Norcantharidin Sensitizes Lung Adenocarcinoma Cells to Multitherapy via Targeting the Deregulated Hedgehog Cascade

Norcantharidin (NCTD), a demethylated analog of cantharidin, has been identified as one of potential anti-tumor drug candidates in various human neoplasms. However, the NCTD-mediated interference with multidrug-resistance development and sustenance of lung adenocarcinoma (LAD) and its underlying molecular interaction mechanisms remains undefined yet. In this study, NCTD significantly inhibited cell growth of LAD cells in a dose-dependent manner when applied alone and magnified the sensitization of LAD cells to multiple therapeutic agents. Selective repression of sonic Hedgehog (SHH) signaling pathway by NCTD dramatically arrested cancer stemness development and maintenance such as the sphere formation capacities of LAD cells. Mechanistic analysis revealed that NCTD prohibited nuclear translocation of GLI1, the key terminal transcription factor of SHH cascade in LAD cells. In vivo studies confirmed that NCTD alone reduced propagation of LAD cells and enhanced the 5-FU and Osimertinib-based cancer progression inhibition while have no side effect on body weight. Taken together, our results demonstrate that NCTD represses SHH cascade-mediated cancer stemness to overcome the intrinsic resistance of LAD cells to multi-drug treatment, which implies that NCTD might be a therapeutic drug candidate that could be a de novo option to eradicate the treatment resistance against multiple therapeutic agents if co-applied in LAD treatment clinically.