NCX-4040, a Unique Nitric Oxide Donor, Induces Reversal of Drug-Resistance in Both ABCB1- and ABCG2-Expressing...

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Multidrug resistance (MDR) in cancer treatment is a major clinical challenge.
• Overexpression of ATP-binding cassette (ABC) transporters, such as P-gp and BCRP, mediates MDR by effluxing anticancer drugs.
• Previous attempts to clinically reverse MDR have had limited success.

Purpose of the Study:

• To investigate the potential of nitric oxide (NO) donors to overcome MDR mediated by ABC transporters.
• To evaluate the efficacy of NCX4040, an NO-donating aspirin derivative, in reversing resistance to adriamycin and topotecan.
• To elucidate the mechanism by which NCX4040 inhibits ABC transporter function.

Main Methods:

• Cytotoxicity assays were performed on human cancer cell lines expressing P-gp and BCRP.
• Molecular docking studies were utilized to analyze the interaction of NCX4040 with ABC transporter ATP-binding domains.
• Comparison with other NO donors, including molsidomine and S-nitroso glutathione.

Main Results:

• NCX4040 significantly reversed adriamycin resistance in P-gp-expressing cells and topotecan resistance in BCRP-expressing cells.
• Molecular docking revealed that NCX4040 binds to the nucleotide-binding domains of ABC transporters, hindering ATP binding and reducing transporter activity.
• Other tested NO donors did not effectively overcome resistance in these cell lines.

Conclusions:

• NCX4040 demonstrates potent inhibition of ABC transporter ATPase function, leading to the reversal of MDR.
• Well-designed NO donors hold promise for sensitizing anticancer drugs in MDR tumors expressing ABC transporters.
• This strategy offers a potential therapeutic approach to combat drug-resistant human cancers.