Novel Pt(IV) complexes to overcome multidrug resistance in gastric cancer by targeting P-glycoprotein

Area of Science:

• Medicinal Chemistry
• Cancer Biology
• Pharmacology

Background:

• Platinum-based drugs are crucial cancer therapeutics but face limitations due to systematic toxicity and acquired multidrug resistance (MDR).
• P-glycoprotein (P-gp) overexpression is a major mechanism contributing to MDR, reducing intracellular drug accumulation and efficacy.
• Novel strategies are needed to overcome P-gp-mediated MDR and enhance the therapeutic index of platinum drugs.

Purpose of the Study:

• To design and synthesize novel platinum(IV) complexes conjugated with P-gp inhibitors to overcome MDR.
• To evaluate the efficacy of these complexes in reversing cisplatin resistance and enhancing anticancer activity.
• To elucidate the underlying mechanisms of action, including P-gp modulation, apoptosis induction, and in vivo tumor inhibition.

Main Methods:

• Synthesis and characterization of four Pt(IV) complexes (12-15) incorporating P-gp inhibitors.
• In vitro evaluation of cytotoxicity, drug resistance reversal in SGC-7901/CDDP cells, and selectivity index against normal HL-7702 cells.
• Mechanistic studies involving P-gp expression analysis, cell cycle arrest, DNA damage assessment, and mitochondrial apoptosis pathway activation.
• In vivo efficacy studies using SGC-7901/CDDP xenograft models to assess tumor inhibition and compare with cisplatin and oxaliplatin.

Main Results:

• Complex 14 demonstrated significant activity with an IC50 of 3.37 μM and a selectivity index of 6.9.
• Complex 14 effectively reversed cisplatin resistance in SGC-7901/CDDP cells by down-regulating P-gp expression, enhancing platinum uptake.
• Mechanistic studies revealed that complex 14 induced apoptosis, arrested cells at G2/M phase, caused DNA damage, and activated the mitochondrial pathway.
• In vivo studies showed complex 14 achieved 75.6% tumor inhibition in xenografts, outperforming cisplatin (25.9%) and oxaliplatin (43%).

Conclusions:

• Complex 14 is a potent P-gp-mediated MDR modulator with enhanced anticancer efficacy and reduced systematic toxicity.
• This novel Pt(IV) complex represents a promising therapeutic candidate for overcoming platinum drug resistance in cancer treatment.
• Targeting P-gp in conjunction with platinum chemotherapy offers a viable strategy to improve clinical outcomes for cancer patients.