Title:Apoptosis Induction by Erucylphosphohomocholine via the 18 kDa Mitochondrial Translocator Protein: Implications for Cancer Treatment
Volume: 14
Issue: 4
Author(s): Leo Veenman, Moshe Gavish and Wilfried Kugler
Affiliation:
Keywords:
ATP, cardiolipin, Erucylphosphohomocholine (ErPC3, erufosine), glioblastoma, 18 kDa translocator protein (TSPO),
mitochondrial apoptosis, mitochondrial membrane potential (ΔΨm), reactive oxygen species (ROS).
Abstract: Many types of cancer, for example glioblastoma, show resistance against current anti-cancer treatments. One reason is that
they are not capable to effectively activate their intracellular cell death pathways. Novel treatments designed to overcome these
deficiencies in cancer cells present promising concepts to eradicate chemotherapy-resistant cancer cells. One of these approaches includes
the membrane seeking compound erucylphosphohomocholine (ErPC3) which is part of the latest generation of alkylphospholipid analogs
developed over the last two-and-a-half decades. ErPC3 exerts potent antineoplastic effects in animal models and against established
cancer cell lines including, for example, glioblastoma and different types of leukemia, while sparing their normal counterparts.
Starting with a historical survey, we report here on the anticancer activity of ErPC3 and on ErPC3’s established mechanisms of action.
We cover the current knowledge on the induction of mitochondrial apoptosis by ErPC3, including its interaction with the 18 kDa
translocator protein (TSPO). In addition we discuss other signaling pathways modulated by ErPC3. Interaction with the TSPO leads to
activation of the mitochondrial apoptosis cascade. This includes cardiolipin oxidation at mitochondrial levels, collapse of the
mitochondrial membrane potential, and release of cytochrome c, the initiating steps of the mitochondrial apoptosis cascade. Other
pathways modulated by ErPC3 include different kinases for the PI3K/Akt/mTOR and the MAP kinase pathways. Furthermore, ErPC3’s
cytotoxic actions may include its effects on phosphatidylcholine synthesis to inhibit the endoplasmic reticulum enzyme
CTP:phosphocholine cytidyltransferase. These basic research data hopefully will lead to effective approaches toward exploitation of
ErPC3 for the treatment of cancer.
