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1.
Biochim Biophys Acta ; 1828(5): 1384-9, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23376656

RESUMEN

Using phase contrast and fluorescence microscopy we study the influence of the alkylphospholipid, ALP, 10-(octyloxy) decyl-2-(trimethylammonium) ethyl phosphate, ODPC, in giant unilamellar vesicles, GUVs, composed of DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine), brain sphingomyelin (SM) and cholesterol (Chol). The results show that adding 100µM ODPC (below CMC) to the outer solution of GUVs promotes DOPC membrane disruption over a period of 1h of continuous observation. On the other hand, the presence of SM and Chol in homogeneous fluid lipid bilayers protects the membrane from disruption. Interestingly, by adding 100µM ODPC to GUVs containing DOPC:SM:Chol (1:1:1), which display liquid ordered (Lo)-liquid disordered (Ld) phase coexistence, the domains rapidly disappear in less than 1min of ODPC contact with the membrane. The lipids are subsequently redistributed to liquid domains within a time course of 14-18min, reflecting that the homogenous phase was not thermodynamically stable, followed by rupture of the GUVs. A similar mechanism of action is also observed for perifosine, although to a larger extent. Therefore, the initial stage of lipid raft disruption by both ODPC and perifosine, and maybe other ALPS, by promoting lipid mixing, may be correlated with their toxicity upon neoplastic cells, since selective (dis)association of essential proteins within lipid raft microdomains must take place in the plasma membrane.


Asunto(s)
Glicerofosfolípidos/química , Membrana Dobles de Lípidos/química , Lípidos de la Membrana/química , Microdominios de Membrana/química , Liposomas Unilamelares/química , Colesterol/química , Fluidez de la Membrana , Microscopía Fluorescente , Microscopía de Contraste de Fase , Modelos Químicos , Modelos Moleculares , Fosfatidilcolinas/química , Fosforilcolina/análogos & derivados , Fosforilcolina/química , Esfingomielinas/química , Termodinámica
2.
Leukemia ; 26(3): 451-60, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21869839

RESUMEN

The vitamin E derivative (+)α-tocopheryl succinate (α-TOS) exerts pro-apoptotic effects in a wide range of tumors and is well tolerated by normal tissues. Previous studies point to a mitochondrial involvement in the action mechanism; however, the early steps have not been fully elucidated. In a model of acute promyelocytic leukemia (APL) derived from hCG-PML-RARα transgenic mice, we demonstrated that α-TOS is as effective as arsenic trioxide or all-trans retinoic acid, the current gold standards of therapy. We also demonstrated that α-TOS induces an early dissipation of the mitochondrial membrane potential in APL cells and studies with isolated mitochondria revealed that this action may result from the inhibition of mitochondrial respiratory chain complex I. Moreover, α-TOS promoted accumulation of reactive oxygen species hours before mitochondrial cytochrome c release and caspases activation. Therefore, an in vivo antileukemic action and a novel mitochondrial target were revealed for α-TOS, as well as mitochondrial respiratory complex I was highlighted as potential target for anticancer therapy.


Asunto(s)
Arsenicales/uso terapéutico , Complejo I de Transporte de Electrón/antagonistas & inhibidores , Leucemia Promielocítica Aguda/tratamiento farmacológico , Mitocondrias/efectos de los fármacos , Óxidos/uso terapéutico , Tretinoina/uso terapéutico , alfa-Tocoferol/farmacología , alfa-Tocoferol/uso terapéutico , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Apoptosis/efectos de los fármacos , Trióxido de Arsénico , Caspasas/metabolismo , Línea Celular Tumoral , Citocromos c/metabolismo , Modelos Animales de Enfermedad , Complejo II de Transporte de Electrones/antagonistas & inhibidores , Humanos , Leucemia Promielocítica Aguda/mortalidad , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ratones Transgénicos , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Proteínas de Fusión Oncogénica/metabolismo , Estabilidad Proteica/efectos de los fármacos , Ratas , Especies Reactivas de Oxígeno/metabolismo , Trasplante Isogénico
3.
Biochim Biophys Acta ; 1798(9): 1714-23, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20488162

RESUMEN

10-(Octyloxy) decyl-2-(trimethylammonium) ethyl phosphate (ODPC) is an alkylphospholipid that can interact with cell membranes because of its amphiphilic character. We describe here the interaction of ODPC with liposomes and its toxicity to leukemic cells with an ED-50 of 5.4, 5.6 and 2.9 microM for 72 h of treatment for inhibition of proliferation of NB4, U937 and K562 cell lines, respectively, and lack of toxicity to normal hematopoietic progenitor cells at concentrations up to 25 microM. The ED-50 for the non-malignant HEK-293 and primary human umbilical vein endothelial cells (HUVEC) was 63.4 and 60.7 microM, respectively. The critical micellar concentration (CMC) of ODPC was 200 microM. Dynamic light scattering indicated that dipalmitoylphosphatidylcholine (DPPC) liposome size was affected only above the CMC of ODPC. Differential calorimetric scanning (DCS) of liposomes indicated a critical transition temperature (T(c)) of 41.5 degrees C and an enthalpy (H) variation of 7.3 kcal mol(-1). The presence of 25 microM ODPC decreased T(c) and H to 39.3 degrees C and 4.7 kcal mol(-1), respectively. ODPC at 250 microM destabilized the liposomes (36.3 degrees C, 0.46 kcal mol(-1)). Kinetics of 5(6)-carboxyfluorescein (CF) leakage from different liposome systems indicated that the rate and extent of CF release depended on liposome composition and ODPC concentration and that above the CMC it was instantaneous. Overall, the data indicate that ODPC acts on in vitro membrane systems and leukemia cell lines at concentrations below its CMC, suggesting that it does not act as a detergent and that this effect is dependent on membrane composition.


Asunto(s)
Antineoplásicos/farmacología , Membrana Celular/efectos de los fármacos , Leucemia/tratamiento farmacológico , Fosfolípidos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Permeabilidad de la Membrana Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Madre Hematopoyéticas/efectos de los fármacos , Humanos , Leucemia/patología , Liposomas , Micelas , Termodinámica
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