Document Detail

ABT-737 synergizes with chemotherapy to kill head and neck squamous cell carcinoma cells via a Noxa-mediated pathway.
MedLine Citation:
PMID:  19246337     Owner:  NLM     Status:  MEDLINE    
Overexpression of Bcl-X(L), an antiapoptotic Bcl-2 family member, occurs in a majority of head and neck squamous cell carcinomas (HNSCCs) and correlates with chemotherapy resistance in this disease. Overexpression of Bcl-2 is also observed in HNSCC, albeit less frequently. We have previously shown that peptides derived from the BH3 domains of proapoptotic proteins can be used to target Bcl-X(L) and Bcl-2 in HNSCC cells, promoting apoptosis. In this report, we examined the impact of ABT-737 (for structure, see Nature 435: 677-681, 2005 ), a potent small-molecule inhibitor of Bcl-X(L) and Bcl-2, on HNSCC cells. As a single agent, ABT-737 was largely ineffective at promoting HNSCC cell death. By contrast, ABT-737 strongly synergized with the chemotherapy drugs cisplatin and etoposide to promote HNSCC cell death and loss of clonogenic survival. Synergism between ABT-737 and chemotherapy was associated with synergistic activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase. Treatment with ABT-737 plus chemotherapy resulted in dramatic up-regulation of proapoptotic Noxa protein, and small interfering RNA (siRNA)-mediated inhibition of Noxa up-regulation partially attenuated cell death by the synergistic combination. Treatment with cisplatin or etoposide, alone or in combination with ABT-737, resulted in substantial down-regulation of Mcl-1L, a known inhibitor of ABT-737 action. Further down-regulation of Mcl-1L using siRNA failed to enhance killing by the cisplatin/ABT-737 synergistic combination, indicating that chemotherapy treatment of HNSCC cells is sufficient to remove this impediment to ABT-737. Together, our results demonstrate potent synergy between ABT-737 and chemotherapy drugs in the killing of HNSCC cells and reveal an important role for Noxa in mediating synergism by these agents.
Rongxiu Li; Yan Zang; Changyou Li; Neil S Patel; Jennifer R Grandis; Daniel E Johnson
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2009-02-25
Journal Detail:
Title:  Molecular pharmacology     Volume:  75     ISSN:  1521-0111     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  2009 May 
Date Detail:
Created Date:  2009-04-24     Completed Date:  2009-05-05     Revised Date:  2014-05-20    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1231-9     Citation Subset:  IM    
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MeSH Terms
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Biphenyl Compounds / pharmacology*
Boronic Acids / pharmacology
Carcinoma, Squamous Cell / drug therapy*,  pathology
Cell Line, Tumor
Cisplatin / pharmacology
Drug Synergism
Head and Neck Neoplasms / drug therapy*,  pathology
Myeloid Cell Leukemia Sequence 1 Protein
Nitrophenols / pharmacology*
Piperazines / pharmacology
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*,  genetics,  physiology
Pyrazines / pharmacology
Signal Transduction
Sulfonamides / pharmacology*
bcl-X Protein / antagonists & inhibitors*
Grant Support
P50 CA097190/CA/NCI NIH HHS; P50-CA097190-01A1/CA/NCI NIH HHS
Reg. No./Substance:
0/ABT-737; 0/Antineoplastic Agents; 0/Biphenyl Compounds; 0/Boronic Acids; 0/Myeloid Cell Leukemia Sequence 1 Protein; 0/Nitrophenols; 0/PMAIP1 protein, human; 0/Piperazines; 0/Proto-Oncogene Proteins c-bcl-2; 0/Pyrazines; 0/Sulfonamides; 0/bcl-X Protein; 0/bortezomib; Q20Q21Q62J/Cisplatin

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