Colorectal cancer (CRC) presents high incidence and mortality, largely due to late diagnosis and the persistence of cancer stem cells (CSCs), which contribute to chemoresistance and poor patient outcomes. TRAIL (TNF-related apoptosis-inducing ligand) is considered a promising therapeutic agent because of its ability to selectively induce apoptosis through DR4/DR5 receptors. Mesenchymal stem cells (MSCs) have been explored as TRAIL delivery vehicles, taking advantage of their tumor-homing capacity and sustained protein expression. However, TRAIL monotherapy has shown limited efficacy, prompting research into strategies to enhance its pro-apoptotic effect, including its combination with chemotherapeutics that upregulate TRAIL receptors. Methods: We evaluated the effect of irinotecan (IRINO) in Caco-2 cells and primary CRC cultures. In addition, we analyzed the cytotoxic activity of sTRAIL-MSCs and its impact on CSC markers, both alone and in combination with IRINO in Caco-2 cells. Results: Caco-2 cells and 87.5% of primary cultures were resistant to IRINO. sTRAIL-MSCs induced higher cell death (50–80%) at ratios of 1:3 and 1:6, while its combination with IRINO achieved 50–60%. Additionally, sTRAIL-MSCs reduced CSC marker expression at 24 and 48 h. Conclusions: IRINO did not enhance the cytotoxicity of sTRAIL-MSC, but it did enhance downregulated markers such as KRT-18, CD44v6, and EpCAM, and it represents a promising therapeutic strategy against CRC.
Quiroz-Reyes et al. (Wed,) studied this question.