WRQ-2, a gemcitabine prodrug, reverses gemcitabine resistance caused by hENT1 inhibition

Abstract

Gemcitabine is widely used in the clinic as a first-line antitumor agent. However, intrinsic and acquired resistance hinders its wide clinical application. In this study, a gemcitabine prodrug nominated as WRQ-2 was designed and synthesized by conjugating gemcitabine with the indole-3-methanol analogue OSU-A9 through a carbamate linkage. WRQ-2 exhibited high cytotoxicity against six cancer cell lines (HeLa, A549, MDA-MB-231, HuH-7, MGC-803, and HCT-116) with IC₅₀ values in low micromolar range. WRQ-2 reversed the resistance of HeLa cells to gemcitabine caused by hENT1 inhibition. Compared to gemcitabine, WRQ-2 induced a higher degree of DNA damage and apoptosis in the presence of hENT1 inhibitor. Our study suggests that compound WRQ-2 is a potential gemcitabine prodrug and worth of further antitumor activity investigation.