{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T02:19:31Z","timestamp":1791253171990,"version":"4.1.0"},"reference-count":69,"publisher":"American Society for Microbiology","issue":"3","license":[{"start":{"date-parts":[[2004,3,1]],"date-time":"2004-03-01T00:00:00Z","timestamp":1078099200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2004,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Miltefosine (hexadecylphosphocholine [HePC]) has proved to be a potent oral treatment for human visceral leishmaniasis due to\n            <jats:italic>Leishmania donovani<\/jats:italic>\n            . The molecular mechanisms that contribute to the antileishmanial activity of HePC are still unknown. We report that in wild-type promastigotes of\n            <jats:italic>Leishmania donovani<\/jats:italic>\n            HePC is able to induce a cell death process with numerous cytoplasmic, nuclear, and membrane features of metazoan apoptosis, including cell shrinkage, DNA fragmentation into oligonucleosome-sized fragments, and phosphatidylserine exposure. None of these changes were detected in an HePC-resistant clone treated with the same drug concentration. Therefore, HePC does not appear to kill\n            <jats:italic>L. donovani<\/jats:italic>\n            promastigotes by a direct toxic mechanism but, rather, kills the promastigotes by an indirect one. Pretreatment of wild-type promastigotes with two broad caspase inhibitors,\n            <jats:italic>z<\/jats:italic>\n            -Val-Ala-\n            <jats:sc>dl<\/jats:sc>\n            -Asp(methoxy)-fluoromethylketone and Boc-Asp(methoxy)-fluoromethylketone, as well as a broad protease inhibitor, calpain inhibitor I, prior to drug exposure interfered with DNA fragmentation but did not prevent cell shrinkage or phosphatidylserine externalization. These data suggest that at least part of the apoptotic machinery operating in wild-type promastigotes involves proteases. Identification of the death-signaling pathways activated in HePC-sensitive parasites appears to be essential for a better understanding of the molecular mechanisms of action and resistance in these parasites.\n          <\/jats:p>","DOI":"10.1128\/aac.48.3.852-859.2004","type":"journal-article","created":{"date-parts":[[2004,2,24]],"date-time":"2004-02-24T17:53:08Z","timestamp":1077645188000},"page":"852-859","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":288,"title":["Miltefosine Induces Apoptosis-Like Death in\n            <i>Leishmania donovani<\/i>\n            Promastigotes"],"prefix":"10.1128","volume":"48","author":[{"given":"Caroline","family":"Paris","sequence":"first","affiliation":[{"name":"UMR 8076 CNRS, Chimiothe\u0301rapie Antiparasitaire"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe M.","family":"Loiseau","sequence":"additional","affiliation":[{"name":"UMR 8076 CNRS, Chimiothe\u0301rapie Antiparasitaire"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Bories","sequence":"additional","affiliation":[{"name":"UMR 8076 CNRS, Chimiothe\u0301rapie Antiparasitaire"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaqueline","family":"Bre\u0301ard","sequence":"additional","affiliation":[{"name":"INSERM U461, Re\u0301cepteurs et Signalisation des Interleukines, Faculte\u0301 de Pharmacie Paris-Sud, 92290 ChA\u0302tenay-Malabry, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","first-page":"285","volume":"2","year":"1995","unstructured":"Ameisen, J. C. 1995. Apoptosis in a unicellular eukaryotes (Trypanosoma cruzi): implications for the evolutionary origin and role of programmed cell in the control of cell proliferation, differentiation and survival. Cell Death Differ. 2:285-300.","journal-title":"Cell"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4400950"},{"key":"e_1_3_2_4_2","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1126\/science.291.5507.1279","volume":"291","year":"2001","unstructured":"Aravind, L., V. M. Dixit, and E. V. Koonin. 2001. Apoptotic molecular machinery: vastly increased complexity in vertebrates revealed by genome comparisons. Science291:1279-1284.","journal-title":"Science"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4400951"},{"key":"e_1_3_2_6_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0005-2760(97)00145-8","volume":"1389","year":"1998","unstructured":"Boggs, K., C. O. Rock, and S. Jackowski. 1998. The antiproliferative effect of hexadecylphosphocholine toward HL60 cells is prevented by exogenous lysophosphatidylcholine. Biochim. Biophys. Acta1389:1-12.","journal-title":"Biochim. Biophys. Acta"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.107.10.2691"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(87)90543-0"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/38.6.1041"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.114.13.2461"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/0012-1606(92)90080-Z"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/0738-081X(96)00057-0"},{"key":"e_1_3_2_13_2","first-page":"1809","volume":"70","year":"1988","unstructured":"D'Mello, S. R., F. Aglieco, M. R. Roberts, K. Borodezt, and J. W. Haycock. 1988. A DEVD-inhibited caspase other than CPP32 is involved in the commitment of cerebellar granule neurons to apoptosis induced by K+ deprivation. J. Neurochem.70:1809-1818.","journal-title":"J. Neurochem."},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/34112"},{"key":"e_1_3_2_15_2","first-page":"1429","volume":"16","year":"1996","unstructured":"Engelmann, J., J. Henke, W. Willker, B. Kutscher, G. Nossner, J. Engel, and D. Leibfritz. 1996. Early stage monitoring of miltefosine induced apoptosis in KB cells by multinuclear NMR spectroscopy. Anticancer Res.16:1429-1439.","journal-title":"Anticancer Res."},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0001-706X(01)00197-8"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.45.6.1872-1875.2001"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.49.32608"},{"key":"e_1_3_2_19_2","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/0005-2760(94)90133-3","volume":"1211","year":"1994","unstructured":"Geilen, C. C., T. Wieder, A. Haase, W. Reutter, D. M. Morre, and D. J. Morre. 1994. Uptake, subcellular distribution and metabolism of the phospholipid analogue hexadecylphosphocholine in MDCK cells. Biochim. Biophys. Acta1211:14-22.","journal-title":"Biochim. Biophys. Acta"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)50485-9"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(02)00347-X"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(91)81018-4"},{"key":"e_1_3_2_23_2","first-page":"37","volume":"34","year":"1999","unstructured":"Henke, J., J. Engelmann, U. Fl\u00f6gel, J. Pfeuffer, B. Kutscher, G. Nobner, J. Engel, R. Voegeli, and D. Leibfritz. 1999. Apoptotic effects of hexadecylphosphocholine on resistant and non-resistant cells monitored by NMR spectroscopy. Drugs Today34:37-50.","journal-title":"Drugs Today"},{"key":"e_1_3_2_24_2","first-page":"4027","volume":"19","year":"1999","unstructured":"Henke, J., J. Engelmann, B. Kutscher, G. Nobner, J. Engel, R. Voegeli, and D. Leibfritz. 1999. Changes of intracellular calcium, fatty acids and phospholipids during miltefosine-induced apoptosis monitored by fluorescence- and 13C NMR-spectroscopy. Anticancer Res.19:4027-4032.","journal-title":"Anticancer Res."},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.70.7.3727-3735.2002"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199912093412403"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2401879"},{"key":"e_1_3_2_28_2","unstructured":"The Joint United Nations Programme on HIV\/AIDS. December 2002. AIDS epidemic update. [Online.] http:\/\/www.unaids.org\n."},{"key":"e_1_3_2_29_2","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/S0001-706X(96)00628-6","volume":"64","year":"1997","unstructured":"Konstantinov, S. M., R. Kaminsky, R. Brun, M. R. Berger, and U. Zillmann. 1997. Efficacy of anticancer alkylphosphocholines in Trypanosoma brucei subspecies. Acta Trop.64:145-154.","journal-title":"Acta Trop."},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.36.8.1630"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4400952"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.42.3.654"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/47.5.537"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4899-0179-8_33"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-6851(00)00278-4"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4652(199605)167:2<305::AID-JCP15>3.0.CO;2-6"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1471-4922(03)00038-2"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M201961200"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-1759(91)90198-O"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.4103\/0022-3859.929"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1471-4922(02)00064-8"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/356397a0"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj3400033"},{"key":"e_1_3_2_44_2","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/S0360-3016(00)01476-0","volume":"49","year":"2001","unstructured":"Ruiter, G. A., M. Verheij, S. F. Zerp, and W. J. Van Blitterswijk. 2001. Alkyl-lysophospholipids as anticancer agents and enhancers of radiation-induced apoptosis. Int. J. Radiat. Oncol. Biol. Phys.49:415-419.","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"e_1_3_2_45_2","first-page":"2457","volume":"59","year":"1999","unstructured":"Ruiter, G. A., S. F. Zerp, H. Bartelink, W. J. Van Blitterswijk, and M. Verheij. 1999. Alkyl-lysophospholipids activate the SAPK\/ JNK pathway and enhance radiation-induced apoptosis. Cancer Res.59:2457-2463.","journal-title":"Cancer Res."},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-2952(01)00715-8"},{"key":"e_1_3_2_47_2","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/S0001-706X(00)00052-8","volume":"75","year":"2000","unstructured":"Santa-Rita, R. M., H. Santos Barbosa, M. N. Meirelles, and S. L. De Castro. 2000. Effect of the alkyl-lysophospholipids on the proliferation and differentiation of Trypanosoma cruzi. Acta Trop.75:219-228.","journal-title":"Acta Trop."},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.46.11.3472-3477.2002"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.45.5.1505-1510.2001"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0924-8579(03)00125-0"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.45.7.2064-2069.2001"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1086\/322689"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-3156.2001.00778.x"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1080\/00034983.1999.11813462"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1086\/318122"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(98)04367-0"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(02)02608-X"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.281.5381.1312"},{"key":"e_1_3_2_59_2","first-page":"133","volume":"34","year":"1998","unstructured":"Unger, C., T. Maniera, P. Kaufmann-Kolle, and H. Eibl. 1998. In vivo antileishmanial activity of hexadecylphosphocholine and other alkylphosphocholines. Drugs Today34:133-140.","journal-title":"Drugs Today"},{"key":"e_1_3_2_60_2","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/0305-7372(90)90054-J","volume":"17","year":"1990","unstructured":"Unger, C., M. Peukert, H. Sindermann, P. Hilgard, G. Nagel, and H. Eibl. 1990. Hexadecylphosphocholine in the topical treatment of skin metastases in breast cancer patients. Cancer Treat. Rev.17:243-246.","journal-title":"Cancer Treat. Rev."},{"key":"e_1_3_2_61_2","first-page":"961","volume":"6","year":"2000","unstructured":"Uren, A. G., K. O'Rourke, L. A. Aravind, M. T. Pisabarro, S. Seshagiri, E. V. Koonin, and V. M. Dixit. 2000. Identification of paracaspases and metacaspases: two ancient families of caspase-like proteins, one of which plays a key role in MALT lymphoma. Mol. Cell6:961-967.","journal-title":"Mol. Cell"},{"key":"e_1_3_2_62_2","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1007\/BF02535537","volume":"22","year":"1987","unstructured":"Van Blitterswijk, W. J., H. Hilkmann, and G. A. Storme. 1987. Accumulation of an alkyl lysophospholipid in tumor cell membranes affects membrane fluidity and tumor cell invasion. Lipids22:820-823.","journal-title":"Lipids"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(99)80459-X"},{"key":"e_1_3_2_64_2","first-page":"39","volume":"184","year":"1995","unstructured":"Vermes, I., C. Haanen, H. Steffens-Nakken, and C. Reutelingsperger. 1995. A novel assay for apoptosis. Flow cytometry detection of phosphatidylserine expression on early apoptotic cells using fluorescein labeled annexin V. J. Immunol. Methods184:39-51.","journal-title":"Flow cytometry detection of phosphatidylserine expression on early apoptotic cells using fluorescein labeled annexin V. J. Immunol. Methods"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.46.3.695-701.2002"},{"key":"e_1_3_2_66_2","first-page":"101","volume":"20","year":"1998","unstructured":"Wang, Y. Z., Y. B. Chang, C. Xing, and D. Fu. 1998. The interference effects of hexadecylphosphocholine on proliferation and membrane phospholipid metabolism in human myeloid leukaemia cell lines. Int. J. Tissue React.20:101-107.","journal-title":"Int. J. Tissue React."},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1590\/S0074-02761999000200020"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.18.11025"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1038\/284555a0"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4401071"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.48.3.852-859.2004","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.48.3.852-859.2004","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T18:18:09Z","timestamp":1645467489000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.48.3.852-859.2004"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004,3]]},"references-count":69,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2004,3]]}},"alternative-id":["10.1128\/AAC.48.3.852-859.2004"],"URL":"https:\/\/doi.org\/10.1128\/aac.48.3.852-859.2004","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2004,3]]},"assertion":[{"value":"2003-07-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2003-10-31","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2004-03-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}