Ferroptosis of Cancer Cells via Tubulin Degradation and Mitochondrial Dysfunction: A Novel Mechanism of Anticancer Effect for Small-Molecule Anion Transporters

Synthetic anion transporters disrupt the homeostasis
of cellular
anions and may therefore be developed as a promising cancer therapy.
Herein, we demonstrated that trifluoromethylation of a benzimidazole-based
anion transporter led to up to 4.84 × 103-fold increase
in the anionophoric activity and promising cytotoxicity toward the
selected solid tumor cells. The most active compound 6 was able to efficiently elevate intracellular chloride anions, induce
the degradation of tubulin, perturb microtubule stability, increase
lipid peroxidation, and impair mitochondrial function. This compound
predominantly triggered ferroptosis, along with apoptosis as a complementary
mechanism, unveiling a new pathway for the anticancer effects of synthetic
anion transporters. Furthermore, compound 6 demonstrated
potent antitumor activity against HeLa xenografts with minimal side
effects and might find high potentials in the field of cancer chemotherapy.