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.
Highlights
Colorectal cancer Colorectal cancer is the 3rd type of cancer most incident. Colorectal cancer is the 2nd leading cause of cancer death
Colorectal cancer (CRC) with KRAS, BRAF and PIK3CA mutations do not respond to EGFR inhibitors
Ru agents decrease the colonogenic ability of CRC cells
Summary
Colorectal cancer Colorectal cancer is the 3rd type of cancer most incident. Colorectal cancer is the 2nd leading cause of cancer death. Ana Rita Brás1,2,3, Pedro Fernandes1,2, Tiago Moreira, Andreia Valente3*, Ana Preto1,2* Colorectal cancer (CRC) is one of the most lethal cancers worldwide, 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.
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