Ferda Kaleağasıoğlu, Maya M. Zaharieva, Spiro M. Konstantinov and Martin R. Berger* Pages 66 - 91 ( 26 )
Background: Alkylphospholipids (APLs) are synthetically derived from cell membrane components, which they target and thus modify cellular signalling and cause diverse effects. This study reviews the mechanism of action of anticancer, antiprotozoal, antibacterial and antiviral activities of ALPs, as well as their clinical use.
Methods: A literature search was used as the basis of this review.
Results: ALPs target lipid rafts and alter 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 is also affected. These changes lead to a G2/M phase cell cycle arrest and subsequently induce programmed cell death. The available knowledge on inhibition of AKT phosphorylation, mTOR phosphorylation and Raf down-regulation renders ALPs as attractive candidates for modern medical treatment, which is based on individualized diagnosis and therapy. Corresponding to their unusual profile of activities, their side effects result from cholinomimetic activity mainly and focus on the gastrointestinal tract. These aspects together with their bone marrow sparing features render APCs well suited for modern combination therapy. Although the clinical success has been limited in cancer diseases so far, the use of miltefosine against leishmaniosis is leading the way to better understanding their optimized use.
Conclusion: Recent synthetic programs generate congeners with the increased therapeutic ratio, liposomal formulations, as well as diapeutic (or theranostic) derivatives with optimized properties. It is anticipated that these innovative modifications will pave the way for the further successful development of ALPs.
Mode of action, modulation of cell signalling, pharmacodynamics, anticancer activities, pharmacokinetics, clinical trials.
Toxicology and Chemotherapy Unit, German Cancer Research Center (DKFZ), Heidelberg, Toxicology and Chemotherapy Unit, German Cancer Research Center (DKFZ), Heidelberg, Toxicology and Chemotherapy Unit, German Cancer Research Center (DKFZ), Heidelberg, Toxicology and Chemotherapy Unit, German Cancer Research Center (DKFZ), Heidelberg