Alkylphospholipids are signal transduction modulators with potential for anticancer therapy.

Alkylphospholipids (APLs) are synthetically derived from cell membrane components. They target cell membranes and modify cellular signalling, thus originating diverse effects, including anti¬cancer, antiprotozoal, antibacterial and antiviral activities. Their actions probably initiate from targeting lipid rafts and altering phospholipase D and C signalling cascades, which in turn will modulate the PI3K/Akt/mTOR and RAS/RAF/MEK/ERK pathways. By feedback coupling, the SAPK/JNK signalling chain will also be affected. These changes lead to a G2/M phase cell cycle arrest and subsequently induce programmed cell death with classi¬cal hallmarks like stimulation of death receptors, chromatin condensation, caspase acti¬vation and PARP cleav¬age. Of note, the comprehensive mode of APL action is still unknown. Never¬theless, the available knowledge on inhibition of AKT phosphorylation, mTOR phosphoryla¬tion and Raf down-regulation render them attractive candidates for modern medical treat¬ment, which is based on individualized diagnosis and therapy. Correspond¬ing to their unusual profile of activities, their side effects result from their cholinomi¬metic activity mainly and thus focus on the gastroin-testinal tract. These mechanistic aspects together with their bone marrow sparing features ren¬der the APC group of agents well suited for mod¬ern combination therapy. Although the clini¬cal success of APLs has been limited in cancer diseases so far, the use of miltefosine as drug against leishmaniosis is leading the way to better understanding their optimized use. Recent synthetic programs contribute to generating congeners with reduced cholinomi¬metic effects and in¬creased efficacy, thus broadening the therapeutic ratio. Preliminary studies with lipo¬somal formulations have shown reduced tox¬icity and seem to be encouraging. It is anticipated that these modern and specific drug properties will pave the way for their further devel-opment.