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  3. Dehydroleucodine inhibits tumor growth in a preclinical melanoma model by inducing cell cycle arrest, senescence and apoptosis

Dehydroleucodine inhibits tumor growth in a preclinical melanoma model by inducing cell cycle arrest, senescence and apoptosis

  • Cancer Lett. 2016 Mar 1;372(1):10-23. doi: 10.1016/j.canlet.2015.12.004.
Valeria V Costantino 1,  Lorena Lobos-Gonzalez 2,  Jorge Ibañez 1,  Dario Fernandez 1,  F Darío Cuello-Carrión 3,  Manuel A Valenzuela 2,  Manuel A Barbieri 4,  Silvana N Semino 1,  Graciela A Jahn 3,  Andrew F G Quest 5,  Luis A Lopez 6
Affiliations

Affiliations

  • 1 Laboratory of Cell Cycle and Cytoskeleton, Instituto de Histología y Embriología Dr. M. H. Burgos (IHEM-CONICET, Mendoza, Argentina.
  • 2 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.
  • 3 Instituto de Medicina y Biología Experimental de Cuyo IMBECU-CONICET, Mendoza, Argentina.
  • 4 Department of Biological Sciences, Florida International University, Miami, FL 33199, USA.
  • 5 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.
  • 6 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.
PMID: 26718258 DOI: 10.1016/j.canlet.2015.12.004
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.

Keywords

Apoptosis; Dehydroleucodine; Mathematical model; Melanoma; Premature senescence; Sesquiterpene lactones.

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