Since response to
platinum-based
therapy in
non-small-cell lung cancer (NSCLC) is poor, the present study was designed to rationally identify novel
drug combinations in cell models including the A549 cell line and the
cisplatin-resistant subline A549/Pt, characterized by reduced sensitivity to
cisplatin-induced apoptosis and by upregulation of efflux transporters of the
ATP binding cassette (ABC) superfamily. Given the molecular features of these cells, we focused on compounds triggering apoptosis through different mechanisms, such as the mitochondria-targeting drug
arsenic trioxide and the phenanthridine analog
sanguinarine, which induce apoptosis through the extrinsic pathway.
Sanguinarine, not recognized by
ABC transporters, could overcome
cisplatin resistance and, when used in combination with
arsenic trioxide, was synergistic in A549 and A549/Pt cells. The
arsenic trioxide/
sanguinarine cotreatment upregulated genes implicated in apoptosis activation through the extrinsic pathway.
Drug combination experiments indicated that
tumor necrosis factor-related apoptosis-inducing
ligand (TRAIL) treatment improved
arsenic trioxide/
sanguinarine efficacy, a feature associated with a striking apoptosis induction, particularly in the
cisplatin-resistant variant. Thus, a synergistic interaction between
sanguinarine and
arsenic trioxide could be obtained independent of relative cell sensitivity to
arsenic trioxide, and an enhanced apoptosis induction could be achieved in combination with TRAIL through modulation of the extrinsic apoptotic pathway. Antitumor activity studies supported the interest of
drug combinations including TRAIL in NSCLC, indicating that drug-resistant NSCLC cells can efficiently be killed by the combination of proapoptotic agents. Our results suggest that the molecular changes occurring in treated cells may be exploited to rationally hit surviving cells.