Bis-(di-4-phenyl-benzylaminethiocarbonyl)disulfide sensitizes ABCC2/ALDH3A1 overexpressing NSCLC cells to cisplatin.

BACKGROUND

Lung cancer presents complex etiopathology involving a mix of genetic predispositions and environmental factors. The best treatment modality is surgical resection. However, it becomes ineffective in the advanced metastatic stage. Thus, cisplatin-based chemotherapy, though restricted by an intrinsic and/or acquired chemo-resistant phenotype, remains the first-line therapy for advanced non-small-cell cancer (NSCLC).

METHODS

Various tools were used to verify the mRNA expression and protein levels of ABC and ALDH proteins in patient-derived non-small-cell lung cancer (NSCLC) samples (GSE102287, GSE43580) and cell lines A549 and NCI-H158 (including their respective cisplatin-resistant variants) to verify the cisplatin-sensitizing abilities of newly synthesized bis-(di-4-phenyl-benzylaminethiocarbonyl)disulfide-non-toxic ALDH and ABCC2 inhibitors.

RESULTS

We identified significant molecular differences in the expression levels of ABCC1, ABCC5, ABCC3, ALDH7A1, and ALDH3A1. Additionally, a fairly significant patient subgroup (Z-score > 1.5), characterized by ABCC2 and ALDH3A1 overexpression, was identified. Importantly, in vitro, ABCC2 and ALDH3A1 accompany the acquisition of cisplatin resistance in A549 cells. Bis-(di-4-phenyl-benzylaminethiocarbonyl)disulfide reverses cisplatin resistance in a cisplatin-resistant variant of A549 cells (via ALDH and ABCC2 inhibition) but not in NCI-H158 cells.

CONCLUSIONS

Molecular categorization of NSCLC cancer is essential for predicting therapy outcomes, enabling the use of bis-(di-4-phenyl-benzylaminethiocarbonyl)disulfide as a cisplatin therapy enhancer for NSCLC patients' subpopulation with significant ABCC2 and ALDH3A1 overexpression.