Enhanced Sensitivity of A549 Cells to Doxorubicin with WS₂ and WSe₂ Nanosheets via the Induction of Autophagy

The excellent physicochemical properties of two-dimensional transition-metal dichalcogenides (2D TMDCs) such as WS₂ and WSe₂ provide potential benefits for biomedical applications, such as drug delivery, photothermal therapy, and bioimaging. WS₂ and WSe₂ have recently been used as chemosensitizers; however, the detailed molecular basis underlying WS₂- and WSe₂-induced sensitization remains elusive. Our recent findings showed that 2D TMDCs with different thicknesses and different element compositions induced autophagy in normal human bronchial epithelial cells and mouse alveolar macrophages at sublethal concentrations. Here, we explored the mechanism by which WS₂ and WSe₂ act as sensitizers to increase lung cancer cell susceptibility to chemotherapeutic agents. The results showed that WS₂ and WSe₂ enhanced autophagy flux in A549 lung cancer cells at sublethal concentrations without causing significant cell death. Through the autophagy-specific RT² Profiler PCR Array, we identified the genes significantly affected by WS₂ and WSe₂ treatment. Furthermore, the key genes that play central roles in regulating autophagy were identified by constructing a molecular interaction network. A mechanism investigation uncovered that WS₂ and WSe₂ activated autophagy-related signaling pathways by interacting with different cell surface proteins or cytoplasmic proteins. By utilizing this mechanism, the efficacy of the chemotherapeutic agent doxorubicin was enhanced by WS₂ and WSe₂ pre-treatment in A549 lung cancer cells. This study revealed a feature of WS₂ and WSe₂ in cancer therapy, in which they eliminate the resistance of A549 lung cancer cells against doxorubicin, at least partially, by inducing autophagy.