Methylthioadenosine (MTA) inhibits melanoma cell proliferation and in vivo tumor growth.
BACKGROUND
Melanoma is the most deadly form of skin cancer without effective treatment. Methylthioadenosine (MTA) is a naturally occurring nucleoside with differential effects on normal and transformed cells. MTA has been widely demonstrated to promote anti-proliferative and pro-apoptotic responses in different cell types. In this study we have assessed the therapeutic potential of MTA in melanoma treatment.


METHODS
To investigate the therapeutic potential of MTA we performed in vitro proliferation and viability assays using six different mouse and human melanoma cell lines wild type for RAS and BRAF or harboring different mutations in RAS pathway. We also have tested its therapeutic capabilities in vivo in a xenograft mouse melanoma model and using variety of molecular techniques and tissue culture we investigated its anti-proliferative and pro-apoptotic properties.


RESULTS
In vitro experiments showed that MTA treatment inhibited melanoma cell proliferation and viability in a dose dependent manner, where BRAF mutant melanoma cell lines appear to be more sensitive. Importantly, MTA was effective inhibiting in vivo tumor growth. The molecular analysis of tumor samples and in vitro experiments indicated that MTA induces cytostatic rather than pro-apoptotic effects inhibiting the phosphorylation of Akt and S6 ribosomal protein and inducing the down-regulation of cyclin D1.


CONCLUSIONS
MTA inhibits melanoma cell proliferation and in vivo tumor growth particularly in BRAF mutant melanoma cells. These data reveal a naturally occurring drug potentially useful for melanoma treatment.
Andreu-Pérez
Pedro
P
Medical Oncology Research Program, Vall d'Hebron Research Institute, Vall d'Hebron Institute of Oncology Vall d'Hebron Hospital Barcelona 08035, Spain.
Hernandez-Losa
Javier
J
Moliné
Teresa
T
Gil
Rosa
R
Grueso
Judit
J
Pujol
Anna
A
Cortés
Javier
J
Avila
Matias A
MA
Recio
Juan A
JA
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D011905:Genes, ras; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D038601:Ribosomal Protein S6 / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D013872:Thionucleosides / Q000494:pharmacology*; D013997:Time Factors; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D038601:Ribosomal Protein S6; D013872:Thionucleosides; D019938:Cyclin D1; C482119:BRAF protein, human; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D000241:Adenosine