Platinum(IV) Prodrugs with Cancer Stem Cell Inhibitory Effects on Lung Cancer for Overcoming Drug Resistance

Acquired
resistance remains a major barrier for the treatment of
non-small cell lung cancer, while cancer stem cells (CSCs) usually
lead to the occurrence of drug resistance. We herein report a series
of platinum­(IV) prodrugs containing CSCs-inhibitory species derived
from a known CSCs inhibitor BBI608 in the axial position. Among them,
complex 15 exerted the most potent cytotoxicity against
A549 and A549/CDDP cancer cells. Besides, 15 could suppress
cancer cell stemness, superior to BBI608, and overcome cisplatin resistance.
Following assays indicated that an enhanced intracellular accumulation
of 15 effectively triggered DNA damage, induced ROS generation,
activated mitochondrial apoptosis pathway, and suppressed cell motility
via p53 pathway in A549/CDDP cells. In vivo tests indicated that 15 exhibited potent antitumor effects without causing loss
in the body weight. Our study provides a novel and efficient approach
to promote the antitumor activity of platinum-based prodrugs and overcome
cisplatin resistance via inhibiting cancer cell stemness.