STY12, a Novel NQO1/HDAC Dual-Targeting Agent, Exhibits Potent Anti-Pancreatic Cancer Activity by ROS-Mediated DNA
Tong Shen1, Xiaojuan Yang2, Zhenhua Han1
1School of Pharmacy, Henan Medical University, Xinxiang 453003, China.
Abstract:
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 (kcat/Km = 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.
Insights
A new agent, STY12, targets both NQO1 and HDAC in pancreatic cancer. It generates reactive oxygen species (ROS) to damage DNA, overcoming resistance and showing potent anti-cancer effects in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Pancreatic cancer (PC) has poor survival rates and limited treatment options.
- Reactive oxygen species (ROS) are crucial in HDAC inhibitor action, enhancing sensitivity and overcoming resistance.
- NQO1-bioactivatable drugs are effective ROS generators, offering a strategy to improve HDAC inhibitor efficacy.
Purpose of the Study:
- To develop and evaluate a novel NQO1/HDAC dual-targeting agent, STY12, for pancreatic cancer treatment.
- To investigate STY12's mechanism of action, focusing on ROS generation and DNA damage.
- To assess STY12's efficacy and safety in preclinical pancreatic cancer models.
Main Methods:
- Synthesis and characterization of the NQO1/HDAC dual-targeting agent STY12.
- In vitro assessment of HDAC1 and HDAC6 inhibition, NQO1 bioactivation, and anti-proliferative effects on pancreatic cancer cell lines.
- Mechanistic studies involving ROS generation, DNA damage assessment, cell cycle analysis, metastasis inhibition, and apoptosis induction.
- In vivo evaluation of STY12's antitumor activity and toxicity compared to existing agents.
Main Results:
- STY12 potently inhibited HDAC1 and HDAC6 (IC50 = 29 nM and 10 nM) and showed excellent NQO1 bioactivation.
- STY12 exhibited significant anti-proliferative effects against PC cell lines (IC50 values 0.14-0.25 μM) with lower toxicity to normal cells.
- Mechanistic studies confirmed STY12 induces ROS-mediated DNA damage, cell cycle arrest (S phase), inhibits metastasis, and promotes apoptosis.
- STY12 demonstrated prominent in vivo antitumor activity with negligible toxic effects compared to SAHA and β-Lap.
Conclusions:
- STY12 is a novel NQO1/HDAC dual-targeting agent with potent anti-pancreatic cancer activity.
- Its efficacy is mediated through ROS generation, DNA damage, and modulation of cell proliferation, metastasis, and apoptosis.
- STY12 shows promise as an effective therapeutic agent for pancreatic cancer with a favorable safety profile.
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