RNA interference targeting of Bcr-Abl increases chronic myeloid leukemia cell killing by 17-allylamino-17-demethoxygeldanamycin.
17-Allylamino-17-demethoxygeldanamycin (17-AAG) induces degradation of Hsp90 client proteins, including Bcr-Abl, however, its clinical use as an anti-tumor agent may be limited by toxicity and modest efficacy. We reasoned that Bcr-Abl targeting by RNA interference (RNAi) might selectively increase the activity of 17-AAG against Bcr-Abl+ leukemia cells. 17-AAG in combination with targeting small interfering RNAs (siRNAs) reduced Bcr-Abl protein levels, triggered increases in markers of apoptosis and decreased cell viability more effectively than did control siRNA and 17-AAG together, or Bcr-Abl targeting siRNA alone. Combination targeting strategies such as this may therefore achieve enhanced therapeutic potency.
Withey
Jane M E
JM
School of Biological Sciences, Royal Holloway University of London, Egham, Surrey TW20 0EX, UK.
Harvey
Amanda J
AJ
Crompton
Mark R
MR
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D016227:Benzoquinones / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D018390:Gene Targeting / Q000379:methods*; D006801:Humans; D020014:K562 Cells; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology*
D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D034741:RNA, Small Interfering; C406060:abl-bcr fusion protein, human; C112765:tanespimycin; D016044:Fusion Proteins, bcr-abl