Antimetastatic, antineoplastic, and toxic effects of 4-hydroxycoumarin in a preclinical mouse melanoma model.
OBJECTIVE
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.
Salinas-Jazmín
Nohemí
N
Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad Universitaria, Apdo. Postal 70-297, México, DF 04510, México.
de la Fuente
Marisol
M
Jaimez
Ruth
R
Pérez-Tapia
Mayra
M
Pérez-Torres
Armando
A
Velasco-Velázquez
Marco A
MA
D015110:4-Hydroxycoumarins / Q000009:adverse effects / Q000627:therapeutic use*; D000818:Animals; D000925:Anticoagulants / Q000009:adverse effects / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis
D015110:4-Hydroxycoumarins; D000925:Anticoagulants; D000970:Antineoplastic Agents; C068805:4-hydroxycoumarin