Discovery of hydroxytyrosol as thioredoxin reductase 1 inhibitor to induce apoptosis and G₁/S cell cycle arrest in human colorectal cancer cells via ROS generation

Abstract

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 G 1 /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.

Use of Oleuropein and Hydroxytyrosol for Cancer Prevention and Treatment: Considerations about How Bioavailability and Metabolism Impact Their Adoption in Clinical Routine

“…This may explain the fact that the mechanism of action of some common cancer treatments (e.g., radiation, inorganic compounds, tyrosine kinase inhibitors, monoclonal antibodies, protease inhibitors, pyrimidine analogues, alkylating agents, and anthracyclines) relies on oxidative stress and ROS-dependent apoptosis [ 286 , 287 , 288 , 289 , 290 , 291 ]. OLE and HT cytotoxic actions themselves in part depend on ROS generation [ 57 , 59 , 63 , 75 , 85 , 88 , 101 , 102 ]; moreover, 200 μM OLE reduced HIF-1α mRNA and protein levels in HNE-1 and HONE-1 nasopharyngeal cancer cell lines [ 278 ], and pro-apoptotic OLE concentration corresponding to 100 μM was able to increase ROS production in MDA-MB-231 cell line, with the maximum peak obtained after 4 h incubation [ 51 ].…”

“…Experimental evidence supports a pro-oxidant action of low doses of HT in colorectal cancer cells. Treatment of human colorectal carcinoma HCT116 cells and human Dukes’ type C colorectal adenocarcinoma SW620 cells with 5–20 μM HT for 24 h determined a raise in the apoptotic rates of both cell lines, ruled by a dose-dependent ROS accumulation detected after 4 h of incubation, which in turn was caused by HT direct inhibition of thioredoxin (Trx) reductase 1 (TrxR1), a key player in redox homeostasis [ 75 , 191 ].…”

Chemoprevention effect of the Mediterranean diet on colorectal cancer: Current studies and future prospects

“…Hydroxytyrosol (3,4-DHPEA) and its secoiridoid derivatives are the main polyphenolic compounds in EVOO, and it originated from the hydrolysis of oleuropein during the ripening of olives ( 43 ). Hydroxytyrosol (HT) is known for its diverse pharmacological effects, including antitumor, anti-inflammatory, immunomodulatory, antimicrobial, and neuroprotective potential ( 44 – 48 ). Recently, Hydroxytyrosol has been tested in mice subjected to dextran sulfate sodium (DSS)-induced colitis ( 49 ).…”

“…It enhanced the expression of the antioxidant enzymes, which emphasized the antiproliferation effect ( 54 , 55 ). As well, another anticancer mechanism of hydroxytyrosol was the inhibition of thioredoxin reductase 1(TrxR1) enzyme and promoted G1/S cell cycle arrest ( 48 ). It is noteworthy that a high level of (TrxR1) enzyme has been detected in CRC cells, which correlated with poor prognosis and chemotherapy response ( 56 , 57 ).…”

Magnetic molecularly imprinted polymers using ternary deep eutectic solvent as novel functional monomer for hydroxytyrosol separation

“…HT can also prevent and cure lung cancer, occult breast cancer, uterine cervical cancer, hormone refractory prostate cancer, etc., promote cancer-later recovery and improve the effect of chemotherapy, because of its free hydroxyl, which has strong anti-cancer properties [ 8 ]. There have been many studies on the pharmacological effects of HT in anti-cancer [ 9 ], anti-thrombosis [ 10 ], anti-arteriosclerosis [ 11 ], prevention and treatment of macular degeneration [ 12 ], protection of cartilage [ 13 ] and other aspects, and also discussed the pharmacological mechanism of HT. However, the yield of HT extracted from olive products is low [ 14 ], which because it exists in esters-Oleuropicrin form.…”