title: Dehydroleucodine inhibits tumor growth in a preclinical melanoma model by inducing cell cycle arrest, senescence and apoptosis.
abstract: Malignant melanoma represents the fastest growing public health risk of all cancer types worldwide. Several strategies and anti-cancer drugs have been used in an effort to improve treatments, but the development of resistance to anti-neoplastic drugs remains the major cause of chemotherapy failure in melanomas. Previously, we showed that the sesquiterpene lactone, dehydroleucodine (DhL), promotes the accumulation of DNA damage markers, such as H2AX and 53BP1, in human tumor cells. Also DhL was shown to trigger either cell senescence or apoptosis in a concentration-dependent manner in HeLa and MCF7 cells. Here, we evaluated the effects of DhL on B16F0 mouse melanoma cells in vitro and in a pre-clinical melanoma model. DhL inhibited the proliferation of B16F0 cells by inducing senescence or apoptosis in a concentration-dependent manner. Also, DhL reduced the expression of the cell cycle proteins cyclin D1 and B1 and the inhibitor of apoptosis protein, survivin. In melanomas generated by subcutaneous injection of B16F0 cells into C57/BL6 mice, the treatment with 20 mg DhL /Kg/day in preventive, simultaneous and therapeutic protocols reduced tumor volumes by 70%, 60% and 50%, respectively. DhL treatments reduced the number of proliferating, while increasing the number of senescent and apoptotic tumor cells. To estimate the long-term effects of DhL, a mathematical model was applied to fit experimental data. Extrapolation beyond experimental time points revealed that DhL administration following preventive and therapeutic protocols is predicted to be more effective than simultaneous treatments with DhL in restricting tumor growth.
authors.affiliation: Laboratory of Cell Cycle and Cytoskeleton, Instituto de Histología y Embriología Dr. M. H. Burgos (IHEM-CONICET, Mendoza, Argentina.
authors.forename: Valeria V
authors.initials: VV
authors.lastname: Costantino
authors.affiliation: Cellular Communication Laboratory, Center for Molecular Studies of the Cell (CEMC), Advanced Center for Chronic Diseases (ACCDiS), Program of Cell and Molecular Biology, Institute of Biomedical Sciences (ICBM), School of Medicine, Universidad de Chile, Santiago 8380453, Chile.
authors.forename: Lorena
authors.initials: L
authors.lastname: Lobos-Gonzalez
authors.affiliation: Laboratory of Cell Cycle and Cytoskeleton, Instituto de Histología y Embriología Dr. M. H. Burgos (IHEM-CONICET, Mendoza, Argentina.
authors.forename: Jorge
authors.initials: J
authors.lastname: Ibañez
authors.affiliation: Laboratory of Cell Cycle and Cytoskeleton, Instituto de Histología y Embriología Dr. M. H. Burgos (IHEM-CONICET, Mendoza, Argentina.
authors.forename: Dario
authors.initials: D
authors.lastname: Fernandez
authors.affiliation: Instituto de Medicina y Biología Experimental de Cuyo IMBECU-CONICET, Mendoza, Argentina.
authors.forename: F Darío
authors.initials: FD
authors.lastname: Cuello-Carrión
authors.affiliation: Cellular Communication Laboratory, Center for Molecular Studies of the Cell (CEMC), Advanced Center for Chronic Diseases (ACCDiS), Program of Cell and Molecular Biology, Institute of Biomedical Sciences (ICBM), School of Medicine, Universidad de Chile, Santiago 8380453, Chile.
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Valenzuela
authors.affiliation: Department of Biological Sciences, Florida International University, Miami, FL 33199, USA.
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Barbieri
authors.affiliation: Laboratory of Cell Cycle and Cytoskeleton, Instituto de Histología y Embriología Dr. M. H. Burgos (IHEM-CONICET, Mendoza, Argentina.
authors.forename: Silvana N
authors.initials: SN
authors.lastname: Semino
authors.affiliation: Instituto de Medicina y Biología Experimental de Cuyo IMBECU-CONICET, Mendoza, Argentina.
authors.forename: Graciela A
authors.initials: GA
authors.lastname: Jahn
authors.affiliation: Cellular Communication Laboratory, Center for Molecular Studies of the Cell (CEMC), Advanced Center for Chronic Diseases (ACCDiS), Program of Cell and Molecular Biology, Institute of Biomedical Sciences (ICBM), School of Medicine, Universidad de Chile, Santiago 8380453, Chile. Electronic address: aquest@med.uchile.cl.
authors.forename: Andrew F G
authors.initials: AF
authors.lastname: Quest
authors.affiliation: Laboratory of Cell Cycle and Cytoskeleton, Instituto de Histología y Embriología Dr. M. H. Burgos (IHEM-CONICET, Mendoza, Argentina. Electronic address: llopez@fcm.uncu.edu.ar.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Lopez
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D056744:Cyclin B1 / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D007783:Lactones / Q000494:pharmacology*; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D012097:Repressor Proteins / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D000077022:Survivin; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; C117749:Birc5 protein, mouse; C534700:Ccnb1 protein, mouse; C530105:Ccnd1 protein, mouse; D056744:Cyclin B1; D051034:Inhibitor of Apoptosis Proteins; D007783:Lactones; D012097:Repressor Proteins; D012717:Sesquiterpenes; D000077022:Survivin; D019938:Cyclin D1; C079949:dehydroleucodine
keywords: Apoptosis; Dehydroleucodine; Mathematical model; Melanoma; Premature senescence; Sesquiterpene lactones