Development of a therapeutic model of precancerous liver using crocin-coated magnetite nanoparticles

Abstract

Despite considerable advances in understanding hepatocellular carcinoma, it is one of the common and deadliest cancers worldwide. Hence, increasing efforts are needed for early diagnosis and effective treatments. Saffron has been recently found to inhibit growth of liver cancer in rats. The aim of this study was to develop an effective method for treatment of liver cancer using magnetite nanoparticles (MNPs) coated with crocin, the main active component of saffron. MNPs were prepared and initially coated with dextran and a cross-linker to enhance conjugation of crocin using a modified coprecipitation method. Cultured HepG2 cells and diethylnitrosamine-injected mice were treated with corcin-coated MNPs and analyzed using cell proliferation assay and immunohistochemical analysis, respectively. Treatment of HepG2 cells with crocin-coated MNPs led to a significant inhibition of their growth as compared to control or those treated with free crocin or uncoated MNPs. Histological examinations of the livers of diethylnitrosamine-injected mice revealed several precancerous changes: multiple proliferative hepatic foci, hyper- or dysplastic transformations of bile ducts/ductules, and nuclear atypia associated with polyploidy, karyomegaly, and vacuolation. Immunohistochemistry using antibodies specific for cell proliferation (Ki-67) and apoptosis (M30-CytoDEATH and Bcl-2) revealed their upregulation during development of precancerous lesions. Using antibodies specific for inflammation (cyclooxygenase-2), oxidative stress (glutathione) and angiogenesis (vascular endothelial growth factor) indicated the involvement of multiple signaling pathways in the development of precancerous lesions. Treatment with crocin-coated MNPs was associated with regression of precancerous lesions, significant upregulation of apoptotic cells and downregulation of Bcl-2 labeling and markers of cell proliferation, inflammation, oxidative stress and angiogenesis. In conclusion, crocin-coated MNPs are more effective than free corcin for treatment of liver precancerous lesions in mice. These findings will help to develop new modalities for early detection and treatment of liver precancerous lesions.

Valeric Acid Suppresses Liver Cancer Development by Acting as a Novel HDAC Inhibitor

“… 31 , 32 However, apoptotic pathways, like CDKN2A/CCND , have not been reported to be affected by HDACi before, which may provide a new direction for further research. 33 , 34 …”

Adenosine Kinase Deficiency Increases Susceptibility to a Carcinogen

“…In this study, we have used the chemical carcinogen DEN in combination with PB as tumor promoter in mice, replicating one of the most widely used experimental models to study hepatocarcinogenesis. [17][18][19]22,23 DEN is a potent hepatocarcinogenic nitrosamine present in many products, such as in tobacco smoke, cured and fried meats, cosmetics, and agricultural chemicals. DEN requires metabolic activation by cytochrome P450 (CYP450) in the liver.…”

“…DEN requires metabolic activation by cytochrome P450 (CYP450) in the liver. [23][24][25] CYP450-dependent metabolism of DEN causes the formation of reactive oxygen species (ROS), including hydrogen peroxide, 18,26 whereas PB promotes carcinogenesis by increasing the expression of P450. 27,28 According to our results, we have seen a higher mortality rate in Adk-tg mice treated with DEN/PB compared with their age-matched WT mice.…”

Regulation effects of total flavonoids in Morus alba L. on hepatic cholesterol disorders in orotic acid induced NAFLD rats

“…Natural products have been used to treat various kinds of diseases, owing to its anti-tumor, anti-inflammatory, antioxidant and hepatoprotective properties [ 10 – 12 ]. Due to the low toxicity and side effects of natural drugs, 40% of FDA-approved treatment are natural ingredients or derivatives [ 12 , 13 ].…”