LLDT-8 attenuates brain metastasis in non-small cell lung cancer <i>via</i> selective p53 activation.

ABSTRACT: Brain metastasis (BM) remains a leading cause of mortality in non-small cell lung cancer (NSCLC) owing to inadequate blood-brain barrier (BBB) penetration and therapy resistance. Here, we developed a brain-tropic A549-BrM2 subline that recapitulates aggressive BM progression and employed it to evaluate LLDT-8, a C14-hydroxylated derivative of triptolide for enhanced BBB permeability. In vitro, LLDT-8 exhibited attenuated cytotoxicity relative to triptolide, yet selectively induced p53-mediated apoptosis in BrM2 cells, an effect absent in parental lines. Transcriptomic profiling revealed that LLDT-8, unlike triptolide, upregulates Tp53 without robustly inducing its negative regulator Mdm2, thereby enabling preferential p53 protein accumulation and activation in the meta

SUBMITTER: Liu J 

PROVIDER: S-EPMC12706912 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature