Author: Wang, C. Y.; Cusack, J. C.; Liu, R.; Baldwin, A. S.
Description: Programmed cell death (apoptosis) seems to be the principal mechanism whereby anti-oncogenic therapies such as chemotherapy and radiation effect their responses. Resistance to apoptosis, therefore, is probably a principal mechanism whereby tumors are able to overcome these cancer therapies. The transcription factor NF-kappaB is activated by chemotherapy and by irradiation in some cancer cell lines. Furthermore, inhibition of NF-kappaB in vitro leads to enhanced apoptosis in response to a variety of different stimuli. We show here that inhibition of NF-kappaB through the adenoviral delivery of a modified form of IkappaBalpha, the inhibitor of NF-kappaB, sensitizes chemoresistant tumors to the apoptotic potential of TNFalpha and of the chemotherapeutic compound CPT-11, resulting in tumor regression. These results demonstrate that the activation of NF-kappaB in response to chemotherapy is a principal mechanism of inducible tumor chemoresistance, and establish the inhibition of NF-kappaB as a new approach to adjuvant therapy in cancer treatment.
Subject headings: Adenoviridae, genetics; Animals; Antineoplastic Agents; Phytogenic, therapeutic use; Apoptosis; Camptothecin, analogs & derivatives, therapeutic use; DNA-Binding Proteins, biosynthesis, genetics; Drug Resistance; Female; Genetic Therapy, methods; I-kappa B Proteins; Irinotecan; Mice; Mice, Nude; NF-KappaB Inhibitor alpha; NF-kappa B, antagonists & inhibitors; Neoplasms; Experimental, therapy; Recombinant Proteins, biosynthesis; Tumor Necrosis Factor-alpha, therapeutic use
Publication year: 1999
Journal or book title: Nature medicine
Volume: 5
Pages: 412-417
Find the full text: https://cdr.lib.unc.edu/downloads/bz60cz31k
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Serial number: 3686