Cancer sensitizing effect of deazaflavin analogs is associated with increased intracellular drug accumulation

Area of Science:

• Medicinal Chemistry
• Cancer Pharmacology
• Molecular Biology

Background:

• Novel deazaflavin analogs were developed as tyrosyl DNA phosphodiesterase 2 (TDP2) inhibitors.
• These compounds are intended for combination therapy with topoisomerase II (TOP2) poisons.
• Some analogs showed increased intracellular drug accumulation, suggesting a novel mechanism for enhancing efficacy.

Purpose of the Study:

• To evaluate deazaflavin TDP2 inhibitors for their effect on anticancer drug retention in cancer cells.
• To identify potent inhibitors that increase intracellular drug accumulation.
• To assess the sensitizing potential of ZW-1226 in combination with anticancer drugs.

Main Methods:

• Synthesis and characterization of deazaflavin analogs.
• Assessment of etoposide (ETP) retention in DT40 cells treated with TDP2 inhibitors.
• Evaluation of ZW-1226's effect on teniposide and pemetrexed accumulation in CCRF-CEM cells.
• Comparison of ZW-1226 with ABC transporter inhibitors (verapamil, elacridar).
• Testing ZW-1226's potentiation of ETP in sensitive and resistant cancer cell lines.

Main Results:

• Most tested TDP2 inhibitors significantly increased ETP retention in DT40 cells.
• ZW-1226, a potent analog, increased intracellular ETP by 13-fold at 3 nM.
• ZW-1226 enhanced the accumulation of teniposide and pemetrexed, outperforming verapamil and elacridar.
• ZW-1226 potentiated ETP's action in sensitive CCRF-CEM cells and resistant non-small-cell lung cancer (NSCLC) cells.

Conclusions:

• Deazaflavin analog ZW-1226 effectively increases intracellular accumulation of multiple anticancer drugs.
• ZW-1226 demonstrates significant potentiation of topoisomerase II poison etoposide in various cancer cells, including resistant types.
• ZW-1226 shows strong potential as a cancer sensitizing agent warranting further investigation.