The so-called alkylphospholipid analogs (APLs) constitute a family of synthetic antitumor compounds that target cell membranes. The
ether phospholipid edelfosine has been considered the long-standing prototype of these
antitumor agents and promotes apoptosis in
tumor cells by a rather selective way, while sparing normal cells. Increasing evidence suggests that
edelfosine-induced apoptosis involves a number of subcellular structures in
tumor cells, including plasma membrane
lipid rafts, endoplasmic reticulum (ER) and mitochondria.
Edelfosine has been shown to accumulate in plasma membrane
lipid rafts, ER and mitochondria in different
tumor cells in a cell type-dependent way.
Edelfosine induces apoptosis in several hematopoietic
cancer cells by recruiting
death receptor and downstream apoptotic signaling molecules into
lipid rafts and displacing survival signaling molecules from these membrane domains. However, in vitro and in vivo evidences suggest that
edelfosine-induced apoptosis in solid
tumor cells is mediated through an ER stress response. Both raft- and ER-mediated proapoptotic responses require a mitochondrial-related step to eventually promote cell death, and overexpression of Bcl-2 or Bcl-xL prevents
edelfosine-induced apoptosis.
Edelfosine can also interact with mitochondria leading to an increase in mitochondrial membrane permeability and loss of mitochondrial membrane potential.
Edelfosine treatment also induced a redistribution of
lipid rafts from the plasma membrane to mitochondria, suggesting a raft-mediated link between plasma membrane and mitochondria. The involvement of
lipid rafts, ER and mitochondria in the apoptotic response induced by
edelfosine may provide new avenues for targeting
cancer cells as well as new opportunities for
cancer therapy.