The Amaryllidaceae isocarbostyril narciclasine induces apoptosis by activation of the death receptor and/or mitochondrial pathways in cancer cells but not in normal fibroblasts

Neoplasia. 2007 Sep;9(9):766-76. doi: 10.1593/neo.07535.

Abstract

Our study has shown that the Amaryllidaceae isocarbostyril narciclasine induces marked apoptosis-mediated cytotoxic effects in human cancer cells but not in normal fibroblasts by triggering the activation of the initiator caspases of the death receptor pathway (caspase-8 and caspase-10) at least in human MCF-7 breast and PC-3 prostate carcinoma cells. The formation of the Fas and death receptor 4 (DR4) death-inducing signaling complex was clearly evidenced in MCF-7 and PC-3 cancer cells. Caspase-8 was found to interact with Fas and DR4 receptors on narciclasine treatment. However, narciclasine-induced downstream apoptotic pathways in MCF-7 cells diverged from those in PC-3 cells, where caspase-8 directly activated effector caspases such as caspase-3 in the absence of any further release of mitochondrial proapoptotic effectors. In contrast, in MCF-7 cells, the apoptotic process was found to require an amplification step that is mitochondria-dependent, with Bid processing, release of cytochrome c, and caspase-9 activation. It is postulated that the high selectivity of narciclasine to cancer cells might be linked, at least in part, to this activation of the death receptor pathway. Normal human fibroblasts appear approximately 250-fold less sensitive to narciclasine, which does not induce apoptosis in these cells probably due to the absence of death receptor pathway activation.

Keywords: Apoptosis; cancer cells; death receptor pathway; fibroblasts; narciclasine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amaryllidaceae Alkaloids / isolation & purification
  • Amaryllidaceae Alkaloids / pharmacology*
  • Antineoplastic Agents, Phytogenic / isolation & purification
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • BH3 Interacting Domain Death Agonist Protein / physiology
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Carcinoma / metabolism
  • Carcinoma / pathology*
  • Caspases / physiology
  • Cytochromes c / analysis
  • DNA Fragmentation
  • Drug Resistance, Neoplasm
  • Enzyme Activation / drug effects
  • Female
  • Fibroblasts / drug effects
  • Humans
  • Male
  • Mitochondria / enzymology
  • Mitochondria / physiology*
  • Narcissus / chemistry
  • Neoplasm Proteins / drug effects
  • Neoplasm Proteins / physiology
  • Phenanthridines / isolation & purification
  • Phenanthridines / pharmacology*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology*
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor / physiology*
  • fas Receptor / drug effects
  • fas Receptor / physiology

Substances

  • Amaryllidaceae Alkaloids
  • Antineoplastic Agents, Phytogenic
  • BH3 Interacting Domain Death Agonist Protein
  • BID protein, human
  • Neoplasm Proteins
  • Phenanthridines
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor
  • TNFRSF10A protein, human
  • fas Receptor
  • narciclasine
  • Cytochromes c
  • Caspases