New ruthenium-cyclopentadienyl agents as a new strategy to fight colorectal cancer

Abstract

Colorectal cancer (CRC) is one of the most lethal cancers worldwide, however it has limited chemotherapeutic agents available. CRC harboring KRAS and BRAF mutations are correlated with resistance to EGFR inhibitors what constitutes a relevant clinical problem. Ruthenium (Ru) drugs had arisen as one of the most promising metallodrugs with features that increase their specificity and selectivity toward cancer cells. Recently, a new family of Ru-cyclopentadienyl conjugates was designed using macromolecules and/or biomolecules. Here, we aimed to study the effect of these new Ru conjugates in CRC cells in order to study the potential increase in selectivity and efficiency in CRC cells. In this work, we used two CRC-derived cell lines with KRAS and BRAF mutations and a normal colon cell line to study cellular cytotoxicity, antiproliferative activity, cell death mechanism, intracellular distribution, MAPK-ERK and PI3K-AKT signaling pathways and actin cytoskeleton effects of the compounds. Our results revealed that Ru agents are more cytotoxic for CRC cells, induce cell cycle arrest, decrease the ability of cells to proliferate, induce apoptosis and preferentially localize in membrane and cytoskeleton of CRC cells. Ru agents also affect F-actin polymerization and MAPK-ERK and PI3K-AKT signaling pathways. Overall, our results showed that Ru compounds present promising anticancer activity in CRC cells, mainly in KRAS mutated cell lines, what could bring new avenues in CRC therapy.