Platinum(IV) Prodrugs with Cancer Stem Cell Inhibitory Effects on Lung Cancer for Overcoming Drug Resistance.
Xinyi WangZhikun LiuYuanjiang WangShaohua GouPublished in: Journal of medicinal chemistry (2022)
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.
Keyphrases
- cancer stem cells
- dna damage
- body weight
- oxidative stress
- cell cycle arrest
- cell death
- induced apoptosis
- diabetic rats
- endoplasmic reticulum stress
- risk assessment
- reactive oxygen species
- cell therapy
- dna repair
- high glucose
- pi k akt
- staphylococcus aureus
- bone marrow
- cell proliferation
- combination therapy
- pseudomonas aeruginosa
- candida albicans
- genetic diversity