Antileukemic effect of caffeic acid 3,4-dihydroxyphenetyl ester. Evidences for its mechanisms of action.

BACKGROUND: Caffeic acid 3,4-dihydroxyphenethyl ester (CADPE) is a natural polyphenolic ester isolated as a minor component from a water extract of the Chinese medicine Zhongjiefeng [Sarcandra glabra (Thunb.) Nakai (Chloranthaceae)] and has previously shown to have activity against solid tumors through the modulation of multiple targets or signal pathways. However, the activity and potential mechanism of CADPE against leukemia cells have not yet been characterized. PURPOSE: To investigate whether and how CADPE kills leukemia cells. METHOD: (1) The activity of CADPE inhibiting the growth of different leukemia cell lines was evaluated by MTT assay; (2) Cell cycle arrest and apoptosis induced by CADPE were determined by flow cytometry with FlowJo software for quantification; (3) The protein levels were analyzed by Western blot and ubiquitin-binding c-Myc was acquired by co-immunoprecipitation. RESULTS: CADPE exerted potent activity against different leukemia cell lines with low toxicity in normal cells. In terms of mechanism of action, CADPE promoted ubiquitin-proteasome-dependent degradation of c-Myc through activating glycogen synthase kinase-3ß (GSK3ß) and downregulating deubiquitinating enzyme USP28 to trigger the interaction of c-Myc with ubiquitin ligase Fbw7, resulting in the downregulation of cell cycle regulators and anti-apoptotic proteins and consequently, cell cycle arrest and cell apoptosis. CONCLUSION: CADPE is a novel c-Myc inhibitor with high activity and a unique mechanism for killing leukemia cells.

[Herb-drug enzyme-mediated interactions and the associated experimental methods: a review].

OBJECTIVE: To review the interactions between herbs and widely used drugs and summarize the associated experimental methods. METHODS: Definite herb-drug interactions were obtained by searching PubMed, other large overseas databases and summarizing new researches from China. We summarize some methods to assess the interaction between herbs and drugs involving microsomal, cell culture and animal experiments, and clinical trials, classifying this method as single ingredient herbs, crude herb extracts, and herbal formulae. RESULTS: Many herbs interact with drugs through a complex cytochrome P450 and/or P-glycoprotein mechanism. Herb-induced enzyme inhibition and/or induction may result in enhanced and/or decreased plasma, tissue, urine and bile drug concentrations, leading to a change in a drug's pharmacokinetic parameters and resulting in the improper treatment of patients and potentially severe side effects. Use of an appropriate method for comprehensively assessing herb-drug interactions can minimize clinical risks. Different methods were used by researchers to assess the pharmacological changes of drugs in vivo and in vitro and the mechanisms of the interactions from microsomal, cell culture and animal experiments, and clinical trials are discussed in this review. CONCLUSION: Co-medication with herbs can result in changes in pharmacological effects of many drugs. This review describes the assessment of single-ingredient herbs, crude herb extracts, and herbal formulae. When choosing a research method to investigate herb-drug interactions, the properties of the drugs and herbs should be considered.

[Construction of biopharmaceutics classification system of Chinese materia medica].

Based on the characteristics of multicomponent of traditional Chinese medicine and drawing lessons from the concepts, methods and techniques of biopharmaceutics classification system (BCS) in chemical field, this study comes up with the science framework of biopharmaceutics classification system of Chinese materia medica (CMMBCS). Using the different comparison method of multicomponent level and the CMMBCS method of overall traditional Chinese medicine, the study constructs the method process while setting forth academic thoughts and analyzing theory. The basic role of this system is clear to reveal the interaction and the related absorption mechanism of multicomponent in traditional Chinese medicine. It also provides new ideas and methods for improving the quality of Chinese materia medica and the development of new drug research.

[Design and analyze mathematical algorithms of intestinal absorption and metabolism of multicomponent drug].

Evaluation of the permeability mainly focuses on intestinal absorption in biopharmaceutics classification system (BCS). It is more complicated that the absorption and metabolism under multicomponent environment in biopharmaceutics classification system of Chinese materia medica (CMMBCS) compared with single component environment, which needs suitable mathematical models to be described. Therefore, with full consideration of existing single component mathematical algorithm combining with the characteristics of intestinal absorption and metabolism, we explored and designed a new mathematical algorithm of intestinal absorption and metabolism of multicomponent drug. Then we put forward a new coefficient, P (influence), the relative change rate of the single component's intestinal absorption and metabolism under multicomponent environment compared with single component environment, which described the influences of intestinal absorption and metabolism of the component under multicomponent environment. Moreover, P (influence) highlights the distinctive characteristics of multicomponent drug's intestinal absorption and metabolism, and lays the foundation for the construction of CMMBCS.

[Application of multicomponent dissolution evaluation method of biopharmaceutics classification system of Chinese materia medica in gegen qinlian tablets].

The study is a paticular embodiment of Chinese patent medicine based on biopharmaceutics classification system of Chinese materia medica (CMMBCS) , focusing on assessment of synchronization issues of dissolution that may affect the timing of the multicomponent absorption. The accumulative dissolution percentages of nine components in Gengen Qinlian tablets in different dissolution solvents and times were determined by HPLC. The dissolution curve was drew and its similarity was evaluated by similarity factors (f2) and cluster method. Results in this experiment showed that the components that peak 7 and peak 8 (baicalin) represented had poor similarity with the reference peak 2 (puerarin). Their similarity factors were both 43 in water dissolution media and 31 and 45 in pH 7.4 dissolution media, respectively. Components that peaks represented had better similarity with the reference peak 2 (puerarin) in other medium. It illustrated that components that peak 3,4,5,6 (berberine) represented had fully synchronous dissolution characteristics with the reference peak 2 (puerarin), components peak 1 and 9 represented had nearly fully synchronous dissolution characteristics with the reference peak 2 (puerarin), while components that peak 7 and 8 (baicalin) represented had no synchronous dissolution characteristics with the reference peak 2 (puerarin).

[Effect of multicomponent environment on intestinal permeability of puerarin in biopharmaceutics classification system of Chinese materia medica].

The evaluation of permeability in biopharmaceutics classification system of Chinese materia medica (CMMBCS) requires multicomponent as a whole in order to conduct research, even in the study of a specific component, should also be put in the multicomponent environment. Based on this principle, the high content components in Gegen Qinlian decoction were used as multicomponent environmental impact factors in the experiment, and the relevant parameters of intestinal permeability about puerarin were measured with using in situ single-pass intestinal perfusion model, to investigate and evaluate the intestinal permeability of puerarin with other high content components. The experimental results showed that different proportions of baicalin, glycyrrhizic acid and berberine had certain influence on intestinal permeability of puerarin, and glycyrrhizic acid could significantly inhibit the intestinal absorption of puerarin, moreover, high concentration of berberine could promote the absorption of puerarin. The research results indicated that the important research ideas of permeability evaluation in biopharmaceutics classification system of Chinese materia medica with fully considering the effects of other ingredients in multicomponent environment.