A novel topoisomerase inhibitor, daurinol, suppresses growth of HCT116 cells with low hematological toxicity compared to etoposide

Neoplasia. 2011 Nov;13(11):1043-57. doi: 10.1593/neo.11972.


We report that daurinol, a novel arylnaphthalene lignan, is a promising potential anticancer agent with adverse effects that are less severe than those of etoposide, a clinical anticancer agent. Despite its potent antitumor activity, clinical use of etoposide is limited because of its adverse effects, including myelosuppression and the development of secondary leukemia. Here, we comprehensively compared the mechanistic differences between daurinol and etoposide because they have similar chemical structures. Etoposide, a topoisomerase II poison, is known to attenuate cancer cell proliferation through the inhibition of DNA synthesis. Etoposide treatment induces G(2)/M arrest, severe DNA damage, and the formation of giant nuclei in HCT116 cells. We hypothesized that the induction of DNA damage and nuclear enlargement due to abnormal chromosomal conditions could give rise to genomic instability in both tumor cells and in actively dividing normal cells, resulting in the toxic adverse effects of etoposide. We found that daurinol is a catalytic inhibitor of human topoisomerase IIa, and it induces S-phase arrest through the enhanced expression of cyclins E and A and by activation of the ATM/Chk/Cdc25A pathway in HCT116 cells. However, daurinol treatment did not cause DNA damage or nuclear enlargement in vitro. Finally, we confirmed the in vivo antitumor effects and adverse effects of daurinol and etoposide in nude mice xenograft models. Daurinol displayed potent antitumor effects without any significant loss of body weight or changes in hematological parameters, whereas etoposide treatment led to decreased body weight and white blood cell, red blood cell, and hemoglobin concentration.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Benzodioxoles / adverse effects
  • Benzodioxoles / pharmacology
  • Benzodioxoles / therapeutic use
  • Carcinoma / drug therapy
  • Carcinoma / pathology*
  • Cell Proliferation / drug effects*
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / pathology*
  • Drugs, Investigational / adverse effects
  • Drugs, Investigational / pharmacology
  • Drugs, Investigational / therapeutic use
  • Etoposide / adverse effects
  • Etoposide / pharmacology*
  • Etoposide / therapeutic use
  • HCT116 Cells
  • Hematologic Diseases / chemically induced*
  • Hematologic Diseases / epidemiology
  • Hep G2 Cells
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Models, Biological
  • Naphthalenes / adverse effects
  • Naphthalenes / pharmacology
  • Naphthalenes / therapeutic use
  • Topoisomerase Inhibitors / adverse effects*
  • Topoisomerase Inhibitors / pharmacology*
  • Topoisomerase Inhibitors / therapeutic use
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Benzodioxoles
  • Drugs, Investigational
  • Naphthalenes
  • Topoisomerase Inhibitors
  • daurinol
  • Etoposide