Faculty Collaboration Database

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. Ann Hematol 2013 Jun;92(6):777-87

Date

02/02/2013

Pubmed ID

23370596

Pubmed Central ID

PMC3648611

DOI

10.1007/s00277-013-1684-6

Scopus ID

2-s2.0-84877790356 (requires institutional sign-in at Scopus site)   13 Citations

Abstract

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.

Author List

Kunkalla K, Liu Y, Qu C, Leventaki V, Agarwal NK, Singh RR, Vega F

MESH terms used to index this publication - Major topics in bold

Anilides
Apoptosis
Apoptosis Regulatory Proteins
Biphenyl Compounds
Cell Line, Tumor
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
Drug Screening Assays, Antitumor
Drug Synergism
Germinal Center
Humans
Inhibitory Concentration 50
Lymphoma, Large B-Cell, Diffuse
Neoplasm Proteins
Nitrophenols
Piperazines
Proto-Oncogene Proteins c-bcl-2
Pyridines
Receptors, G-Protein-Coupled
Signal Transduction
Smoothened Receptor
Sulfonamides