Alterations in the homeostasis of phospholipids and cholesterol by antitumor alkylphospholipids

Abstract

The alkylphospholipid analog miltefosine (hexadecylphosphocholine) is a membrane-directed antitumoral and antileishmanial drug belonging to the alkylphosphocholines, a group of synthetic antiproliferative agents that are promising candidates in anticancer therapy. A variety of mechanisms have been suggested to explain the actions of these compounds, which can induce apoptosis and/or cell growth arrest. In this review, we focus on recent advances in our understanding of the actions of miltefosine and other alkylphospholipids on the human hepatoma HepG2 cell line, with a special emphasis on lipid metabolism. Results obtained in our laboratory indicate that miltefosine displays cytostatic activity and causes apoptosis in HepG2 cells. Likewise, treatment with miltefosine produces an interference with the biosynthesis of phosphatidylcholine via both CDP-choline and phosphatidylethanolamine methylation. With regard to sphingolipid metabolism, miltefosine hinders the formation of sphingomyelin, which promotes intracellular accumulation of ceramide. We have demonstrated for the first time that treatment with miltefosine strongly impedes the esterification of cholesterol and that this effect is accompanied by a considerable increase in the synthesis of cholesterol, which leads to higher levels of cholesterol in the cells. Indeed, miltefosine early impairs cholesterol transport from the plasma membrane to the endoplasmic reticulum, causing a deregulation of cholesterol homeostasis. Similar to miltefosine, other clinically-relevant synthetic alkylphospholipids such as edelfosine, erucylphosphocholine and perifosine show growth inhibitory effects on HepG2 cells. All the tested alkylphospholipids also inhibit the arrival of plasma-membrane cholesterol to the endoplasmic reticulum, which induces a significant cholesterogenic response in these cells, involving an increased gene expression and higher levels of several proteins related to the pathway of biosynthesis as well as the receptor-mediated uptake of cholesterol. Thus, membrane-targeted alkylphospholipids exhibit a common mechanism of action through disruption of cholesterol homeostasis. The accumulation of cholesterol within the cell and the reduction in phosphatidylcholine and sphingomyelin biosyntheses certainly alter the ratio of choline-bearing phospholipids to cholesterol, which is critical for the integrity and functionality of specific membrane microdomains such as lipid rafts. Alkylphospholipid-induced alterations in lipid homeostasis with probable disturbance of the native membrane structure could well affect signaling processes vital to cell survival and growth.

Multi-analytical platform metabolomic approach to study miltefosine mechanism of action and resistance in Leishmania

“…MT is supposed to interact with cell membranes [60], and kill parasites via oxidative stress [24,61]. As such, resistance relies on either avoidance of intracellular accumulation of the drug [30], or to prevention of induction of incidental cell death [12] as the final lethal process where the different detrimental effects of the drug converge.…”

Repurposing Miltefosine for the Treatment of Immune-Mediated Disease?

“…Miltefosine increases the membrane fluidity in macrophages (Ghosh et al, 2013), an effect that was reported to decrease antigen presentation and stimulation of T cells (Chakraborty et al, 2005). On the other hand, miltefosine has an affinity for sterols and is known to stabilize sterol-rich areas, such as lipid rafts, which increase antigen presentation (Jiménez-López et al, 2010). Indeed, macrophages treated with miltefosine show an enhanced ability to stimulate T cells, resulting in higher production of IL-2, IL-12, TNF-a, and NO (Ghosh et al, 2013).…”

Potential antitumor activity of novel DODAC/PHO-S liposomes

“…These effects are attributed to agents such as edelfosine, ilmofosine, and miltefosine. 2,3,9,10 However, the use of nanocarriers as drug delivery systems for chemotherapeutic agents may be an alternative to decrease the chance of unanticipated adverse effects and maximize the therapeutic effects of encapsulated drugs. 11 Recently, the use of liposome-encapsulated paclitaxel and miltefosine provided synergistic effect on human glioblastoma cells resistant to chemotherapeutic agents, with a sustained release of these drugs and reversal of resistance.…”