Glycyrrhetinic Acid as a Hepatocyte Targeting Ligand-Functionalized Platinum(IV) Complexes for Hepatocellular Carcinoma Therapy and Overcoming Multidrug Resistance

Promising
targeted therapy options to overcome drug resistance
and side effects caused by platinum(II) drugs for treatment in hepatocellular
carcinoma are urgently needed. Herein, six novel multifunctional platinum(IV)
complexes through linking platinum(II) agents and glycyrrhetinic acid
(GA) were designed and synthesized. Among them, complex 20 showed superior antitumor activity against tested cancer cells including
cisplatin resistance cells than cisplatin and simultaneously displayed
good liver-targeting ability. Moreover, complex 20 can
significantly cause DNA damage and mitochondrial dysfunction, promote
reactive oxygen species generation, activate endoplasmic reticulum
stress, and eventually induce apoptosis. Additionally, complex 20 can effectively inhibit cell migration and invasion and
trigger autophagy and ferroptosis in HepG-2 cells. More importantly,
complex 20 demonstrated stronger tumor inhibition ability
than cisplatin or the combo of cisplatin/GA with almost no systemic
toxicity in HepG-2 or A549 xenograft models. Collectively, complex 20 could be developed as a potential anti-HCC agent for cancer
treatment.