Anti-cancer alkyl-lysophospholipids inhibit the phosphatidylinositol 3-kinase–Akt/PKB survival pathway

Abstract

Synthetic alkyl-lysophospholipids (ALPs) represent a new class of anti-tumor agents that target cell membranes and induce apoptosis. However, the exact mechanisms by which ALPs exert these effects remain unclear. Here, we investigated in the epithelial carcinoma cell lines A431 and HeLa the effect of three clinically relevant ALPs [Et-18-OCH3 (Edelfosine), HePC (Miltefosine) and D-21266 (Perifosine)] on the phosphatidylinositol 3-kinase (PI3K)-Akt/PKB survival pathway. We found that growth factor-induced Akt/PKB activation in these cells is dependent on PI3K and that all three ALPs inhibited this pathway in a dose-dependent manner. We further showed that inhibition of the PI3K-Akt/PKB pathway by wortmannin or ALPs is associated with activation of the pro-apoptotic SAPK/JNK pathway. Inhibition of the PI3K-Akt/PKB survival pathway represents a novel mode of action of ALPs that may significantly contribute to the induction of apoptosis.

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

“…Perifosine (NSC 639966/D-21266 compound 31, Figure 5) appears to block the activation and phosphorylation of Akt in cellular settings (Kondapaka et al, 2003;Ruiter et al, 2003). Perifosine is an alkylphosphocholine structurally related to miltefosine, but has an improved tolerability profile with regard to the dose-limiting gastrointestinal side effects reported for the latter.…”

The anti-leishmanial drug miltefosine causes insulin resistance in skeletal muscle cells in vitro

“…Miltefosine has been reported to inhibit Akt/PKB phosphorylation leading to cell death in A431 and HeLa cell lines [5]. To investigate whether miltefosine causes similar effect(s) in skeletal muscle cells, differentiated L6E9 cells were pretreated with different concentrations of miltefosine for 30 min and subsequent insulin-stimulated activity was determined by Western immunoblotting.…”

“…[1,3,4]. Although no consensus has emerged regarding the mode of action of miltefosine in cancer cells or in parasites, several likely intracellular targets related to signal transduction and lipid biosynthesis have been identified [1,5]. Using A431 and HeLa cell lines, it has been reported that miltefosine inhibits the phosphatidylinositol 3-kinase (PI3K)-Akt/protein kinase B (PKB) pathway [5].…”

“…Although no consensus has emerged regarding the mode of action of miltefosine in cancer cells or in parasites, several likely intracellular targets related to signal transduction and lipid biosynthesis have been identified [1,5]. Using A431 and HeLa cell lines, it has been reported that miltefosine inhibits the phosphatidylinositol 3-kinase (PI3K)-Akt/protein kinase B (PKB) pathway [5]. Since PI3K and Akt/PKB are considered to be the central mediators of insulin signalling [6], it can be speculated that inhibition of the PI3K-Akt/ PKB pathway in skeletal muscle may inhibit insulinsignalling pathways or promote the accumulation of molecules capable of inhibiting insulin action.…”

Silencing of anti-apoptotic transmembrane protein lifeguard sensitizes solid tumor cell lines MCF-7 and SW872 to perifosine-induced cell death activation

“…This may explain differences in the biological activity of modified alkylphospholipids as found in the study by Mravljak et al (17) which confirms our results of reduced sensitivity of MCF-7 cells to treatment with perifosine. It is crucial to determine whether prolonged treatment with perifosine induces any changes in the LFG expression since perofisone is a known regulator of survival and proliferation pathways, such as PI3K/Akt and ERK 1/2 (7,18,19). Previously, we demonstrated that LFG is a new target gene of the Akt/LEF-1 pathway (6) and consequently a potential target of perifosine activity as well.…”