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- Title
Sphingolipid-Based Synergistic Interactions to Enhance Chemosensitivity in Lung Cancer Cells.
- Authors
Mesén-Porras, Susana; Rojas-Céspedes, Andrea; Molina-Mora, José Arturo; Vega-Baudrit, José; Siles, Francisco; Quiros, Steve; Mora-Rodríguez, Rodrigo
- Abstract
Tumor heterogeneity leads to drug resistance in cancer treatment with the crucial role of sphingolipids in cell fate and stress signaling. We analyzed sphingolipid metabolism and autophagic flux to study chemotherapeutic interactions on the A549 lung cancer model. Loaded cells with fluorescent sphingomyelin analog (BODIPY) and mCherry-EGFP-LC3B were used to track autophagic flux and assess cytotoxicity when cells are exposed to chemotherapy (epirubicin, cisplatin, and paclitaxel) together with sphingolipid pathway inhibitors and autophagy modulators. Our cell model approach employed fluorescent sphingolipid biosensors and a Gaussian Mixture Model of cell heterogeneity profiles to map the influence of chemotherapy on the sphingolipid pathway and infer potential synergistic interactions. Results showed significant synergy, especially when combining epirubicin with autophagy inducers (rapamycin and Torin), reducing cell viability. Cisplatin also synergized with a ceramidase inhibitor. However, paclitaxel often led to antagonistic effects. Our mapping model suggests that combining chemotherapies with autophagy inducers increases vesicle formation, possibly linked to ceramide accumulation, triggering cell death. However, the in silico model proposed ceramide accumulation in autophagosomes, and kinetic analysis provided evidence of sphingolipid colocalization in autophagosomes. Further research is needed to identify specific sphingolipids accumulating in autophagosomes. These findings offer insights into potential strategies for overcoming chemotherapy resistance by targeting the sphingolipid pathway.
- Subjects
DRUG resistance in cancer cells; LUNG cancer; CANCER cells; GAUSSIAN mixture models; PACLITAXEL; CELL survival; POLYMERSOMES
- Publication
Cells (2073-4409), 2023, Vol 12, Issue 22, p2588
- ISSN
2073-4409
- Publication type
Article
- DOI
10.3390/cells12222588