chrysin and Pancreatic-Neoplasms

Pancreatic adenocarcinoma (PDAC) and lung cancer are expected to represent the most common cancer types worldwide until 2030. Under typical conditions, mitochondria provide the bulk of the energy needed to sustain cell life. For that inhibition of mitochondrial complex ΙΙ (CΙΙ) and ubiquinone oxidoreductase with natural treatments may represent a promising cancer treatment option. A naturally occurring flavonoid with biological anti-cancer effects is chyrsin. Due to their improved bioavailability, penetrative power, and efficacy, chitosan-chrysin nano-formulations (CCNPs) are being used in medicine with increasing frequency. Chitosan (cs) is also regarded as a highly versatile and adaptable polymer. The cationic properties of Cs, together with its biodegradability, high adsorption capacity, biocompatibility, effect on permeability, ability to form films, and adhesive properties, are advantages. In addition, Cs is thought to be both safe and economical. CCNPs may indeed be therapeutic candidates in the treatment of pancreatic adenocarcinoma (PDAC) and lung cancer by blocking succinate ubiquinone oxidoreductase.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Chitosan; Flavonoids; Humans; Lung Neoplasms; Nanoparticles; Pancreatic Neoplasms; Succinate Dehydrogenase; Ubiquinone

Pancreatic cancer (PC) has a high mortality rate due to its poor prognosis and the possibility of surgical resection in patients with the disease. Importantly, adjuvant chemotherapy is necessary to improve PC prognosis. Chrysin, a natural product with anti-inflammatory, antioxidant, and anticancer properties, has been studied for several years. Our previous study demonstrated that chrysin induced G protein-coupled estrogen receptor (GPER) expression and regulated its activity in breast cancer. Herein, we investigated whether chrysin-induced GPER activation suppresses PC progression in MIA PaCa-2 cells and a xenograft model. To determine its mechanism of action, cytotoxicity and clonogenic assays, a FACS analysis, and Western blotting were performed. Furthermore, the delay in tumor growth was evaluated in the MIA PaCa-2-derived xenograft model. Tumor tissues were investigated by Western blotting, immunohistochemistry, and a proteomic analysis. Chrysin caused cell cycle arrest and significantly decreased cell viability. Following co-treatment with chrysin and 17β-estradiol, the inhibitory effect of chrysin on cell proliferation was enhanced. In the xenograft model, chrysin and G1 (a GPER agonist) significantly delayed tumor growth and reduced both Ki-67 (a proliferation marker) and c-Myc expressions in tumor tissues. The proteomic analysis of tumor tissues identified that rho-associated coiled-coil containing protein kinase 1 (ROCK1), transgelin 2 (TAGLN2), and FCH and Mu domain containing endocytic adaptor 2 (FCHO2) levels were significantly reduced in chrysin-treated tumor tissues. High

Topics: Cell Line, Tumor; Cell Proliferation; Estrogens; Flavonoids; GTP-Binding Proteins; Humans; Pancreatic Neoplasms; Proteomics; Receptors, Estrogen; Receptors, G-Protein-Coupled; rho-Associated Kinases

Recent studies have verified that inducing reactive oxygen species (ROS) is one of the gemcitabine anti-tumor mechanisms of action. Human carbonyl reductase 1 (CBR1) plays an important role in protecting cells against oxidative damage. However, it is unclear whether CBR1 is involved in pancreatic cancer (PC) progression and resistance to gemcitabine. Based on the GEPIA database, we analyzed tumor tissue samples from PC patients using immunohistochemistry (IHC) and revealed that CBR1 was highly expressed in PC tissues and that this was significantly correlated with the clinicopathological features of PC. Genetic inhibition of CBR1 suppressed PC cell proliferation by regulating ROS generation. Furthermore, gemcitabine upregulated CBR1 expression, which could limit the anti-tumor activity of gemcitabine, and attenuation of CBR1 enhanced gemcitabine sensitivity in vitro and in vivo. Additionally, we report that chrysin directly binds to CBR1, which inhibited its enzymatic activity both at the molecular and cellular levels. Inhibition of CBR1 by chrysin increased cellular ROS levels and led to ROS-dependent autophagy, which resulted in the degradation of ferritin heavy polypeptide 1 (FTH1) and an increase in the intracellular free iron level that participates in ferroptosis in PC cells. Finally, our results showed that chrysin enhanced PC sensitivity to gemcitabine by inducing ferroptotic death in vitro and in vivo. Collectively, these findings indicate that CBR1 is a potential therapeutic target for PC treatment. In addition, we elucidated a novel mechanism underlying the anti-tumor effects of chrysin.

Topics: Alcohol Oxidoreductases; Animals; Antineoplastic Agents; Autophagy; Cell Line, Tumor; Cytosol; Deoxycytidine; Drug Delivery Systems; Drug Resistance, Neoplasm; Ferroptosis; Flavonoids; Gemcitabine; Gene Expression Regulation, Neoplastic; Humans; Lipid Peroxidation; Male; Mice; Mice, Nude; Molecular Docking Simulation; Oxidative Stress; Pancreatic Neoplasms; Reactive Oxygen Species; Up-Regulation; Xenograft Model Antitumor Assays

Three new flavonoids, (2R,3R)-3,5-dihydroxy-7-methoxyflavanone 3-(2-methyl)butyrate (1), (7''R)-8-[1-(4'-hydroxy-3'-methoxyphenyl)prop-2-en-1-yl]chrysin (2), and (7''R)-8-[1-(4'-hydroxy-3'-methoxyphenyl)prop-2-en-1-yl]galangin (3), together with 41 known compounds (4-44) were isolated from a methanolic extract of Mexican propolis. Compounds 2 and 3 are unique natural flavones containing a 1-phenylallyl moiety. The in vitro preferential cytotoxicity of all the isolates was evaluated against a PANC-1 human pancreatic cell line. Compound 3 displayed the most potent preferential cytotoxicity (PC(50) 4.6 microM) in the nutrient-deprived medium (NDM) and triggered apoptosis-like morphological changes in PANC-1 cells.

Topics: Animals; Antineoplastic Agents; Apoptosis; Bees; Drug Screening Assays, Antitumor; Flavonoids; Humans; Mexico; Molecular Structure; Pancreatic Neoplasms; Propolis; Stereoisomerism