Journal
CELL DEATH AND DIFFERENTIATION
Volume 17, Issue 5, Pages 872-882Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2009.171
Keywords
Bcl-2 homology proteins; experimental therapeutics; chemoresistance; BH3 mimetics; neuroblastoma
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Funding
- NIH [CA97323, K08-CA128925]
- King Family
- Richard and Sheila Sanford Chair in Pediatric Oncology
- Alex's Lemonade Stand Foundation
- Caitlin Robb Foundation
- Hope Street Kids Foundation
- NATIONAL CANCER INSTITUTE [P01CA097323, K08CA128925] Funding Source: NIH RePORTER
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Bcl-2 family proteins regulate mitochondrial apoptosis downstream of diverse stressors. Cancer cells frequently deregulate Bcl-2 proteins leading to chemoresistance. We have optimized a platform for solid tumors in which Bcl-2 family resistance patterns are inferred. Functional mitochondria were isolated from neuroblastoma (NB) cell lines, exposed to distinct BH3-domain peptides, and assayed for cytochrome c release. Such BH3 profiles revealed three patterns of cytochrome c response. A subset had a dominant NoxaBH3 response implying Mcl1 dependence. These cells were more sensitive to small molecules that antagonize Mcl1 (AT-101) than those that antagonize Bcl-2, Bcl-xL and Bcl-w (ABT-737). A second subset had a dominant BikBH3 response, implying a Bcl-xL/-w dependence, and was exquisitely sensitive to ABT-737 (IC50 <200 nM). Finally, most NB cell lines derived at relapse were relatively resistant to pro-death BH3 peptides and Bcl-2 antagonists. Our findings define heterogeneity for apoptosis resistance in NB, help triage emerging Bcl-2 antagonists for clinical use, and provide a platform for studies to characterize post-therapy resistance mechanisms for NB and other solid tumors. Cell Death and Differentiation (2010) 17, 872-882; doi:10.1038/cdd.2009.171; published online 6 November 2009
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