Xiaojuan Yang

Pancreatic cancer (PC) usually results in poor survival with limited treatment options. Reactive oxygen species (ROS) play a key role in the action of HDAC inhibitors. In combination with a ROS generator, it can increase sensitivity to HDAC inhibitors and also overcome resistance to HDAC inhibitors. NQO1-bioactivatable drugs are efficient ROS generators. Therefore, to reduce HDAC inhibitor resistance and enhance its anti-pancreatic cancer activity, in this study, we reported a novel NQO1/HDAC dual-targeting agent, STY12, which exhibited potent anti-pancreatic cancer activity through ROS-mediated DNA damage. STY12 strongly inhibited HDAC1 and HDAC6 activity (IC₅₀ = 29 nM and 10 nM, respectively) and exhibited excellent reduction rates by NQO1 (k_cat/K_m = 5.59 × 10⁶ M⁻¹s⁻¹). STY12 showed good anti-proliferative effects on PC MIA PaCa-2, SW1990, and Capan-2 cells, with IC₅₀ values of 0.23 ± 0.01, 0.25 ± 0.01 and 0.14 ± 0.02 μM, respectively, and lower anti-proliferative effects against normal hTERT-HPNE and BEAS-2B cells. Mechanistic analysis revealed that STY12 suppressed the proliferation of MIA PaCa-2 cells by increasing the acetylation of histone 3 (H3) and α-tubulin, and increasing ROS-mediated DNA damage. Moreover, STY12 arrested the cell cycle at the S phase, inhibited the metastasis of MIA PaCa-2 cells, and promoted their apoptosis. Moreover, compared to SAHA and β-Lap, STY12 exhibited prominent in vivo antitumor activity with negligible toxic effects. Therefore, STY12 can serve as an effective NQO1/HDAC dual-targeting agent for the treatment of PC.