CELL DEATH INDUCED BY RUTHENIUM(II) / AMINO ACIDS / DIPHOSPHINE COMPLEXES IN BREAST CANCER CELLS CAN BE RELATED WITH L-TYPE AMINO ACID TRANSPORTER 1

Francyelli M. S. Mello, Wanessa C. Pires, Vicente R. C. Irusta, Alzir A. Batista, Elisângela de P. Silveira-Lacerda

Institution: Department of Genetics, ICB, UFG, GO, Brazil

“Ruthenium(II)/amino acids/diphosphine complexes are effective in vitro and in vivo against murine breast cancer. Studies in vivo show high antitumor activity, with increased mean survival time. However, the mechanism of action these compounds have does not yet been fully elucidated against hormone-nonresponsive breast cancer. In this study, we investigated whether the dysregulated metabolism in cancer could have relationship with antitumor activity of the Ru(II)/amino acids/diphosphine complexes in hormone-nonresponsive breast cancer cells. First, to evaluate responses to L-type amino acid transporter 1 (LAT1), the cells were treated with Ru(II)/amino acids/diphosphine complexes in the presence and/or absence of system L competitive inhibitor (BCH). The glucose uptake was measured and the determining the activity of lactate dehydrogenase (LDH) leaking out of the cell it was also measured 48 hours post-treatment. Moreover, the apoptosis was determined by flow cytometric analysis using Annexin V-FITC and PI staining. To evaluate if these compounds can block the cell migration, it was performed the Migration assay. Treatment with the LAT1 inhibitor decreased the sensitivity of the hormone-nonresponsive breast cancer cells to Ru(II)/amino acids/diphosphine complexes. Ru(II)/amino acids/diphosphine complexes led to decrease in glucose uptake by breast cancer cells after treatment comparing to non-treated tumor cells. Additionally, theses complexes caused increase in LDH levels leaking out of the cells, induced apoptosis with an increasing number of Annexin V-positive cells, and decreased cell migration. Our results suggesting that the effects of Ru(II)/amino acids/diphosphine complexes observed in vitro and in vivo can be related with the LAT1 uptake of the complexes to the interior of the breast cancer cells. They could be inhibitors that selectively block transport by LAT1, and thereby deprive the tumor cells of the nutrients required for growth and proliferation, inducing cell death and inhibiting cell migration.

Key-words: ruthenium, LAT1, glucose, LDH”