Quinacrine sensitizes hepatocellular carcinoma cells to TRAIL and chemotherapeutic agents

Cancer Biol Ther. 2011 Aug 1;12(3):229-38. doi: 10.4161/cbt.12.3.17033. Epub 2011 Aug 1.

Abstract

Quinacrine has been widely explored in treatment of malaria, giardiasis, and rheumatic diseases. We find that quinacrine stabilizes p53 and induces p53-dependent and independent cell death. Treatment by quinacrine alone at concentrations of 10-20 mM for 1-2 d cannot kill hepatocellular carcinoma cells, such as HepG2, Hep3B, Huh7, which are also resistant to TRAIL. However, quinacrine renders these cells sensitive to treatment by TRAIL. Co-treatment of these cells with quinacrine and TRAIL induces overwhelming cell death within 3-4 h. Levels of DR5, a pro-apoptotic death receptor of TRAIL, are increased upon treatment with quinacrine, while levels of Mcl-1, an anti-apoptotic member of the Bcl-2 family, are decreased. While the synergistic effect of quinacrine with TRAIL appears to be in part independent of p53, knockdown of p53 in HepG2 cells by siRNA results in more cell death after treatment by quinacrine and TRAIL. The mechanism by which quinacrine sensitizes hepatocellular carcinoma cells to TRAIL and chemotherapies, and the potential for clinical application currently are being further explored. Lastly, quinacrine synergizes with chemotherapeutics, such as adriamycin, 5-FU, etoposide, CPT11, sorafenib, and gemcitabine, in killing hepatocellular carcinoma cells in vitro and the drug enhances the activity of sorafenib to delay tumor growth in vivo.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Benzenesulfonates / pharmacology
  • Camptothecin / analogs & derivatives
  • Camptothecin / pharmacology
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / pathology
  • Cell Death / drug effects
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cytoplasm / drug effects
  • Cytoplasm / metabolism
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Doxorubicin / pharmacology*
  • Drug Synergism
  • Etoposide / pharmacology
  • Female
  • Fluorouracil / pharmacology
  • Genes, p53
  • Humans
  • Irinotecan
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / pathology
  • Mice
  • Microtubule-Associated Proteins / metabolism
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Niacinamide / analogs & derivatives
  • Phenylurea Compounds
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Pyridines / pharmacology
  • Quinacrine / pharmacokinetics
  • Quinacrine / pharmacology*
  • RNA, Small Interfering
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
  • Sorafenib
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Benzenesulfonates
  • MAP1LC3A protein, human
  • Mcl1 protein, mouse
  • Microtubule-Associated Proteins
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Phenylurea Compounds
  • Proto-Oncogene Proteins c-bcl-2
  • Pyridines
  • RNA, Small Interfering
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF10A protein, human
  • Deoxycytidine
  • Niacinamide
  • Etoposide
  • Irinotecan
  • Doxorubicin
  • Sorafenib
  • gemcitabine
  • Quinacrine
  • Fluorouracil
  • Camptothecin