Combination of the anti-tumour cell ether lipid edelfosine with sterols abolishes haemolytic side effects of the drug

Busto, Jon V.; Canto-Jañez, Esther del; Goñi, Félix M.; Mollinedo, Faustino; Alonso, Alicia

doi:10.1007/s12154-008-0009-z

Cited by 40 publications

(52 citation statements)

References 18 publications

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“…We have previously shown that edelfosine increases cytosolic [Ca 2 þ ] in HeLa cells (Nieto-Miguel et al, 2007). On these grounds, and taking into account the interaction of edelfosine with cell membranes and lipids (Gajate et al, , 2009a(Gajate et al, , 2009bZaremberg et al, 2005;Mollinedo and Gajate, 2006;Torrecillas et al, 2006;Busto et al, 2007Busto et al, , 2008Ausili et al, 2008;, it might be envisaged that the increase in cytosolic [Ca 2 þ ] could be due to an increased permeability of the plasma membrane, resulting in Ca 2 þ entry from the extracellular medium, which it then leads to the herein reported increase in [Ca 2 þ ] ER , well above the steady state levels in control cells. The effect on [Ca 2 þ ] ER may seem puzzling, because ER stress has been rather associated with ER-stored Ca 2 þ release.…”

Section: Discussionmentioning

confidence: 98%

Antitumor alkyl-lysophospholipid analog edelfosine induces apoptosis in pancreatic cancer by targeting endoplasmic reticulum

et al. 2011

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Pancreatic cancer remains as one of the most deadly cancers, and responds poorly to current therapies. The prognosis is extremely poor, with a 5-year survival of less than 5%. Therefore, search for new effective therapeutic drugs is of pivotal need and urgency to improve treatment of this incurable malignancy. Synthetic alkyl-lysophospholipid analogs (ALPs) constitute a heterogeneous group of unnatural lipids that promote apoptosis in a wide variety of tumor cells. In this study, we found that the anticancer drug edelfosine was the most potent ALP in killing human pancreatic cancer cells, targeting endoplasmic reticulum (ER). Edelfosine was taken up in significant amounts by pancreatic cancer cells and induced caspaseand mitochondrial-mediated apoptosis. Pancreatic cancer cells show a prominent ER and edelfosine accumulated in this subcellular structure, inducing a potent ER stress response, with caspase-4, BAP31 and c-Jun NH 2 -terminal kinase (JNK) activation, CHOP/GADD153 upregulation and phosphorylation of eukaryotic translation initiation factor 2 a-subunit that eventually led to cell death. Oral administration of edelfosine in xenograft mouse models of pancreatic cancer induced a significant regression in tumor growth and an increase in apoptotic index, as assessed by TUNEL assay and caspase-3 activation in the tumor sections. The ER stress-associated marker CHOP/ GADD153 was visualized in the pancreatic tumor isolated from edelfosine-treated mice, indicating a strong in vivo ER stress response. These results suggest that edelfosine exerts its pro-apoptotic action in pancreatic cancer cells, both in vitro and in vivo, through its accumulation in the ER, which leads to ER stress and apoptosis. Thus, we propose that the ER could be a key target in pancreatic cancer, and edelfosine may constitute a prototype for the development of a new class of antitumor drugs targeting the ER.

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Section: Discussionmentioning

confidence: 98%

Antitumor alkyl-lysophospholipid analog edelfosine induces apoptosis in pancreatic cancer by targeting endoplasmic reticulum

et al. 2011

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“…Hence, edelfosine can be considered as the paradigm of this new raft-targeted therapy. The accumulation of edelfosine in rafts might be explained by its high affinity for cholesterol (Ausili et al, 2008;Busto et al, 2008), because of geometry compensation of the 'cone shape' of sterols and the 'inverted cone shape' of edelfosine that leads to a stable bilayer (Busto et al, 2008). Edelfosine targets membrane rafts of malignant cells, inducing raft aggregates that act as scaffolds for the recruitment and concentration of Fas/ CD95 and TRAIL receptors.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, cancer cells have been reported to display higher levels of cholesterol-rich lipid rafts than their normal counterparts (Li et al, 2006). Edelfosine shows a high affinity for cholesterol, and for cholesterol-enriched membranes such as rafts (Ausili et al, 2008;Busto et al, 2008), because of the complementarity of the molecular geometrics of sterols and edelfosine (Busto et al, 2008), and this feature may have interesting biomedical applications. The high cholesterol content in tumor cells, together with the avidity for cholesterol of edelfosine, might contribute in part to the accumulation of edelfosine in tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Lipid raft-targeted therapy in multiple myeloma

et al. 2010

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Despite recent advances in treatment, multiple myeloma (MM) remains an incurable malignancy. By using in vitro, ex vivo and in vivo approaches, we have identified here that lipid rafts constitute a new target in MM. We have found that the phospholipid ether edelfosine targets and accumulates in MM cell membrane rafts, inducing apoptosis through co-clustering of rafts and death receptors. Raft disruption by cholesterol depletion inhibited drug uptake by tumor cells as well as cell killing. Cholesterol replenishment restored MM cell ability to take up edelfosine and to undergo drug-induced apoptosis. Ceramide addition displaced cholesterol from rafts, and inhibited edelfosineinduced apoptosis. In an MM animal model, edelfosine oral administration showed a potent in vivo antimyeloma activity, and the drug accumulated preferentially and dramatically in the tumor. A decrease in tumor cell cholesterol, a major raft component, inhibited the in vivo antimyeloma action of edelfosine and reduced drug uptake by the tumor. The results reported here provide the proofof-principle and rationale for further clinical evaluation of edelfosine and for this raft-targeted therapy to improve patient outcome in MM. Our data reveal cholesterolcontaining lipid rafts as a novel and efficient therapeutic target in MM, opening a new avenue in cancer treatment.

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“…Moreover, the reduction in the capability of APLs to release the cholesterol from cells in the presence of exogenous cholesterol may be the reason for the lower hemolytic effect found by other authors in the presence of combinations of APLs and cholesterol (Busto et al, 2008).…”

mentioning

confidence: 87%

Antitumoral Alkylphospholipids Induce Cholesterol Efflux from the Plasma Membrane in HepG2 Cells

Ríos-Marco¹,

Jiménez-López²,

Marco³

et al. 2010

J Pharmacol Exp Ther

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Alkylphospholipid (APL) analogs are promising candidates in the search for treatments of cancer. Previous studies conducted in our laboratory indicate that, after prolonged treatment, they alter cholesterol homeostasis in HepG2 cells. Here we describe the effects that different APLs exert upon this cell line after a 1-h exposure in a serum-free medium, including 1) a rapid, significant increase in cholesterol efflux into the extracellular medium, which consequently provoked a depletion of cholesterol in the plasma membrane (further assays conducted in an attempt to return to control cholesterol levels were only partially successful); 2) use of methyl-␤-cyclodextrin, which indicated that APLs acted in a way similar to this agent that is used frequently to modulate membrane cholesterol levels; 3) the phosphorylation of Akt that showed that this critical regulator for cell survival was modulated by changes in cholesterol levels induced in the plasma membrane by APLs; and 4) membrane cholesterol depletion that is not related to the impairment of cholesterol traffic produced by APLs. Thus, we have found that antitumoral APLs efficiently deplete membrane cholesterol, which may be one important factor in determining the early biological actions of APLs.

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Combination of the anti-tumour cell ether lipid edelfosine with sterols abolishes haemolytic side effects of the drug

Cited by 40 publications

References 18 publications

Antitumor alkyl-lysophospholipid analog edelfosine induces apoptosis in pancreatic cancer by targeting endoplasmic reticulum

Antitumor alkyl-lysophospholipid analog edelfosine induces apoptosis in pancreatic cancer by targeting endoplasmic reticulum

Lipid raft-targeted therapy in multiple myeloma

Antitumoral Alkylphospholipids Induce Cholesterol Efflux from the Plasma Membrane in HepG2 Cells

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