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Colorectal cancer (CRC) is one of the most common cancer types and a leading cause of cancer-associated mortality in China. Increased thioredoxin reductase 1 (TrxR1) levels have been previously identified as possible target for CRC. The present study revealed that the natural product hydroxytyrosol (HT), which exhibits a polyphenol scaffold, is a potent inhibitor of TrxR1. Inhibition of TrxR1 was indicated to result in accumulation of reactive oxygen species, inhibit proliferation and induce apoptosis and G1/S cell cycle arrest of CRC cells. Using a C-terminal mutant TrxR1 enzyme activity assay, TrxR1 RNA interference assay and HT binding model assay, the present study demonstrated the core character of the selenocysteine residue in the interaction between HT and TrxR1. HT can serve as polyphenol scaffold to develop novel TrxR1 inhibitors for CRC treatment in the future.

Targeting the Trp-Kyn pathway is an attractive approach for cancer immunotherapy. Thioredoxin reductase (TrxR) enzymes are reactive oxygen species (ROS) modulators that are involved in the tumor cell growth and survival processes. The 4-phenylimidazole scaffold is well-established as useful for indoleamine 2,3-dioxygenase 1 (IDO1) inhibition, while piperlongumine (PL) and its derivatives have been reported to be inhibitors of TrxR. To take advantage of both immunotherapy and TrxR inhibition, we designed a first-generation dual IDO1 and TrxR inhibitor (ZC0101) using the structural combination of 4-phenylimidazole and PL scaffolds. ZC0101 exhibited better dual inhibition against IDO1 and TrxR in vitro and in cell enzyme assays than the uncombined forms of 4-phenylimidazole and PL. It also showed antiproliferative activity in various cancer cell lines, and a selective killing effect between normal and cancer cells. Furthermore, ZC0101 effectively induced apoptosis and ROS accumulation in cancer cells. Knockdown of TrxR1 and IDO1 expression induced cellular enzyme inhibition and ROS accumulation effects during ZC0101 treatment, but only reduced TrxR1 expression was able to improve ZC0101's antiproliferation effect. This proof-of-concept study provides a novel strategy for cancer treatment. ZC0101 represents a promising lead compound for the development of novel antitumor agents that can also be used as a valuable probe to clarify the relationships and mechanisms of cancer immunotherapy and ROS modulators.

Resistance is a major concern when administering chemotherapy to patients with non-small cell lung cancer (NSCLC). Chemosensitizer are agents that can reverse resistance to chemotherapeutic drugs, thereby enhancing the chemosensitivity of tumor cells. Thus, their development will improve therapeutic efficacy in cancer. However, few effective chemosensitizer have been identified to date. Piperlongumine (PL) has been shown to effectively reverse resistance to chemotherapeutic drugs in several types of cancers. However, the mechanisms associated with the chemotherapy resistance reversal effect of PL and its regulation of target factors in chemotherapy resistance cells are still unclear. This study investigated the reversal effect of PL both in vitro and in vivo, and provided evidence that PL inhibited the phosphorylation of Akt via the accumulation of reactive oxygen species in chemotherapy resistance cells. Consequently, various Akt activation-dependent genes caused a reduction of drug efflux and induction of apoptosis in cisplatin-resistant A549 NSCLC cells. Our results indicate that Akt phosphorylation may play a functional role in the reversal effect of PL and contribute, at least in part, to the treatment outcomes of patients with chemotherapy resistance.

With the aim of discovering novel cyclin-dependent kinase 8 (CDK8) inhibitors, a combined similarity search and molecular docking approach was employed, which led to 32 hits. Biological tests led to the discovery of several novel submicromolar inhibitors. In particular, compound C768-0769 (ZC0201) showed good CDK8 inhibitory activity, and compound ZC0201 effectively suppressed HCT-116 colorectal cancer cell proliferation by inducing G1/S transition arrest. Furthermore, modulation of phosphorylated signal transducer and activator of transcription 1 (Ser 727) (STAT1SER727), a pharmacodynamic biomarker of CDK8 activity, demonstrated that ZC0201 may cause G1/S transition arrest through CDK8 activity inhibition. Due to its good cellular activity, ZC0201 may be an ideal lead compound for further modification as a potential cancer therapeutic agent.