Control of inducible chemoresistance: enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-kappaB.
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.
Wang
C Y
CY
Lineberger Comprehensive Cancer Center, Department of Endodontics, School of Dentistry, University of North Carolina at Chapel Hill, 27599-7295, USA.
Cusack
J C
JC
Liu
R
R
Baldwin
A S
AS
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D017209:Apoptosis; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D004351:Drug Resistance; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D020672:I-kappa B Proteins; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009374:Neoplasms, Experimental / Q000628:therapy*; D011994:Recombinant Proteins / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use*
D000972:Antineoplastic Agents, Phytogenic; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D000077146:Irinotecan; D002166:Camptothecin