Glycyrrhetinic Acid as a Hepatocyte Targeting Ligand-Functionalized Platinum(IV) Complexes for Hepatocellular...

Area of Science:

• Medicinal Chemistry
• Oncology
• Drug Discovery

Background:

• Hepatocellular carcinoma (HCC) treatment faces challenges with platinum(II) drug resistance and side effects.
• Novel therapeutic strategies are needed to improve efficacy and reduce toxicity in HCC therapy.

Purpose of the Study:

• To design and synthesize novel platinum(IV) complexes for targeted HCC treatment.
• To evaluate the antitumor activity, liver-targeting ability, and mechanism of action of a lead compound.

Main Methods:

• Synthesis of six novel platinum(IV) complexes linked with glycyrrhetinic acid (GA).
• In vitro evaluation of antitumor activity against various cancer cells, including cisplatin-resistant ones.
• In vivo studies using HepG-2 and A549 xenograft models to assess tumor inhibition and systemic toxicity.
• Mechanistic studies involving DNA damage, mitochondrial dysfunction, reactive oxygen species (ROS) generation, endoplasmic reticulum (ER) stress, apoptosis, cell migration, invasion, autophagy, and ferroptosis.

Main Results:

• Complex 20 exhibited superior antitumor activity compared to cisplatin, even in resistant cells.
• Complex 20 demonstrated significant liver-targeting ability and potent inhibition of tumor growth in vivo with minimal systemic toxicity.
• Mechanistic investigations revealed that complex 20 induces apoptosis via DNA damage, mitochondrial dysfunction, ROS generation, and ER stress, while also inhibiting migration and invasion and triggering autophagy and ferroptosis.

Conclusions:

• Complex 20 is a promising multifunctional platinum(IV) agent with enhanced antitumor efficacy and liver-targeting properties for HCC treatment.
• The compound's ability to overcome drug resistance and its favorable safety profile suggest its potential as a novel anti-HCC therapeutic agent.