Nature polyphenols widely present in plants and foods are promising candidates in cancer chemotherapy. Emerging evidence has shown that plant polyphenols regulate the expression of miRNAs to exert the anti-Multidrug resistance (MDR) activity, which partly attributes to their regulation on miRNAs methylation. Our previous study found that bound polyphenol from foxtail millet bran (BPIS) had potential as an anti-MDR agent for colorectal cancer (CRC), but its mechanism remains unclear. The present findings demonstrated that BPIS upregulated the expression of miR-149 by reducing the methylation of its CpG islands, which subsequently induced the cell cycle arrest in G2/M phase, resulting in enhancing the chemo-sensitivity of HCT-8/Fu cells. Mechanically, BPIS and its active components (FA and p-CA) reduced miR-149 methylation by inhibiting the expression levels of DNA methyltransferases, promoting a remarkable increase of miR-149 expression. Further, the increased miR-149 induced cell cycle arrest in G 2 /M phase by inhibiting the expression of Akt, Cyclin B1 and CDK1, thus increasing the chemosensitivity of HCT-8/Fu cells. Additionally, a strong inducer of DNA de-methylation (5-aza-dc) treatment markedly increased the chemosensitivity of CRC through elevating miR-149 expression, which indicates the hypermethylation of miR-149 may be the key cause of drug resistance in CRC. The study indicates that the enhanced chemosensitivity of BPIS on CRC is mainly attributed to the increase of miR-149 expression induced by methylation inhibition.
Yang Lu,Shuhua Shan,Hanqing Li,Jiangying Shi,Xiaoli Zhang,Zhuoyu Li
Foxtail millet is the second-most widely planted species of millet and the most important cereal food in China. Our previous study showed that bound polyphenol of inner shell (BPIS) from foxtail millet bran displayed effective antitumor activities in vitro and in vivo. The present research further implied that BPIS has the ability to reverse the multidrug resistance of colorectal cancer in human HCT-8/Fu cells, the IC50 values of 5-fluorouracil (5-Fu), oxaliplatin (L–OHP), and vincristine (VCR) were decreased form 6593 ± 53.8, 799 ± 48.9, and 247 ± 10.3 μM to 5350 ± 22.3 (3261 ± 56.9), 416 ± 16.6 (252 ± 15.6), and 144 ± 8.30 (83.8 ± 5.60) μM when HCT-8/Fu cells were pretreated with 0.5 (1.0) mg/mL BPIS for 12 h. The 12 phenolic acid compounds of BPIS were identified by ultraperformance liquid chromatography-triple-time of flight/mass spectrometry (UPLC-Triple-TOF/MS) method. Especially, the fraction of molecular weight (MW) < 200 of BPIS reversed the multidrug resistance in HCT-8/Fu cells, and ferulic acid and p-coumaric acid were the main active components, the IC50 values were 1.23 ± 0.195 and 2.68 ± 0.163 mg/mL, respectively. The present data implied that BPIS significantly enhanced the sensitivity of chemotherapeutic drugs through inhibiting cell proliferation, promoting cell apoptosis, and increasing the accumulation of rhodamine-123 (Rh-123) in HCT-8/Fu cells. Real-time polymerase chain reaction (RT-PCR) and Western blot data indicated that BPIS also decreased the expression levels of multidrug resistance protein 1 (MRP1), P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). Collectively, these results show that BPIS has potential ability to be used as a new drug-resistance reversal agent in colorectal cancer.
危险品化学品经营许可证（带存储）