TY - JOUR
T1 - Antimetastatic, antineoplastic, and toxic effects of 4-hydroxycoumarin in a preclinical mouse melanoma model
AU - Salinas-Jazmín, Nohemí
AU - De La Fuente, Marisol
AU - Jaimez, Ruth
AU - Pérez-Tapia, Mayra
AU - Pérez-Torres, Armando
AU - Velasco-Velázquez, Marco A.
N1 - Funding Information:
Acknowledgments We thank Irma López-Martínez, Ivonne Sán-chez-Cervantes, Diana Barrera, and Nestor Ocón for technical assistance as well as Aliesha González-Arenas for critical reading of the manuscript. This research was supported by UNAM and Conacyt (203595).
PY - 2010/4
Y1 - 2010/4
N2 - Purpose: We have previously reported that in vitro treatment of B16-F10 melanoma cells with 4-hydroxycoumarin (4-HC) decreases their metastatic potential. However, the antimetastatic efficacy of 4-HC in vivo is unknown; therefore, we investigated the antimetastatic and antineoplastic effects of 4-HC in a mouse melanoma model. Based on the findings, the immunomodulatory and toxic effects of 4-HC were also studied. Methods: Experimental metastasis assay was performed in C57BL/6 mice that received 4-HC before intravenous injection of B16-F10 cells. Antitumor and antimetastatic efficacy of 4-HC was assessed in mice implanted subcutaneously with melanoma cells. Possible immunostimulant and toxic effects of 4-HC were studied in healthy mice. Results: 4-HC reduced the number of experimental lung metastases. Moreover, 4-HC diminished primary tumor growth and increased survival time in mice bearing melanoma tumors. Treatments also decrease spontaneous lung metastases in the same animals. Different to other coumarins, the antitumor effect of 4-HC seems to be unrelated to immunostimulation, since plasma concentrations of cytokines remained unchanged. In contrast, toxic histological changes in nephrons and bronchiolar epithelium and a pronounced anticoagulant effect were found in 4-HC treated animals. Conclusions: These results show that 4-HC not only exhibit antimetastatic effect in vivo, but also effectively reduces tumor growth and improves survival, even when it produce toxic effects. Although the molecular mechanism of 4-HC actions needs to be further defined, our data suggest that 4-HC may lead to the development of agents that could be used as adjuvants in the therapy of melanoma.
AB - Purpose: We have previously reported that in vitro treatment of B16-F10 melanoma cells with 4-hydroxycoumarin (4-HC) decreases their metastatic potential. However, the antimetastatic efficacy of 4-HC in vivo is unknown; therefore, we investigated the antimetastatic and antineoplastic effects of 4-HC in a mouse melanoma model. Based on the findings, the immunomodulatory and toxic effects of 4-HC were also studied. Methods: Experimental metastasis assay was performed in C57BL/6 mice that received 4-HC before intravenous injection of B16-F10 cells. Antitumor and antimetastatic efficacy of 4-HC was assessed in mice implanted subcutaneously with melanoma cells. Possible immunostimulant and toxic effects of 4-HC were studied in healthy mice. Results: 4-HC reduced the number of experimental lung metastases. Moreover, 4-HC diminished primary tumor growth and increased survival time in mice bearing melanoma tumors. Treatments also decrease spontaneous lung metastases in the same animals. Different to other coumarins, the antitumor effect of 4-HC seems to be unrelated to immunostimulation, since plasma concentrations of cytokines remained unchanged. In contrast, toxic histological changes in nephrons and bronchiolar epithelium and a pronounced anticoagulant effect were found in 4-HC treated animals. Conclusions: These results show that 4-HC not only exhibit antimetastatic effect in vivo, but also effectively reduces tumor growth and improves survival, even when it produce toxic effects. Although the molecular mechanism of 4-HC actions needs to be further defined, our data suggest that 4-HC may lead to the development of agents that could be used as adjuvants in the therapy of melanoma.
KW - 4-Hydroxycoumarin
KW - Coumarin
KW - Melanoma
KW - Metastasis
UR - http://www.scopus.com/inward/record.url?scp=77649180895&partnerID=8YFLogxK
U2 - 10.1007/s00280-009-1100-z
DO - 10.1007/s00280-009-1100-z
M3 - Artículo
SN - 0344-5704
VL - 65
SP - 931
EP - 940
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 5
ER -