Selective activation of apoptosis by a novel set of 4-aryl-3-(3-aryl-1-oxo-2-propenyl)-2(1H)-quinolinones through a Myc-dependent pathway.
Oncogene addiction due to Myc deregulation has been identified in a variety of tumor types. In order to identify pharmacological agents that cause selective apoptosis in tumors with deregulated Myc expression, we designed a cell-based screening assay based on our Anti-cancer Screening Apoptosis Program (ASAP) technology targeting increased activity in a "Myc-addicted" cancer cell panel. We have identified a novel set of substituted 4-aryl-3-(3-aryl-1-oxo-2-propenyl)-2(1H)-quinolinones that activates apoptosis in cancer cell lines with deregulated Myc, but show low activity in cell lines where Myc is not deregulated. Apoptosis induced by these compounds is rapid, and is associated with a significant downregulation of Myc protein. Selective knockdown of Myc levels in these cells by RNA interference increased sensitivity to apoptosis with compound treatment. By targeting the Myc pathway in Myc-addicted cancer cells, we have identified a novel class of apoptotic inducers that selectively and efficiently target cancer cells with deregulated Myc.
Claassen
Gisela
G
EpiCept Corporation, Department of Biology, 6650 Nancy Ridge Drive, San Diego, CA 92121, USA. GClaassen@epicept.com
Brin
Elena
E
Crogan-Grundy
Candace
C
Vaillancourt
Mei Ting
MT
Zhang
Han Zhong
HZ
Cai
Sui Xiong
SX
Drewe
John
J
Tseng
Ben
B
Kasibhatla
Shailaja
S
D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004789:Enzyme Activation; D016259:Genes, myc; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D016133:Polymerase Chain Reaction; D015363:Quinolones / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering; D054875:Ubiquitination
D015363:Quinolones; D034741:RNA, Small Interfering; D020169:Caspases