharmacology)
• Drug Resistance, Neoplasm
• Female
• Gene Expression (drug effects)
• Genes, Reporter
• Humans
• Inhibitory Concentration 50
• Luciferases (genetics)
• NF-kappa B (antagonists & inhibitors, genetics, metabolism)
• Nitriles
• Organic Chemicals
• Paclitaxel (pharmacology)
• Sulfones
• Tumor Cells, Cultured (cytology, drug effects)