Anti-metastatic action of an N4-aryl substituted thiosemicarbazone on advanced triple negative breast cancer.
A.M. Sólimo,
M.C. Soraires Santacruz,
S. Vanzulli,
O. Coggiola,
E. Bal de Kier Joffé,
L. Finkielsztein,
M.A. Callero
Affiliations
A.M. Sólimo
Universidad de Buenos Aires, Instituto de Oncología “Ángel H. Roffo”, Área Investigación, Dpto. Inmunobiología, Ciudad Autónoma de Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Argentina
M.C. Soraires Santacruz
Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Farmacología, Cátedra de Química Medicinal, Ciudad Autónoma de Buenos Aires, Argentina; CONICET-Universidad de Buenos Aires, Instituto de Química y Metabolismo del Fármaco (IQUIMEFA), Ciudad Autónoma de Buenos Aires, Argentina
S. Vanzulli
Instituto de Investigaciones Hematológicas (IIHEMA), Academia de Medicina, Ciudad Autónoma de Buenos Aires, Argentina
O. Coggiola
Universidad de Buenos Aires, Instituto de Oncología “Ángel H. Roffo”, Laboratorio Central, Buenos Aires, Argentina
E. Bal de Kier Joffé
Universidad de Buenos Aires, Instituto de Oncología “Ángel H. Roffo”, Área Investigación, Dpto. Inmunobiología, Ciudad Autónoma de Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Argentina
L. Finkielsztein
Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Farmacología, Cátedra de Química Medicinal, Ciudad Autónoma de Buenos Aires, Argentina; CONICET-Universidad de Buenos Aires, Instituto de Química y Metabolismo del Fármaco (IQUIMEFA), Ciudad Autónoma de Buenos Aires, Argentina
M.A. Callero
Universidad de Buenos Aires, Instituto de Oncología “Ángel H. Roffo”, Área Investigación, Dpto. Inmunobiología, Ciudad Autónoma de Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Argentina; Corresponding author.
Purpose: Advanced triple negative breast cancer (ATNBC) is defined by a lack of expression of hormones receptors as well as HER2/neu and its high probability of visceral metastasis. This pathology is associated with a poor prognosis. Previously, we found that T2, an N4-arylsubstituted thiosemicarbazone (N4-TSC), had cytotoxic effect on human breast cancer cells lines. Hence, in this study, we investigated the anti-metastasic action of T2 on ATNBC. Methods: In order to deepen T2 action mode on ATNBC, we first confirmed T2 cytotoxicity on a panel of TNBC cells and then continued studying T2 effects in vitro an in vivo on the syngeneic 4T1 mouse model. Results: We found that T2 had a cytotoxic effect comparable to chemotherapeutics used in present treatment schemes for ATNBC. T2 treatment not only induced apoptosis, but it also down-modulated 4T1 invasive and metastatic-associated capacities, such as clonogenicity, migration and metallo-proteases activity. Moreover, this agent reduced the number of 4T1 cancer stem cells. Finally, T2 treatment induced a more differentiated cell phenotype and the overexpression of the metastasis suppressor gene NDRG-1. In vivo assays showed that T2 reduced tumor burden, down modulated local tumor invasion and significantly reduced the number of lung metastases in the 4T1 advanced TNBC murine model, while the compound did not exhibit intolerable toxicity. Conclusion: This study provided evidence that T2 not only exerted an anti-tumor activity but it also showed anti-invasive and anti-metastatic actions on ATNBC in vivo and in vitro, suggesting that T2 could be considered as a promising therapy that deserves further analysis.
