In vivo Performance of a Ruthenium-cyclopentadienyl Compound in an Orthotopic Triple Negative Breast Cancer Model

Authors and Affiliations:

Nuno Mendes^a,b, Francisco Tortosa^c, Andreia Valente^d, Fernanda Marques^e, António Matos^f, Tânia S. Morais^d, Ana Isabel Tomaz^d, Fátima Gärtner^a,b,g and M. Helena Garcia^d

^a i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal;

^b Ipatimup-Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Portugal;

^c Instituto de Anatomia Patológica, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal and Departamento de Medicina, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain;

^d Centro de Química Estrutural, Faculdade de Ciências da Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal;

^e Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139.7) 2695-066 Bobadela LRS, Portugal;

^f CiiEM-Centro de Investigação Interdisciplinar Egas Moniz, Campus Universitário, Quinta da Granja, Monte de Caparica, 2829-511 Caparica, Portugal and Centro de Estudos do Ambiente e do Mar (CESAM/FCUL)-Faculdade de Ciências da Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal;

^g ICBAS-Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, Portugal

Abstract:

Ruthenium-based anti-cancer compounds are proposed as viable alternatives that might circumvent the disadvantages of platinum-based drugs, the only metallodrugs in clinical use for chemotherapy. Organometallic complexes in particular hold great potential as alternative therapeutic agents since their cytotoxicity involves different modes of action and present reduced toxicity profiles. During the last few years our research group has been reporting on a series of organometallic ruthenium(II)-cyclopentadienyl complexes that showed important cytotoxicity against several cancer cell lines, surpassing cisplatin in activity.

We report herein our preliminary in vivo studies with one representative compound of this family, which was chosen due to its exceptional activity against several human cancer cell lines, including the glycolytic and highly metastatic MDAMB231 cell line used in this study.

The anti-tumor activity of our compound was studied in vivo on N:NIH(S)II-nu/nu nude female mice bearing triple negative breast cancer (TNBC) orthotopic tumors. Administration of 2.5 mg/kg per day, during ten days, caused cell death mostly by necrosis (both in vitro and in vivo), inducing tumor growth suppression of about 50% in treated animals when compared to controls. The most remarkable result supporting the effectiveness and potential of this drug was the absence of metastases in the main organs of treated animals, while metastases were present in the lungs of all control mice, as revealed by histopathological and immunohistochemical analysis.

These in vivo studies suggest a dual effect for our drug not only by suppressing growth at the primary tumor site but also by inhibiting its metastatic behavior. Altogether, these results represent a benchmark and a solid starting point for future studies.

Journal: Anti-Cancer Agents in Medicinal Chemistry

Link: http://www.eurekaselect.com/145730/article