Antitumor Lipids—Structure, Functions, and Medical Applications

Kostadinova, Aneliya; Topouzova-Hristova, Tanya; Momchilova, Albena; Tzoneva, Rumiana; Berger, Martin R.

doi:10.1016/bs.apcsb.2015.08.001

Cited by 30 publications

(21 citation statements)

References 151 publications

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“…Ether lipids have been shown to have anti-tumor properties, including reduction of tumor cell invasion and inhibition of tumor metastases. It is proposed that these chemotherapeutic agents interfere with lipid homeostasis due to their similarity with endogenous PL, targeting membrane lipid rafts and altering lipid-linked signalling, hence leading to apoptosis [ 98 , 99 ]. Typical representatives of this group are ether PL ET-18-OCH 3 (edelfosine) and BM 41.440 (ilmofosine) as well as hexadecylphosphocholine (miltefosine) [ 100 ].…”

Section: Anti-tumor Properties Of Synthetic Plasmalogens and Analoguementioning

confidence: 99%

“…Encouraging results have been found with all these compounds and novel, promising analogues such as erucylphosphocholine (ErPC) and its homocholine analogue erufosine (ErPC3) also hold promise as a single-agent (monotherapy) or in combination regimens [ 101 ]. Several studies combining the more recent ether lipids derivatives with diverse antineoplastic agents provide clinically significant benefits [ 99 ]. Shin et al [ 102 ] described the synthetic pathway applied to the synthesis of 1-O-1′- (Z) -hexadecenyl-2-O-methyl-rac-glycero-3-phosphocholine, the Z-vinyl ether analogue of ET-18- OMe, which shows significant antitumor activity in pancreatic tumor cells.…”

Section: Anti-tumor Properties Of Synthetic Plasmalogens and Analoguementioning

confidence: 99%

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Plasmalogen lipids: functional mechanism and their involvement in gastrointestinal cancer

et al. 2018

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The plasmalogens are a class of glycerophospholipids which contain a vinyl-ether and an ester bond at the sn-1 and sn-2 positions, respectively, in the glycerol backbone. They constitute 10 mol% of the total mass of phospholipids in humans, mainly as membrane structure components. Plasmalogens are important for the organization and stability of lipid raft microdomains and cholesterol-rich membrane regions involved in cellular signaling. In addition to their structural roles, a subset of ether lipids are thought to function as endogenous antioxidants and emerging studies suggest that they are involved in cell differentiation and signaling pathways. Although the clinical significance of plasmalogens is linked to peroxisomal disorders, the pathophysiological roles and their possible metabolic pathways are not fully understood since they present unique structural attributes for the different tissue types. Studies suggest that changes in plasmalogen metabolism may contribute to the development of various types of cancer. Here, we review the molecular characteristics of plasmalogens in order to significantly increase our understanding of the plasmalogen molecule and its involvement in gastrointestinal cancers as well as other types of cancers.Electronic supplementary materialThe online version of this article (10.1186/s12944-018-0685-9) contains supplementary material, which is available to authorized users.

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Section: Anti-tumor Properties Of Synthetic Plasmalogens and Analoguementioning

confidence: 99%

Section: Anti-tumor Properties Of Synthetic Plasmalogens and Analoguementioning

confidence: 99%

Plasmalogen lipids: functional mechanism and their involvement in gastrointestinal cancer

et al. 2018

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“…Therefore, they can induce apoptosis in rapidly growing cells, such as tumor cells. They can lead to selective reduction of tumor metastases, impairment of angiogenesis, differentiation of tumor cells, impediment of cytokinesis, cell cycle halt, immune stimulation and intensification of immune reactions against tumors (Van Blitterswijk and Verheij, 2008;Kostadinova et al, 2015;Kaleagasioglu et al, 2019;Zaremberg et al, 2019). Among their mechanism of actions are interference with phospholipid metabolism, the inhibition of survival pathways and alteration of signal transduction (e.g.…”

Section: Alkylphosphocholinesmentioning

confidence: 99%

Multiple Facets of Autophagy and the Emerging Role of Alkylphosphocholines as Autophagy Modulators

2020

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Autophagy is a highly conserved multistep process and functions as passage for degrading and recycling protein aggregates and defective organelles in eukaryotic cells. Based on the nature of these materials, their size and degradation rate, four types of autophagy have been described, i.e. chaperone mediated autophagy, microautophagy, macroautophagy, and selective autophagy. One of the major regulators of this process is mTOR, which inhibits the downstream pathway of autophagy following the activation of its complex 1 (mTORC1). Alkylphosphocholine (APC) derivatives represent a novel class of antineoplastic agents that inhibit the serine-threonine kinase Akt (i.e. protein kinase B), which mediates cell survival and cause cell cycle arrest. They induce autophagy through inhibition of the Akt/mTOR cascade. They interfere with phospholipid turnover and thus modify signaling chains, which start from the cell membrane and modulate PI3K/Akt/ mTOR, Ras-Raf-MAPK/ERK and SAPK/JNK pathways. APCs include miltefosine, perifosine, and erufosine, which represent the first-, second-and third generation of this class, respectively. In a high fraction of human cancers, constitutively active oncoprotein Akt1 suppresses autophagy in vitro and in vivo. mTOR is a downstream target for Akt, the activation of which suppresses autophagy. However, treatment with APC derivatives will lead to dephosphorylation (hence deactivation) of mTOR and thus induces autophagy. Autophagy is a double-edged sword and may result in chemotherapeutic resistance as well as cancer cell death when apoptotic pathways are inactive. APCs display differential autophagy induction capabilities in different cancer cell types. Therefore, autophagy-dependent cellular responses need to be well understood in order to improve the chemotherapeutic outcome.

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“…The unique way by which APLs can trigger cell apoptosis, through perturbation of the cell membranes, gives these compounds an advantage over conventional chemotherapeutic agents that interact with DNA. Furthermore, the action of APLs appears to be specific for tumor cells, and both cellular uptake and APL-induced apoptosis are increased in the malignant state of the cells (Kostadinova et al, 2015 ). Significant efforts have thus been made to synthesize metabolically stable analogs of lysoPCs with potential antineoplastic activity.…”

Section: Introductionmentioning

confidence: 99%

Dual Gene Delivery Reagents From Antiproliferative Alkylphospholipids for Combined Antitumor Therapy

et al. 2020

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Alkylphospholipids (APLs) have elicited great interest as antitumor agents due to their unique mode of action on cell membranes. However, their clinical applications have been limited so far by high hemolytic activity. Recently, cationic prodrugs of erufosine, a most promising APL, have been shown to mediate efficient intracellular gene delivery, while preserving the antiproliferative properties of the parent APL. Here, cationic prodrugs of the two APLs that are currently used in the clinic, miltefosine, and perifosine, are investigated and compared to the erufosine prodrugs. Their synthesis, stability, gene delivery and self-assembly properties, and hemolytic activity are discussed in detail. Finally, the potential of the pro-miltefosine and pro-perifosine compounds M E12 and P E12 in combined antitumor therapy is demonstrated using pUNO1-hTRAIL, a plasmid DNA encoding TRAIL, a member of the TNF superfamily. With these pro-APL compounds, we provide a proof of concept for a new promising strategy for cancer therapy combining gene therapy and APL-based chemotherapy.

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Antitumor Lipids—Structure, Functions, and Medical Applications

Cited by 30 publications

References 151 publications

Plasmalogen lipids: functional mechanism and their involvement in gastrointestinal cancer

Plasmalogen lipids: functional mechanism and their involvement in gastrointestinal cancer

Multiple Facets of Autophagy and the Emerging Role of Alkylphosphocholines as Autophagy Modulators

Dual Gene Delivery Reagents From Antiproliferative Alkylphospholipids for Combined Antitumor Therapy

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