Trans-[Pt(amine)Cl₂(PPh₃)] Complexes Target Mitochondria and Endoplasmic Reticulum in Gastric Cancer Cells

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Gastric cancer prognosis remains poor despite advancements in diagnosis and treatment.
• Platinum-based chemotherapy is standard but limited by toxicity and efficacy.
• Trans platinum (II) complexes are being investigated as potential alternatives.

Purpose of the Study:

• To synthesize and evaluate two novel phosphine-based trans platinum (II) complexes, P1 and P2.
• To assess their cytotoxicity and mechanism of action in gastric cancer cells.
• To compare their efficacy and toxicity against cisplatin.

Main Methods:

• Synthesis of trans-[Pt(amine)Cl2(PPh3)] complexes (P1 and P2).
• Cytotoxicity analysis on gastric cancer and healthy cells.
• Assays for Reactive Oxygen Species generation, DNA damage, and mitochondrial membrane potential.
• Western blot analysis for apoptosis-related proteins (BAX/BAK, BIM, MCL1) and endoplasmic reticulum stress markers (p62, LC3).

Main Results:

• P2 demonstrated significant cytotoxicity against gastric cancer cells, outperforming cisplatin.
• P2 exhibited slightly lower toxicity in healthy cells compared to cisplatin.
• Both complexes induced apoptosis via an intrinsic pathway, involving ROS generation, DNA damage, and mitochondrial depolarization.
• P2 also induced endoplasmic reticulum stress and affected autophagy markers.

Conclusions:

• Phosphine-based trans platinum (II) complexes, particularly P2, represent promising candidates for novel gastric cancer therapies.
• P2's efficacy and reduced toxicity profile warrant further investigation in preclinical models.
• Elucidating the biomolecular mechanisms, including apoptosis and ER stress induction, provides a foundation for developing these agents.