Nanoencapsulation of Ruthenium Complex Ru(ThySMet): A Strategy to Improve Selective Cytotoxicity Against Breast Tumor Cells in 2D and 3D Culture Models.

BACKGROUND: Ruthenium complexes have shown promise in treating many cancers, including breast cancer. Previous studies of our group have demonstrated the potential of the trans-[Ru(PPh3)2(N,N-dimethylN'-thiophenylthioureato-k2O,S)(bipy)]PF6 complex, the Ru(ThySMet), in the treatment of breast tumor cancers, both in 2D and 3D culture systems. Additionally, this complex presented low toxicity when tested in vivo. AIMS: Improve the Ru(ThySMet) activity by incorporating the complex into a microemulsion (ME) and testing its in vitro effects. METHODS: The ME-incorporated Ru(ThySMet) complex, Ru(ThySMet)ME, was tested for its biological effects in two- (2D) and three-dimensional (3D) cultures using different types of breast cells, MDA-MB-231, MCF-10A, 4T1.13ch5T1 and Balb/C 3T3 fibroblasts. RESULTS: An increased selective cytotoxicity of the Ru(ThySMet)ME for tumor cells was found in 2D cell culture, compared with the original complex. This novel compound also changed the shape of tumor cells and inhibited cell migration with more specificity. Additional 3D cell culture tests using the non-neoplastic S1 and the triple-negative invasive T4-2 breast cells have shown that Ru(ThySMet)ME presented increased selective cytotoxicity for tumor cells compared with the 2D results. The morphology assay performed in 3D also revealed its ability to reduce the size of the 3D structures and increase the circularity in T4-2 cells. CONCLUSION: These results demonstrate that the Ru(ThySMet)ME is a promising strategy to increase its solubility, delivery, and bioaccumulation in target breast tumors.

Acetylation of cedrelone increases its cytotoxic activity and reverts the malignant phenotype of breast cancer cells in 3D culture.

Cedrelone is a limonoid isolated from the plant Trichilia catigua (Meliaceae). Previous studies have demonstrated that cedrelone (1) has several damaging effects on triple negative breast tumor (TNBC) cell line MDA-MB-231. In this work we investigated two new derivatives of cedrelone, the acetate (1a) and the mesylate (1b), to examine whether their effects are improved in comparison to the lead molecule. Cedrelone acetate (1a) was the most cytotoxic compound on TNBC cells and was chosen for additional analyses in traditional two-dimensional (2D) monolayer cultures and three-dimensional (3D) assays. In 2D, 1a induced cell cycle arrest, apoptosis and inhibited essential steps of the metastasis process of the MDA-MB-231 cells, in vitro. Moreover, 1a was able to revert the malignant phenotype of the T4-2 cells in 3D. These effects were concomitant with the downregulation of EGFR, ß1-integrin and phospho-Akt, which could have resulted in a decrease of NFκB levels and MMP9 activity. These results suggest that 1a could be used as an important model for the design of a new drug to be applied in cancer treatment and be further studied in vivo for its antitumor and antimetastatic effects.

Copper (II) and 2,2'-bipyridine complexation improves chemopreventive effects of naringenin against breast tumor cells.

Cancer is the second leading cause of death worldwide and there is epidemiological evidence that demonstrates this tendency is emerging. Naringenin (NGEN) is a trihydroxyflavanone that shows various biological effects such as antioxidant, anticancer, anti-inflammatory, and antiviral activities. It belongs to flavanone class, which represents flavonoids with a C6-C3-C6 skeleton. Flavonoids do not exhibit sufficient activity to be used for chemotherapy, however they can be chemically modified by complexation with metals such as copper (Cu) (II) for instance, in order to be applied for adjuvant therapy. This study investigated the effects of Cu(II) and 2,2'-bipyridine complexation with naringenin on MDA-MB-231 cells. We demonstrated that naringenin complexed with Cu(II) and 2,2'-bipyridine (NGENCuB) was more efficient inhibiting colony formation, proliferation and migration of MDA-MB-231 tumor cells, than naringenin (NGEN) itself. Furthermore, we verified that NGENCuB was more effective than NGEN inhibiting pro-MMP9 activity by zymography assays. Finally, through flow cytometry, we showed that NGENCuB is more efficient than NGEN inducing apoptosis in MDA-MB-231 cells. These results were confirmed by gene expression analysis in real time PCR. We observed that NGENCuB upregulated the expression of pro-apoptotic gene caspase-9, but did not change the expression of caspase-8 or anti-apoptotic gene Bcl-2. There are only few works investigating the effects of Cu(II) complexation with naringenin on tumor cells. To the best of our knowledge, this is the first work describing the effects of Cu(II) complexation of a flavonoid on MDA-MB-231 breast tumor cells.