Combination treatments with ABT-263 and an immunotoxin produce synergistic killing of ABT-263-resistant small cell lung cancer cell lines

Int J Cancer. 2013 Feb 15;132(4):978-87. doi: 10.1002/ijc.27732. Epub 2012 Aug 16.

Abstract

Synergistic killing was achieved when Small Cell Lung Cancer (SCLC) cell lines were incubated with ABT-263 and an immunotoxin directed to the transferrin receptor. SCLC lines are variably sensitive to the BH-3 only peptide mimetic, ABT-263. To determine their sensitivity to toxin-based reagents, we incubated four representative SCLC lines with a model Pseudomonas exotoxin-based immunotoxin directed to the transferrin receptor. Remarkably in 4-of-4 lines, there was little evidence of immunotoxin-mediated cytotoxicity despite near complete inhibition of protein synthesis. However, when combinations of ABT-263 and immunotoxin were added to the ABT-263-resistant cell lines (H196 and H69AR), there was synergistic killing as evidenced by increased activation of caspase 3/7, annexin V staining, and loss of cell integrity. Synergistic killing was evident at 6 hr and correlated with loss of Mcl-1. This synergy was also noted when the closely related compound ABT-737 was combined with the same immunotoxin. To establish that the synergy seen in tissue culture could be achieved in vivo, H69AR cells were grown as tumors in nude mice and shown to be susceptible to the killing action of an immunotoxin-ABT-737 combination but not to either agent alone. When immunotoxin-ABT combinations were added to ABT-263-sensitive lines (H146 and H1417), killing was additive. Our data support combination approaches for treating ABT-263-resistant SCLC with ABT-263 and a second agent that provides synergistic killing action.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Aniline Compounds / pharmacology
  • Aniline Compounds / therapeutic use*
  • Animals
  • Biphenyl Compounds / pharmacology*
  • Caspase 3 / metabolism
  • Caspase 7 / metabolism
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / drug effects
  • Drug Synergism
  • Humans
  • Immunotoxins / pharmacology
  • Immunotoxins / therapeutic use*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Nitrophenols / pharmacology*
  • Piperazines / pharmacology
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis
  • Receptors, Transferrin / immunology
  • Small Cell Lung Carcinoma / drug therapy*
  • Sulfonamides / pharmacology*
  • Sulfonamides / therapeutic use*

Substances

  • ABT-737
  • Aniline Compounds
  • Biphenyl Compounds
  • Immunotoxins
  • Mcl1 protein, mouse
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Nitrophenols
  • Piperazines
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Transferrin
  • Sulfonamides
  • Caspase 3
  • Caspase 7
  • navitoclax