Bcl-2 is a better therapeutic target than c-Myc, but attacking both could be a more effective treatment strategy for B-cell lymphoma with concurrent Bcl-2 and c-Myc overexpression

Exp Hematol. 2011 Aug;39(8):817-28.e1. doi: 10.1016/j.exphem.2011.05.002. Epub 2011 May 11.

Abstract

Objective: The prognosis for diffuse large B-cell lymphomas with concomitant overexpression of c-Myc and Bcl-2 remains dismal; there is an urgent need to clarify the significance of these two oncogenes as therapeutic targets for a more effective treatment strategy.

Materials and methods: We established two novel cell lines, KPUM-MS3 and KPUM-UH1, from two chemoresistant patients with diffuse large B-cell lymphomas with concomitant overexpression of c-Myc and Bcl-2, and investigated the significance of c-Myc and Bcl-2 as therapeutic targets.

Results: KPUM-MS3 possesses t(14;18)(q32;q21) chromosomal translocation and KPUM-UH1 bcl-2 gene amplification, both of which account for Bcl-2 overexpression. Chromosomal translocation t(8;14)(q24;q34) was found to coexist only in KPUM-UH1, overexpression of pvt-1 messenger RNA was detected only in KPUM-MS3, and reduced expression of miR-143 and miR-145 was identified in both. Working together, these abnormalities can contribute to c-Myc overexpression. Using ABT-263, an inhibitor for Bcl-2, and 10058-F4, an inhibitor for c-Myc, we found that both cell lines were more highly sensitive to cell death as a result of Bcl-2 inhibition than of c-Myc inhibition. When combined with genotoxic agents, ABT-263 exerted additive and/or synergistic cell-killing effects, while 10058-F4 showed, at most, a modest combinatory effect. Importantly, the combination of ABT-263 and 10058-F4 had a synergistic cell-killing effect on both cell lines.

Conclusions: Our data suggest that Bcl-2 is a better therapeutic target than c-Myc, but attacking both Bcl-2 and c-Myc would be an even more effective treatment strategy for diffuse large B-cell lymphomas with concurrent Bcl-2 and c-Myc overexpression.

MeSH terms

  • Aniline Compounds / pharmacology
  • Antineoplastic Agents / pharmacology
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Chromosomes, Human, Pair 14 / genetics
  • Chromosomes, Human, Pair 18 / genetics
  • Cytarabine / pharmacology
  • Dose-Response Relationship, Drug
  • Doxorubicin / pharmacology
  • Drug Synergism
  • Etoposide / pharmacology
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Lymphoma, Large B-Cell, Diffuse / genetics
  • Lymphoma, Large B-Cell, Diffuse / metabolism
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • MicroRNAs / genetics
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-bcl-2 / genetics*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Proto-Oncogene Proteins c-myc / antagonists & inhibitors
  • Proto-Oncogene Proteins c-myc / genetics*
  • Proto-Oncogene Proteins c-myc / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Spectral Karyotyping
  • Sulfonamides / pharmacology
  • Thiazoles / pharmacology
  • Translocation, Genetic*

Substances

  • 5-(4-ethylbenzylidene)-2-thioxothiazolidin-4-one
  • Aniline Compounds
  • Antineoplastic Agents
  • MIRN143 microRNA, human
  • MIRN145 microRNA, human
  • MYC protein, human
  • MicroRNAs
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins c-myc
  • Sulfonamides
  • Thiazoles
  • Cytarabine
  • Etoposide
  • Doxorubicin
  • navitoclax