Discovery of New Monocarbonyl Ligustrazine–Curcumin Hybrids for Intervention of Drug-Sensitive and Drug-Resistant Lung Cancer

The elevation of oxidative stress
preferentially in cancer cells
by inhibiting thioredoxin reductase (TrxR) and/or enhancing reactive
oxygen species (ROS) production has emerged as an effective strategy
for selectively targeting cancer cells. In this study, we designed
and synthesized 21 ligustrazine–curcumin hybrids (10a–u). Biological evaluation indicated that the
most active compound 10d significantly inhibited the
proliferation of drug-sensitive (A549, SPC-A-1, LTEP-G-2) and drug-resistant
(A549/DDP) lung cancer cells but had little effect on nontumor lung
epithelial-like cells (HBE). Furthermore, 10d suppressed
the TrxR/Trx system and promoted intracellular ROS accumulation and
cancer cell apoptosis. Additionally, 10d inhibited the
NF-κB, AKT, and ERK signaling, P-gp-mediated efflux of rhodamine
123, P-gp ATPase activity, and P-gp expression in A549/DDP cells.
Finally, 10d repressed the growth of implanted human
drug-resistant lung cancer in mice. Together, 10d acts
a novel TrxR inhibitor and may be a promising candidate for intervention
of lung cancer.