The water soluble ruthenium(II) organometallic compound [Ru(p-cymene)(bis(3,5 dimethylpyrazol-1-yl)methane)Cl]Cl suppresses triple negative breast cancer growth by inhibiting tumor infiltration of regulatory T cells

• Published in: Pharmacological research 2016-05, Vol.107, p.282-290
• Main Authors: Montani, Maura, Pazmay, Gretta V. Badillo, Hysi, Albana, Lupidi, Giulio, Pettinari, Riccardo, Gambini, Valentina, Tilio, Martina, Marchetti, Fabio, Pettinari, Claudio, Ferraro, Stefano, Iezzi, Manuela, Marchini, Cristina, Amici, Augusto
• Format: Article
• Language: English
• Subjects: Animals; Anticancer drugs; Antineoplastic Agents - blood; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cell Line, Tumor; Female; Humans; In vivo tests; Kidney - metabolism; Liver - drug effects; Liver - metabolism; Liver - pathology; Mice; Organometallic arene complexes; Organometallic Compounds - blood; Organometallic Compounds - pharmacokinetics; Organometallic Compounds - pharmacology; Organometallic Compounds - therapeutic use; Ruthenium - blood; Ruthenium - pharmacokinetics; Ruthenium - pharmacology; Ruthenium - therapeutic use; Ruthenium(II); T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; Triple negative breast cancer; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - immunology; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Tumor Burden - drug effects; Tumor infiltrating regulatory T cells
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2016.03.032

[Display omitted] Ruthenium compounds have become promising alternatives to platinum drugs by displaying specific activities against different cancers and favorable toxicity and clearance properties. Here, we show that the ruthenium(II) complex [Ru(p-cymene)(bis(3,5-dimethylpyrazol-1-yl)methane)Cl]Cl (UNICAM-1) exhibits potent in vivo antitumor effects. When administered as four-dose course, by repeating a single dose (52.4mgkg-1) every three days, UNICAM-1 significantly reduces the growth of A17 triple negative breast cancer cells transplanted into FVB syngeneic mice. Pharmacokinetic studies indicate that UNICAM-1 is rapidly eliminated from kidney, liver and bloodstream thanks to its high hydrosolubility, exerting excellent therapeutic activity with minimal side effects. Immunohistological analysis revealed that the efficacy of UNICAM-1, mainly relies on its capacity to reverse tumor-associated immune suppression by significantly reducing the number of tumor-infiltrating regulatory T cells. Therefore, UNICAM-1 appears very promising for the treatment of TNBC.