ATP Mimetic Attack on the Nucleotide-Binding Domain to Overcome ABC Transporter Mediated Chemoresistance

Area of Science:

• Biochemistry
• Pharmacology
• Oncology

Background:

• Transporter-mediated multidrug resistance (MDR) in tumor cells is a significant challenge in cancer therapy.
• Efflux transporters, particularly ATP-binding cassette (ABC) transporters like P-glycoprotein (P-gp), play a crucial role in MDR.
• Targeting the nucleotide-binding domain (NBD) of these transporters offers a rational approach to developing novel MDR modulators.

Purpose of the Study:

• To design and evaluate small molecule ATP mimetics targeting the NBD of ABC transporters.
• To assess the ability of these compounds to inhibit ATP-dependent drug efflux and overcome MDR.
• To investigate the therapeutic potential of these ATP mimetics in combination with chemotherapeutic agents.

Main Methods:

• Synthesis and utilization of various ATP mimetics.
• Assay of fluorescent substrate and paclitaxel efflux from resistant cancer cells.
• Measurement of transporter ATPase activity.
• Evaluation of combined efficacy of paclitaxel and ATP mimetics in vitro and in vivo.
• Assessment of compound toxicity and induction of transporter overexpression.

Main Results:

• ATP mimetics effectively suppressed the efflux of fluorescent substrates and paclitaxel from cancer cells.
• These compounds inhibited the ATPase activity of ABC transporters.
• Combined treatment with paclitaxel and ATP mimetics significantly enhanced antitumor efficacy, including in MDR cells.
• The tested compounds demonstrated no toxicity at effective concentrations and did not induce transporter overexpression.
• The developed ATP mimetics were effective against both P-glycoprotein (P-gp)-mediated and Breast Cancer Resistance Protein (BCRP)-mediated drug resistance.

Conclusions:

• The designed ATP mimetics are promising agents for developing therapeutic efflux modulators.
• Targeting the nucleotide-binding domain of ABC transporters provides a viable strategy to combat multidrug resistance in cancer.
• These compounds offer a potential approach to improve the efficacy of existing chemotherapies and overcome resistance mechanisms.