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Effective tumor cell death by sigma-2 receptor ligand siramesine involves lysosomal leakage and oxidative stress

Marie Stampe Ostenfeld1, Nicole Fehrenbacher, Maria Høyer-Hansen

  • 1Apoptosis Department, Institute for Cancer Biology, Danish Cancer Society, Copenhagen, Denmark.

Cancer Research
|October 6, 2005
PubMed

Insights

Siramesine, a sigma-2 receptor ligand, induces programmed cell death independent of caspases in cancer cells. This novel compound shows promise as an anti-cancer drug for tumors resistant to traditional therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Acquired resistance to caspase-mediated apoptosis is a significant challenge in human cancer treatment.
  • Novel therapeutic strategies are needed to overcome resistance to conventional cancer therapies.

Purpose of the Study:

  • To investigate the potential of siramesine, a sigma-2 receptor ligand, in inducing cancer cell death.
  • To elucidate the mechanism of siramesine-induced cell death and its efficacy in preclinical cancer models.

Main Methods:

  • Siramesine was used to treat immortalized and transformed cells, and its effects on cell death pathways were analyzed.
  • Reactive oxygen species (ROS) levels, lysosomal membrane permeabilization, and morphologic changes were assessed.
  • The role of antioxidants, cathepsin B, Bcl-2, p53, and various protease inhibitors in siramesine-induced cell death was evaluated.
  • The impact of oncogene transformation on siramesine sensitivity was studied.
  • Antitumorigenic effects of siramesine were tested in murine breast cancer and fibrosarcoma models.

Main Results:

  • Siramesine induced caspase-independent programmed cell death, characterized by increased ROS, lysosomal permeabilization, and cellular changes.
  • Lipid-soluble antioxidants (alpha- and gamma-tocopherol) protected cells, while cathepsin B inhibitors offered partial protection.
  • Bcl-2 overexpression, p53 deficiency, and inhibitors of caspases, calpains, or serine proteases did not prevent siramesine-induced death.
  • Oncogenic transformation with c-src or v-Ha-ras sensitized cells to siramesine.
  • Siramesine demonstrated significant antitumorigenic effects in vivo in mouse models.

Conclusions:

  • Siramesine effectively triggers a unique form of programmed cell death that bypasses caspase pathways.
  • The drug's mechanism involves oxidative stress and lysosomal destabilization, with lipid antioxidants showing protective effects.
  • Siramesine exhibits potent antitumor activity in preclinical models, highlighting its potential as a therapeutic agent for drug-resistant cancers.

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