Chemo-Sensitization of CD133+ Cancer Stem Cell Enhances the Effect of Mesenchymal Stem Cell Expressing TRAIL in Non-Small Cell Lung Cancer Cell Lines

SIMPLE SUMMARY: The anti-tumor properties of mesenchymal stem cell (MSCs) expressing TNF-related apoptosis inducing ligand (TRAIL) or MSC-TRAIL have been well documented by several reports. However, some tumors are resistant to TRAIL due to the existence of cancer stem cells (CSCs). Chemo-sensitization of tumors and their CSCs has been reported to enhance TRAIL-mediated inhibition. In this study, we examined the effect of pre-treatment using first-line chemotherapies on MSC-TRAIL-induced inhibition in non-small cell lung cancers (NSCLCs)–derived CSCs. We found that these chemotherapies were able to induce a chemo-sensitization effect to the CSC, thus improving the MSC-TRAIL-induced inhibition. We also noticed that the effect of chemo-sensitization was cell type specific and selecting chemotherapies for the right NSCLC subtypes might help in inducing a more meaningful combinatory effect. As such, this study has proven that chemo-sensitization of the CSCs was able to enhance the MSC-TRAIL-induced inhibition in NSCLC cell lines. ABSTRACT: Pre-clinical studies have demonstrated the efficacy of mesenchymal stem cells (MSCs) expressing tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) or MSC-TRAIL against several tumors. However, due to the existence of cancer stem cells (CSCs), some tumors, including non-small cell lung cancer (NSCLC), exhibit TRAIL resistance. This study was designed to evaluate the capacity of using first-line chemotherapies including cisplatin, 5-fluorouracil (5-FU) and vinorelbine to act as a chemo-sensitizer on CD133+ (prominin-1 positive) CSCs derived from NSCLC cell lines (A549, H460 and H2170) for the purpose of MSC-TRAIL-induced inhibition. We showed that MSC-TRAIL was resistant to all three chemotherapies compared to the NSCLC cell lines, suggesting that the chemotherapies had little effect on MSC-TRAIL viability. Pre-treatment using either cisplatin or 5-FU, but not with vinorelbine, was able to increase the efficacy of MSC-TRAIL to kill the TRAIL-resistant A549-derived CSCs. The study also demonstrated that both 5-FU and vinorelbine were an effective chemo-sensitizer, used to increase the anti-tumor effect of MSC-TRAIL against H460- and H2170-derived CSCs. Furthermore, pre-treatment using cisplatin was noted to enhance the effect of MSC-TRAIL in H460-derived CSCs; however, this effect was not detected in the H2170-derived CSCs. These findings suggest that a pre-treatment using certain chemotherapies in NSCLC could enhance the anti-tumor effect of MSC-TRAIL to target the CSCs, and therefore the combination of chemotherapies and MSC-TRAIL may serve as a novel approach for the treatment of NSCLC.