Breast Cancer: Targets and Therapy (Jul 2024)
Unveiling Paclitaxel-Induced Mesenchymal Stem Cells: orchestrating Nrf2 Modulation and Apoptosis in CD44+/CD24- Cancer Stem Cells
Abstract
Dedy Hermansyah,1 Siti Syarifah,2 Adi Muradi Muhar,3 Agung Putra4,5 1Department of Surgery, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia; 2Department of Pharmacology, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia; 3Department of Doctoral Degree Program, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia; 4Stem Cell and Cancer Research Indonesia, Semarang, Central Java, Indonesia; 5Department of Pathology Anatomy, Faculty of Medicine, Universitas Islam Sultan Agung, Semarang, Central Java, IndonesiaCorrespondence: Dedy Hermansyah, Department of Surgery, Faculty of Medicine, Universitas Sumatera Utara, Jl. Dr. Mansyur No. 5, Padang Bulan, Kec. Medan Baru, Kota Medan, Sumatera Utara, 20155, Indonesia, Email [email protected]: Mesenchymal Stem Cells (MSCs) and Cancer Stem Cells (CSC) play pivotal roles in cancer progression and therapeutic responses. This study aimed to explored the effect of MSCs induced by paclitaxel on CSC expressing the CD44+/CD24- phenotype, focusing on Nrf2 modulation and apoptosis induction.Methods: MSCs were characterized for adherence, differentiation potential, and surface markers via standard culture, staining assays, and flow cytometry, respectively. CSCs isolated from MDA-MB-231 using MACS and were characterized based on morphology and CD44+/CD24- expression. Co-culture experiments evaluated the cytotoxic effect of Paclitaxel-induced MSCs on CSC viability using MTT assays. Flow cytometry analysis assessed apoptosis induction via annexin V-PI staining and Nrf2 and Caspase-3 gene expression were measure by qRT-PCR analysis.Results: MSCs exhibited typical adherence and differentiation capabilities, confirming their mesenchymal lineage. CSCs displayed an elongated morphology and expressed CD44+/CD24-, characteristic of stem-like behavior. Paclitaxel induced dose-dependent Nrf2 gene expression in MSCs. Co-culture with Paclitaxel-induced MSCs reduced CSC viability in a dose-dependent manner, with a significant decrease observed at a 5:1 MSCs:CSC ratio. Co-culture decreased the Nrf2 gene expression and increased apoptosis in CSCs, with higher caspase-3 gene expression compared to solitary paclitaxel treatment.Conclusion: Paclitaxel-induced MSCs decreased Nrf2 expression and significantly decreased CSC viability while enhancing apoptosis. This suggests a potential strategy to mitigate paclitaxel resistance in CD44+/CD24- CSCs. Leveraging Paclitaxel-induced MSCs presents a promising avenue for targeting Nrf2 and promoting apoptosis in CSCs, potentially improving the efficacy of chemotherapy and addressing resistance mechanisms in cancer treatment.Keywords: MSCs, paclitaxel, CSC, apoptosis, Nrf2
