icaritin and Neoplasms

The concept of the inflammatory pre-metastatic niche (PMN) provides a new and promising direction for the prevention and treatment of metastasis. The excessive activation of the GAS-STING signaling leads to augmented metastasis by promoting the formation of the inflammatory PMN. In this study, tumor-derived microparticles (MP) were used to establish the PMN model both in vitro and in vivo, and pro-inflammatory mediators were also employed to evaluate the effects of Icaritin (ICT). It was demonstrated that ICT could inhibit the pulmonary metastasis of B16BL6 melanoma cells in mice via interfering with PMN. The phosphorylation and dimerization of STING and its downstream signaling TBK1-IFNβ were proved to be diminished in the presence of ICT. Furthermore, we revealed that ICT suppressed the generation of pro-inflammatory PMN through conferring the inactivation of the STING signaling pathway. CETSA and DARTS assay also confirmed that STING tended to be a target for the action of ICT. Collectively, our findings highlight a new binding mechanism between STING and ICT for the inhibition of transduction of the STING signaling pathway, suggesting that pharmacological or therapeutic intervention of the STING-TBK1-IFNβ singling axis may serve as an effective strategy to prevent the progression of inflammatory PMN and lung metastasis.

Topics: Animals; Flavonoids; Membrane Proteins; Mice; Neoplasms; Nucleotidyltransferases; Signal Transduction

Topics: Cell Line, Tumor; Flavonoids; Humans; Nanoparticles; Neoplasms; Paclitaxel; Particle Size

Prenyl flavonoid icaritin (1) and β-anhydroicaritin (2) are two natural products with important biological and pharmacological effects. such as antiosteoporosis, estrogen regulation and antitumor properties.. The present study investigates the synthesis and cytotoxic activities on three Human cancer cell lines (Hela, HCC1954 and SK-OV-3) of icaritin and β-anhydroicaritin Mannich base derivatives in vitro models.. Preylated flavonoid icaritin (1) upon treatment with formic acid under microwave assistance gave another natural product β-anhydroicaritin (2) in good yield (89%). Based on Mannich reaction of 1 or 2 with various secondary amines and formaldehyde, two series eighteen new 6-aminomethylated flavonoids Mannich base derivatives 3-11 and 12-20 were synthesized. Their cytotoxic potential against three human cancer cell lines (Hela, HCC1954 and SK-OV-3) were evaluated by the standard MTT method with cis-Platin and Paclitaxel as positive control.. Our research showed that most of these flavonoid Mannich base derivatives displayed equal or higher (lower IC50 values) cytotoxic activities than the positive control cis-Platin. Some compounds possess the IC50 value below 10µM. Compounds 6-(diisopropylamino)methyl- and 6-morpholinylmethyl substituted β-anhydroicaritin (15 and 19) showed selective cytotoxicity against HCC1954 cells (IC50 12.688 µM) and Hela cells (IC50 6.543 µM) respectively.. Our finding most of icaritin and β-anhydroicaritin Mannich base derivatives possessing moderate to potent cytotoxicity against these three cancer cells (Hela, HCC1954 and SK-OV-3). Compound 15 and 19 showed selective cytotoxicity against HCC1954 cells and Hela cells respectively, they are potential and selective anticancer agent and worthy of further development.

Topics: Antineoplastic Agents; Benzopyrans; Cell Line, Tumor; Cell Survival; Drug Screening Assays, Antitumor; Flavonoids; Humans; Mannich Bases; Neoplasms