RESUMO
Notoginsenoside R7 was isolated from Panax notoginseng, a plant used commonly in traditional Chinese medicine. We investigated the anti-cancer effects of R7 in HeLa cells in vitro and in vivo, and explored the underlying mechanisms of action. R7 dose-dependently inhibited HeLa cell proliferation and induced apoptosis in vitro, In silico docking-based screening assays showed that R7 can directly bind Akt. Pretreatment with the Akt inhibitor LY294002 synergistically enhanced the R7 anti-proliferation and anti-apoptosis effects in HeLa cells, confirming that R7 acts through the PI3K/Akt pathway. Consistent with the in vitro findings, R7 exerted anti-tumor effects in a mouse xenograft model by targeting PI3K (PTEN) and Akt, activating the pro-apoptotic Bcl-2 family and, subsequently, caspase family members. R7 treatment activated PTEN and downregulated mTOR phosphorylation without affecting mTOR expression, though regulatory-associated protein of mTOR (raptor) expression declined. Our study suggests that R7 is a promising chemotherapeutic agent for the treatment of cervical cancer and other PI3K/PTEN/Akt/mTOR signaling-associated tumors.
RESUMO
BACKGROUND: Pitavastatin, a fully synthetic ß-hydroxy-ß-methylglutaryl-coenzyme A reductase inhibitor, is potent for the treatment of primary hyperlipidemia and mixed dyslipidemia. Recently, the original product and some generic products of pitavastatin calcium have become available in China. However, the intrasubject variability and interchangeability of this newly developed generic product and the branded innovator product have rarely been investigated in the Chinese population. PURPOSE: The aim of this study is to develop and compare the scaled-average, population, and individual bioequivalence (BE) of pitavastatin calcium tablets in healthy Chinese volunteers. This study will be used to allow for the interchangeability (switchability and prescribability) of the 2 products in clinical medication in China. METHODS: A single-dose, reference-replicated, 3-period crossover BE study was conducted in 36 healthy male volunteers. Plasma samples were collected before and after oral administration of 2-mg test or reference tablets. A LC-MS/MS method was used to determine the concentration of pitavastatin calcium. A noncompartmental method was used to investigate the pharmacokinetic parameters. The ANOVA and 90% CIs of ln(AUC0-t) and ln(Cmax) were used for statistical analysis of scaled-average BE. A nonparametric test (Wilcoxon signed rank test) was performed to Tmax. The analyses of population BE and individual BE were used to assess the switchability and prescribability of the 2 products. FINDINGS: Thirty-six volunteers were enrolled in this clinical research; 33 volunteers completed the 3 treatment periods. The mean (SD) relative bioavailability calculated from the ratios (T/R) of AUC0-t was 101.3% (19.7%). The mean ln(AUC0-t) and ln(Cmax) were 98.64 (90% CI, 93.44-104.13) and 98.68 (90% CI, 91.88-105.99) within previously stipulated ranges recommended by the US Food and Drug Administration and the China Food and Drug Administration (CFDA). The intrasubject %CVs of AUC0-t and Cmax were 12.0% and 18.0% for the reference tablet and 13.0% and 17.0% for the test tablet. No significant differences were found among Tmax (0.742 ± 0.276, 0.674 ± 0.202, and 0.689 ± 0.226, respectively) for reference tablet 1, reference Supplemental Table II in the online version at 10.1016/j.clinthera.2014.06.21, and test tablet by a Wilcoxon test (P > 0.05). For ln(AUC0-t) and ln(Cmax), the statistical test-reference ratios were 99.13% and 98.95%, respectively. After inspecting the results for reference and mixed scaling, all the upper confidence limits were <0; therefore, population and individual BE were given. IMPLICATIONS: In the healthy Chinese males, the generic and branded name tablets of pitavastatin calcium are bioequivalent at the rate and extent of absorption after a comparison of scaled-average, population, and individual BE and thus may be used interchangeably. Both the formulations are generally well tolerated. Chinese Clinical Trial identifier: ChiCTR-TTRCC-13003973.