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Updated: Jan 9, 2026
High-Throughput In Vitro Assay using Patient-Derived Tumor Organoids
Published on: June 14, 2021
Structure-Guided optimization of PAO-PDT yields TrxR inhibitors as potential anticancer agent
Suntao Shi1, Jingwen Tu1, Miao Zhong1
1State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, China.
Abstract:
Thioredoxin reductase (TrxR) is a critical enzyme in maintaining cellular redox balance, and its inhibition has emerged as a promising anticancer strategy by compromising the antioxidant capacity of tumor cells and inducing oxidative stress-mediated apoptosis. In our previous work, we identified PAO-PDT as a highly potent organoarsenic TrxR inhibitor, revealing a novel mode of TrxR inhibition at nanomolar concentrations. Building on this discovery, we aim to augment the antitumor efficacy of organoarsenic compounds by incorporating cinnamic acid, a naturally occurring compound derived from cinnamon, which has been reported to exhibit potent anticancer activity. A series of CA-conjugated organoarsenic derivatives were rationally designed and synthesized. After preliminary screening, As-CA11 demonstrated potent antiproliferative activity against HL-60 cells (IC50 = 0.28 ± 0.05 μM) and exhibited strong inhibition of TrxR in vitro (IC50 = 18.7 ± 0.02 nM). Mechanistic investigations revealed that As-CA11 promotes intracellular ROS accumulation through TrxR inhibition, thereby disrupting redox homeostasis and inducing apoptosis. These effects were further confirmed in a 4T1 tumor-bearing mouse model. Collectively, our results highlight the potential of structurally modifying organoarsenic scaffolds with bioactive natural product moieties to improve antitumor efficacy, offering promising leads for the development of next-generation organoarsenic-based therapeutics.
Insights
New organoarsenic compounds conjugated with cinnamic acid show potent anticancer activity by inhibiting thioredoxin reductase (TrxR). This strategy enhances antitumor efficacy and induces cancer cell apoptosis via oxidative stress.
Area of Science:
- Medicinal Chemistry
- Biochemistry
- Oncology
Background:
- Thioredoxin reductase (TrxR) is crucial for cellular redox balance.
- TrxR inhibition is a promising anticancer strategy inducing oxidative stress and apoptosis.
- Previous work identified PAO-PDT as a potent organoarsenic TrxR inhibitor.
Purpose of the Study:
- To enhance the antitumor efficacy of organoarsenic compounds.
- To synthesize and evaluate cinnamic acid (CA)-conjugated organoarsenic derivatives.
- To explore novel therapeutic leads for cancer treatment.
Main Methods:
- Rational design and synthesis of CA-conjugated organoarsenic derivatives.
- In vitro antiproliferative activity assays against HL-60 cells.
- In vitro TrxR inhibition assays.
- Mechanistic studies on reactive oxygen species (ROS) and apoptosis.
- In vivo evaluation in a 4T1 tumor-bearing mouse model.
Main Results:
- As-CA11 demonstrated potent antiproliferative activity (IC50 = 0.28 ± 0.05 μM) and TrxR inhibition (IC50 = 18.7 ± 0.02 nM).
- As-CA11 induced intracellular ROS accumulation by inhibiting TrxR, disrupting redox homeostasis.
- The compound promoted apoptosis and showed antitumor effects in a mouse model.
Conclusions:
- Structurally modifying organoarsenic scaffolds with natural product moieties like cinnamic acid can improve antitumor efficacy.
- As-CA11 is a promising lead compound for developing next-generation organoarsenic-based therapeutics.
- Targeting TrxR with novel organoarsenic derivatives offers a viable anticancer strategy.
