Enhanced chemosensitivity to irinotecan by RNA interference-mediated down-regulation of the nuclear factor-kappaB p65 subunit.
In preclinical tumor models, inhibition of nuclear factor-kappaB (NF-kappaB) has been associated with increased sensitivity to chemotherapeutic agents such as irinotecan (CPT-11). This is based on the fact that a variety of chemotherapy agents such as CPT-11 activate NF-kappaB to result in the expression of genes such as c-IAP1 and c-IAP2 that might be responsible for the inhibition of chemotherapy-induced apoptosis. In this study, RNA interference [small interfering RNA (siRNA)] was used to down-regulate the NF-kappaB p65 subunit in the HCT116 colon cancer cell line, and its role, in the presence and absence of CPT-11, was assessed on cell growth and apoptosis. Reduction of endogenous p65 by siRNA treatment significantly impaired CPT-11-mediated NF-kappaB activation, enhanced apoptosis, and reduced colony formation in soft agar. Furthermore, the in vivo administration of p65 siRNA reduced HCT116 tumor formation in xenograft models in the presence but not the absence of CPT-11 administration. These data indicate that the administration of siRNA directed against the p65 subunit of NF-kappaB can effectively enhance in vitro and in vivo sensitivity to chemotherapeutic agents.
Guo
Jun
J
Division of Hematology-Oncology, Department of Medicine, Harold Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Verma
Udit N
UN
Gaynor
Richard B
RB
Frenkel
Eugene P
EP
Becerra
Carlos R
CR
D000362:Agar / Q000737:chemistry; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D000077146:Irinotecan; D051379:Mice; D016328:NF-kappa B / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D009368:Neoplasm Transplantation; D009841:Oligonucleotides / Q000737:chemistry; D011506:Proteins / Q000378:metabolism; D012313:RNA / Q000737:chemistry; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D044767:Ubiquitin-Protein Ligases
D000972:Antineoplastic Agents, Phytogenic; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D009841:Oligonucleotides; D011506:Proteins; D034741:RNA, Small Interfering; D012313:RNA; D000077146:Irinotecan; D000362:Agar; C494833:BIRC2 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; C494834:Birc2 protein, mouse; C494835:Birc3 protein, mouse; D044767:Ubiquitin-Protein Ligases; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D002166:Camptothecin