Enhanced anticancer effect of thymidylate synthase dimer disrupters by promoting intracellular accumulation

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Thymidylate synthase (TS) is vital for DNA synthesis and a target for cancer therapy.
• Drug resistance, due to efflux or reduced influx, limits the efficacy of anti-TS drugs.
• Understanding TS function and resistance mechanisms is key for developing effective cancer treatments.

Purpose of the Study:

• To evaluate the cytotoxic efficacy of novel TS dimer disrupters (Ddis).
• To investigate strategies for enhancing intracellular accumulation of Ddis to overcome drug resistance.
• To assess the impact of Ddis on TS protein levels and cell cycle progression.

Main Methods:

• Tested novel TS dimer disrupters (Ddis) in ovarian and colon cancer cells.
• Utilized inhibitors of drug efflux pumps to block compound extrusion.
• Employed the SAINT-Protein transfection agent for enhanced cellular uptake of Ddis.
• Measured TS protein levels and cell cycle perturbation.

Main Results:

• Ddis demonstrated increased cytotoxic efficacy when combined with drug efflux inhibitors.
• Ddis were identified as substrates for cellular drug extruders.
• SAINT-Protein mediated delivery enhanced intracellular accumulation and cell-killing effects.
• Observed reduction in TS protein levels and cell cycle perturbation correlated with Ddis efficacy.

Conclusions:

• Novel TS dimer disrupters show promise as targeted cancer therapeutics.
• Strategies to increase intracellular accumulation, such as inhibiting efflux or enhancing uptake, are crucial for optimizing Ddis efficacy.
• This approach offers a potential method to overcome resistance in TS-targeted cancer therapy.