Gang Wang,Qi Xiao,Wenxiu Wu,Yao Wu,Yingjie Wei,Yue Jing,Zhunan Gong
Background Asiatic acid (AA; 2α,3β,23-trihydroxyurs-12-ene-28-oic acid) is an active compound derived from Centella asiatica, a traditional medicinal plant used widely in many Asian countries, particularly for the treatment of cancer. However, the modified AA derivative N-(2α,3β,23-acetoxyurs-12-en-28-oyl)-l-proline methyl ester (AA-PMe) has shown markedly better anti-tumor activity than AA. Material/Methods We evaluated the toxicity of AA and AA-PMe on zebrafish morphology, mortality, and hatching rate and determined the effect on SGC7901 cancer cells by acute toxicity assay. AA-PMe absorption in vitro in SGC7901 cells and in vivo in zebrafish was determined by establishing a highly accurate and reproducible HPLC protocol. Results In zebrafish, the toxicity of AA-PMe was lower than AA, with an acute toxic dose of AA-PMe above 25 μM, compared to acute toxicity at doses above 10 μM for AA. However, chronic toxicity of AA-PMe began occurring at doses below 25 μM but became apparent for AA at doses below 10 μM. Although low doses of AA-PMe were tolerated acutely, it became chronically toxic during zebrafish development, resulting in morphological abnormalities, including peripheral and abdominal edema, hemorrhage, abnormal body shape, enlarged yolk sac, and reduced motility. At low concentrations, absorption of AA-PMe by cells and zebrafish embryos occurred in a dose-dependent manner, but this stabilized as the concentration increased. Conclusions This pharmacokinetic study outlines the cellular and organismal effects of AA-PMe and suggests a theoretical basis that may underlie its mechanism of action.
MicroRNAs (miRNAs) are a class of short noncoding RNAs that negatively regulate gene expression and act as oncogenes or tumor suppressors. Numerous miRNAs have been reported be associated with the occurrence and development of gastric carcinoma (GC). For instance, miR‑92a has been observed to be overexpressed in GC; however, the precise mechanisms underlying the role of miR‑92a in GC and its role in clinical therapy require further investigation. In the present study, it was reported that miR‑92a expression was significantly upregulated in GC tissues compared with in adjacent tissues. Additionally, suppression of miR‑92a significantly reduced SGC7901 cell viability as demonstrated by a Cell Counting Kit‑8 and colony formation assays. Suppression of miR‑92a inhibited SGC7901 cell proliferation as determined by Ki‑67 immunofluorescence staining, and the expression levels of proliferating cell nuclear antigen, cyclin dependent kinase (CDK)4 and CDK6, and increased that of p53. In addition, we reported that suppression of miR‑92a induced apoptosis in SGC7901 cells. Furthermore, bioinformatics analysis identified that ING2 as a potential target of miR‑92a. Downregulation of miR‑92a significantly increased ING2 expression at the mRNA and protein levels. A dual‑luciferase reporter assay validated a direct binding site of miR‑92a on ING2. In addition, SGC7901 cells with suppression of miR‑92a were more sensitive to doxorubicin treatment. Knockdown of miR‑92a reduced the half‑maximal inhibitory concentration of doxorubicin from 147.6 nM to 82.1 nM in SGC7901 cells. Knockdown of miR‑92a also reduced SGC7901 cell survival under doxorubicin stimulation. Furthermore, SGC7901 cells with suppression of miR‑92a harbored a greater number of DNA damage foci upon doxorubicin treatment compared with in control cells. The findings of the present study revealed that miR‑92a contributes to cell proliferation, apoptosis and doxorubicin chemosensitivity in GC cells, which suggests a potential therapeutic strategy for the treatment of GC.
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