Document Detail

Functional inhibition of BCL2 is needed to increase the susceptibility to apoptosis to SMO inhibitors in diffuse large B-cell lymphoma of germinal center subtype.
MedLine Citation:
PMID:  23370596     Owner:  NLM     Status:  MEDLINE    
Previously, we have demonstrated that inhibition of Hedgehog pathway induces predominantly apoptosis in diffuse large B-cell lymphoma (DLBCL) cell lines of activated B-cell (ABC) type but predominantly cell cycle arrest in those of germinal center (GC). Here, we explored the possibility of overcoming the resistance to apoptosis to SMO inhibitors in five DLBCL cells of GC type using the combination of the SMO inhibitor HhAntag (Genentech Inc) with the BH3 mimetic ABT-737 (Abbott Laboratories). As controls we have used two DLBCL of ABC type (OCI-LY10 and OCI-LY3). Combinatorial treatments were performed with increasing concentrations of the HhAntag with low doses (equal or less than the IC20) of ABT-737. MTS assays were used to detect changes in cell viability and Annexin-V and PARP1 cleavage assays were used to detect apoptosis. Combining low doses of ABT-737 with increasing concentrations of HhAntag in GC DLBCL cell lines resulted in significantly increase of apoptosis in comparison to treatments with the SMO inhibitor alone. We concluded that in GC DLBCL cell lines, in contrast to those of ABC type, functional inhibition of BCL2 family members is usually needed to overcome the resistance to apoptosis to SMO inhibitors. These findings provide a rationale to explore the use of SMO and BCL2 inhibitors as adjuvant therapy for treatment of DLBCL of GC type.
Kranthi Kunkalla; Yadong Liu; Changju Qu; Vasiliki Leventaki; Nitin K Agarwal; Rajesh R Singh; Francisco Vega
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-02-01
Journal Detail:
Title:  Annals of hematology     Volume:  92     ISSN:  1432-0584     ISO Abbreviation:  Ann. Hematol.     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-05-07     Completed Date:  2013-07-09     Revised Date:  2014-06-03    
Medline Journal Info:
Nlm Unique ID:  9107334     Medline TA:  Ann Hematol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  777-87     Citation Subset:  IM    
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MeSH Terms
Anilides / pharmacology*
Apoptosis / drug effects*
Apoptosis Regulatory Proteins / biosynthesis,  genetics
Biphenyl Compounds / pharmacology*
Cell Line, Tumor / drug effects,  pathology
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm / drug effects
Drug Screening Assays, Antitumor
Drug Synergism
Germinal Center / pathology
Inhibitory Concentration 50
Lymphoma, Large B-Cell, Diffuse / pathology*
Neoplasm Proteins / antagonists & inhibitors*,  biosynthesis,  genetics
Nitrophenols / pharmacology*
Piperazines / pharmacology
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
Pyridines / pharmacology*
Receptors, G-Protein-Coupled / antagonists & inhibitors*
Signal Transduction / drug effects
Sulfonamides / pharmacology*
Grant Support
1K08 CA143151-01/CA/NCI NIH HHS; 1P50CA136411-01A1/CA/NCI NIH HHS; K08 CA143151/CA/NCI NIH HHS
Reg. No./Substance:
0/ABT-737; 0/Anilides; 0/Apoptosis Regulatory Proteins; 0/Biphenyl Compounds; 0/HhAntag691; 0/Neoplasm Proteins; 0/Nitrophenols; 0/Piperazines; 0/Proto-Oncogene Proteins c-bcl-2; 0/Pyridines; 0/Receptors, G-Protein-Coupled; 0/SMO protein, human; 0/Sulfonamides

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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