Listeriolysin O Potentiates Immunotoxin and Bleomycin Cytotoxicity

Bioconjug Chem. Nov-Dec 1997;8(6):781-4. doi: 10.1021/bc970124+.

Abstract

Antitumor immunotoxins were formed by covalently attaching the ribosome-inactivating protein ricin A chain (RA) to the antitumor antibodies BR96 and L6. In vitro cytotoxicity assays established that BR96-RA was cytotoxic to H2987 human lung adenocarcinoma cells (IC50 = 6 nM), while L6-RA exhibited very low levels of cytotoxic activity (18% cell kill at 67 nM). The virulence factor from the intracellular pathogen Listeria monocytogenes, listeriolysin O (LLO), was able to potentiate the cytotoxicity of BR96-RA and L6-RA by 120- and > 1340-fold, respectively, resulting in IC50 values of approximately 50 pM. LLO also potentiated the cytotoxicity of the peptide anticancer drug bleomycin by a factor of > 2500 but had no effect on the cytotoxic activities of the anticancer drugs cytarabine and etoposide phosphate. In addition, LLO did not potentiate the cytotoxic activity of unconjugated ricin A chain or L6-RA on H2987 cells that were saturated with L6 prior to conjugate treatment. These results are attributed to LLO-induced alteration of the intracellular trafficking of molecules that are incorporated into acidic vesicles.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Antibiotics, Antineoplastic / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Bacterial Proteins / administration & dosage
  • Bacterial Toxins*
  • Bleomycin / administration & dosage
  • Drug Synergism
  • Heat-Shock Proteins / administration & dosage
  • Hemolysin Proteins / administration & dosage
  • Humans
  • Immunotoxins / administration & dosage
  • Lung Neoplasms / drug therapy*
  • Ricin / administration & dosage
  • Tumor Cells, Cultured

Substances

  • Antibiotics, Antineoplastic
  • Bacterial Proteins
  • Bacterial Toxins
  • Heat-Shock Proteins
  • Hemolysin Proteins
  • Immunotoxins
  • Bleomycin
  • Ricin
  • hlyA protein, Listeria monocytogenes