Lycorine, the main phenanthridine Amaryllidaceae alkaloid, exhibits significant antitumor activity in cancer cells that display resistance to proapoptotic stimuli: an investigation of structure-activity relationship and mechanistic insight

J Med Chem. 2009 Oct 22;52(20):6244-56. doi: 10.1021/jm901031h.

Abstract

Twenty-two lycorine-related compounds were investigated for in vitro antitumor activity using four cancer cell lines displaying different levels of resistance to proapoptotic stimuli and two cancer cell lines sensitive to proapoptotic stimuli. Lycorine and six of its congeners exhibited potency in the single-digit micromolar range, while no compound appeared more active than lycorine. Lycorine also displayed the highest potential (in vitro) therapeutic ratio, being at least 15 times more active against cancer than normal cells. Our studies also showed that lycorine exerts its in vitro antitumor activity through cytostatic rather than cytotoxic effects. Furthermore, lycorine provided significant therapeutic benefit in mice bearing brain grafts of the B16F10 melanoma model at nontoxic doses. Thus, the results of the current study make lycorine an excellent lead for the generation of compounds able to combat cancers, which are naturally resistant to proapoptotic stimuli, such as glioblastoma, melanoma, non-small-cell-lung cancers, and metastatic cancers, among others.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Amaryllidaceae Alkaloids / chemistry*
  • Amaryllidaceae Alkaloids / pharmacology*
  • Amaryllidaceae Alkaloids / therapeutic use
  • Amaryllidaceae Alkaloids / toxicity
  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Agents / toxicity
  • Apoptosis / drug effects
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cytoskeleton / drug effects
  • Cytoskeleton / metabolism
  • Drug Resistance, Neoplasm / drug effects*
  • Female
  • Humans
  • Inhibitory Concentration 50
  • Maximum Tolerated Dose
  • Melanoma / drug therapy
  • Mice
  • Phenanthridines / chemistry*
  • Phenanthridines / pharmacology*
  • Phenanthridines / therapeutic use
  • Phenanthridines / toxicity
  • Structure-Activity Relationship
  • Xenograft Model Antitumor Assays

Substances

  • Actins
  • Amaryllidaceae Alkaloids
  • Antineoplastic Agents
  • Phenanthridines
  • lycorine