Membrane targeted anticancer drugs: potent inducers of apoptosis and putative radiosensitisers.
In the last two decades, cellular membranes have been identified as novel targets for antineoplastic drugs. Two classes of synthetic phospholipid analogues: the alkyllysophospholipids (ALP) with the prototypical 1-O-Octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (Et-18-OCH3, Edelfosine), as well as the alkylphosphocholines (APC) with the prototypical hexadecylphosphocholine (HePC, Miltefosine), have been identified targeting cellular membranes and exerting potent antineoplastic effects in cell culture and animal models. In contrast to most of the chemotherapeutic agents in clinical use, APC and ALP primarily interfere with cellular membranes without direct interaction with the DNA. They modulate membrane permeability and fluidity, membrane lipid composition, metabolism of phospholipids and proliferation signal transduction. Interestingly, similar to DNA-damaging drugs, ALP and APC induce apoptotic cell death. Furthermore, combination experiments with cytotoxic drugs or radiation revealed a synergistic effect in leukaemic and brain tumour cell lines. These findings together with the observations that ALP and APC selectively kill malignant cells, that they lack bone marrow toxicity and even exert growth stimulatory effects on hematopoietic progenitor cells make ALP and APC a promising tool for novel approaches in cancer chemotherapy. In this contribution, novel findings on the mechanism of action, apoptotic signalling pathways and putative radiosensitising effects of ALP and APC were reviewed, with a special focus on erucylphosphocholine (ErPC), the prototype of the novel intravenously applicable APC derivatives.
Jendrossek
V
V
Department of Radiation Oncology, University of Tuebingen, Hoppe-Seyler-Str. 3, D-72076 Tuebingen, Germany. verena.jendrossek@uni-tuebingen.de
Handrick
R
R
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*
D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents