| 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 |
Abstract/OtherAbstract:
|
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. |
| | |
Authors:
|
Rongxiu Li; Yan Zang; Changyou Li; Neil S Patel; Jennifer R Grandis; Daniel E Johnson |
Related Documents
:
|
18762897 - Effects of inhibition of ubiquitin-proteasome pathway on human primary leukemic cells. 7595537 - Bcl-2 protects neural cells from cyanide/aglycemia-induced lipid oxidation, mitochondri... 19499887 - Influence of 2-methoxyestradiol on mcf-7 cells: an improved differential interference c... 12785167 - Expression of bcl-2 oncoprotien in oral squamous cell carcinoma--an immunohistochemical... 3734687 - Pattern discontinuity, polarity and directional intercalation in axolotl limbs. 14764667 - Visualization of antigen presentation by actin-mediated targeting of glycolipid-enriche... |
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: 2013-04-11 |
Medline Journal Info:
|
Nlm Unique ID: 0035623 Medline TA: Mol Pharmacol Country: United States |
Other Details:
|
Languages: eng Pagination: 1231-9 Citation Subset: IM |
Affiliation:
|
Department of Medicine, University of Pittsburgh, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
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 Humans 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 | |
ID/Acronym/Agency:
|
P50-CA097190-01A1/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/ABT-737; 0/Antineoplastic Agents; 0/Biphenyl Compounds; 0/Boronic Acids; 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; 0/myeloid cell leukemia sequence 1 protein; 15663-27-1/Cisplatin |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Flax lignan complex slows down the progression of atherosclerosis in hyperlipidemic rabbits.
Next Document: Novel function for interleukin-7 in dendritic cell development.