Glycosidated phospholipids: uncoupling of signalling pathways at the plasma membrane

Abstract

Cell expansion and metastasis are considered hallmarks of tumour progression. Therefore, efforts have been made to develop novel anti-cancer drugs that inhibit both the proliferation and the motility of tumour cells. Synthetic alkylphospholipids, compounds with aliphatic side chains that are ether linked to a glycerol backbone, are structurally derived from plateletactivating factor and represent a new class of drugs with anti-proliferative properties in tumour cells. These compounds do not interfere with the DNA or mitotic spindle apparatus of the cell. Instead, they are incorporated into cell membranes, where they accumulate and interfere with lipid metabolism and lipid-dependent signalling pathways. Recently, it has been shown that the most commonly studied alkylphospholipids inhibit proliferation by inducing apoptosis in malignant cells while leaving normal cells unaffected. This review focuses on a novel group of synthetic alkylphospholipids, the glycosidated phospholipids, which contain carbohydrates or carbohydrate-related molecules at the sn-2 position of the glycerol backbone. Members of this subfamily also exhibit anti-proliferative capacity and modulate the cell adhesion, differentiation, and migration of tumour cells. Among this group, Ino-C2-PAF shows the highest efficacy and low cytotoxicity. Apart from its anti-proliferative effect, Ino-C2-PAF strongly reduces cell motility via its inhibitory effect on the phosphorylation of the cytosolic tyrosine kinases FAK and Src. Signalling pathways under the control of the FAK/Src complex are normally required for both migration and proliferation and play a prominent role in tumour progression. We intend to highlight the potential of glycosidated phospholipids, especially Ino-C2-PAF, as a promising new group of drugs for the treatment of hyperproliferative and migration-based skin diseases.

Evidence for activation of BKCa channels by a known inhibitor of focal adhesion kinase, PF573228

“…Such kinase can regulate cell adhesion, apoptosis, differentiation, cell motility/movement, cell cycle progression, and the permeability barrier of tight junction in different epithelia and/or endothelia (Danker et al, 2010;Lafrenaye and Fuss, 2010;Parsons et al, 2008;Tomar et al, 2009;Zhao and Guan, 2009). FAK expression was also reported to be increased in many cancers, including breast and prostate cancer (Zhao and Guan, 2009).…”

Design, synthesis and antitumor properties of glycosylated antitumor ether lipid (GAEL)- chlorambucil-hybrids

“…It includes phosphorus-GAELs (glycosyl-containing phospholipid ethers) such as glucosamine-PAF, 35 and non-phosphorus GAELs in which the sugar moiety replaces the phosphobase moiety (Figure 1-2). The non-phosphorus GAEL can further be grouped according to the types and nature of sugars substituted for the phosphocholine base.…”

Synthetic glycosidated phospholipids induce apoptosis through activation of FADD, caspase-8 and the mitochondrial death pathway

“…Synthetic alkyl-phospholipid analogs (APLs) are a new class of antitumor agents which target cell membranes [3][4][5][6][7][8][9][10]. These compounds differ from conventional anticancer therapeutics that act either via a DNA damage-induced stress response or, in the case of the new targeted therapeutics, via interference with kinase pathways.…”