Journal of Chinese Pharmaceutical Sciences

Cancers chemoprevention by dietary phytochemicals and traditional Chinese medicines: epigenetics and cellular signaling pathways

Ah-Ng Tony Kong, Siwang Yu

2016, 25(4): 233-234.

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The incidence and mortality of cancer have been increasing alarmingly in China and worldwide^[1]. Unlike other chronic diseases such as metabolic, cardiovascular, and neuropathies, most cancers, especially metastatic ones, are still essentially uncontrollable in spite of significant progresses such as early diagnosis and immunotherapies. Fortunately, human cancer generally takes about 10–30 years to develop; hence there is a window of opportunity to prevent cancer before it becoming metastatic and radio/chemotherapeutic resistant. Indeed, prevention has made huge contribution to cancer control in the United States and some European countries, and chemoprevention is one of the most attractive strategies.

Targeting obesity-related inflammation in skin cancer: molecular and epigenetic insights for cancer chemoprevention by dietary phytochemicals

Ximena Paredes-Gonzalez, Francisco Fuentes, Yaoping Lu, Ah Ng Tony Kong

2016, 25(4): 235-249. DOI: 10.5246/jcps.2016.04.028

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Non-melanoma skin cancer (NMSC) is one of the most common cancers in the US, although the role of obesity in skin cancer remains unclear. In vivo studies have consistently demonstrated that obese mice challenged with UVB radiation show increased skin tumorigenesis in comparison with leaner control mice. Growing evidence suggests that enhanced inflammation, oxidative stress and impaired apoptosis may play important roles in the development of skin cancer. Interventions such as voluntary exercise and the surgical removal of parametrial fat have been demonstrated to be effective in reducing adipose tissue that may influence the development of skin cancer; however, these interventions are not achievable in all obese patients. Therefore, the use of dietary natural phytochemicals that may modify and reverse the deregulated molecular and epigenetic events related to obesity and cancer development might represent a potential therapeutic modality due to their potential efficacy and low toxicity. In this review, we aim to provide the molecular and epigenetic basis of the NMSC-obesity relationship and to highlight the potential anti-cancer chemopreventive benefits of dietary phytochemicals such as sulforaphane and epigallocatechin-3-gallate.

The role of Helicobacter pylori infection in gastric carcinogenesis and its prevention by using Chinese medicinal herbs

Fangyuan Li, Guiyu Zhang, Rilan Ou, Ying Wang, Xiaoxiao Qi, Zhongqiu Liu, Linlin Lu

2016, 25(4): 250-265. DOI: 10.5246/jcps.2016.04.029

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As the fifth most common cancer and the third most common cause of cancer deaths worldwide, gastric cancer remains a significant public health concern and an economic burden in developed and developing countries. Gastric inflammation induced by Helicobacter pylori may initiate superficial gastritis, which then progresses to atrophic gastritis, gastric epithelial dysplasia, and finally gastric cancer. The pathogenesis of H. pylori infection is related to its virulence factors, including urease, flagella, vacuolating cytotoxin A and cytotoxin-associated gene antigen. The relevant mechanisms of H. pylori-induced inflammation include activation of nuclear factor-κB, mitogen-activated protein kinase pathway, and oxidative stress. To date, therapeutic strategies and results in this infection remain undesirable. Complicated treatment issues include antibiotic resistance, adverse effects of chemical drugs, and recurrence after operation. Therefore, chemoprevention has been regarded as an important measure, and Chinese medicinal herbs have been the research hotspot. This review aimed to summarize the effects of Chinese medicinal herbs on the prevention of gastric cancer, mechanism of action and the treatment prospects, with emphasis H. pylori-induced effects.

The use of a new functional glucose conjugate material, TPGS1000-Glu, in treatment of brain glioma by incorporating into epirubicin liposomes

Limin Mu, Jiashuan Wu, Hongjun Xie, Lei Liu, Fan Zeng, Yan Yan, Yao Zhao, Yingjie Hu, Yingzi Bu, Wanliang Lu

2016, 25(4): 266-274. DOI: 10.5246/jcps.2016.04.030

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Most of anticancer agents can not be used for treatment of brain glioma due to the existence of the blood brain barrier (BBB). The over-expression of glucose transporters (GLUTs) on the BBB and brain glioma cells enables the possibility that the GLUTs ligand modified drug carrier transports across the BBB, and targets to the brain glioma cells. The objectives of the present study were to synthesize a new glucose conjugate material, TPGS₁₀₀₀-Glu, develop a kind of TPGS₁₀₀₀-Glu modified epirubicin liposomes, and evaluate their efficacy. The studies were performed on the BBB co-culture model and brain glioma cells in vitro. TPGS1000-Glu was synthesized by conjugating TPGS_1000-COOH with 4-aminophenyl-β-D-glucopyranoside (Glu), and confirmed by MALDI-TOF-MSspectrum. TPGS₁₀₀₀-Glu modified epirubicin liposomes were prepared with a high drug encapsulation efficiency (>97%), a nanosize (approximately 90 nm), and a minimal drug leakage in fetal bovine serum (FBS)-containing buffer system. The BBB co-culture model was established, and after applying TPGS₁₀₀₀-Glu modified epirubicin liposomes to the model, transport of liposomal drug across the BBB was evidenced. Besides, TPGS₁₀₀₀-Glu modified epirubicin liposomes showed the strongest cellular drug uptake and anti-glioma efficacy after transport across the BBB in vitro. The synthesized TPGS1000-Glu material could offer a new targeting ligand for the BBB, while the developed TPGS₁₀₀₀-Glu modified epirubicin liposomes might provide a potential anticancer formulation for treatment of brain glioma.

HPLC determination of Nimodipine in plasma with an improved sample refining method and its application in pharmacokinetic studies

Xiaona Wang, Ruilian Chen, Wenli Liu, Junbo Gong, Yongli Wang, Zhenping Wei

2016, 25(4): 275-283. DOI: 10.5246/jcps.2016.04.031

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In order to prepare samples for HPLC analysis with maximum drug recovery and impurity elimination, a revised method for the extraction and purification of a target substance from plasma was developed and applied in a pharmacokinetic study with Nimodipine as a model drug. After protein precipitation of a plasma sample using pure methanol and evaporation of the supernatant to dryness, methanol of various concentrations from 10% to 100% were used to dissolve the remaining residues with the goal of maximizing drug recovery and impurity elimination. Through rigorous screening with HPLC peaks from residual impurity and recovered drug as the criteria, a methanol concentration of 30% was chosen. The standard curve was linear (r²≥ 0.999) over the range of 2–160 ng/mL with a limit of quantification (LOQ) of 2 ng/mL. Intra- and inter-day precision values were below 15%, and the accuracy ranged from –1.70% to 5.88% at all three quality control (QC) levels. The wavelength of maximum absorption was 238 nm, and a smaller LOQ value of 2 ng/mL was achieved compared with the reported method. The revised method was successfully applied in a pharmacokinetic study of Nimodipine in rats and sample preparations of lidocaine hydrochloride.

Influence of the post-fermentation by four Aspergillus strains on the aroma of pu-erh tea

Jing Ye, Wenguang Wang, Jun Li, Xiaoyu Guo, Mingbo Zhao, Yong Jiang, Pengfei Tu

2016, 25(4): 284-290. DOI: 10.5246/jcps.2016.04.032

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Aroma is one of the most important factors for the flavor, taste, and quality of pu-erh tea, and the post-fermentation process has an important influence on the aroma of pu-erh tea. In the present study, the influence of fungi fermentation on the flavor of pu-erh tea was investigated and compared. Volatile compounds from pu-erh tea fermented by four Aspergillus strains, includingA. niger, A. oryzae, A. awamori, and A. glaucus, were extracted and analyzed using ultrasound-assisted extraction-dispersive liquid-liquid microextraction-gas chromatography-mass spectrometry (UAE-DLLME-GC-MS), and a total of 63 volatile compounds were identified. In comparison with the sun-dried green tea, fermented pu-erh tea contained high levels of methoxyphenolic compounds, such as 1,2,3-trimethoxybenzene, which was the most abundant one. Our results confirmed that the characteristic methoxyphenolic compounds were produced by the activity of Aspergillus during the post-fermentation process, and A. niger andA. awamori were the most important strains forthe formation of aroma quality of pu-erh tea.

A rapid and simple ultraperformance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) method for the detection of glucuronic acid-conjugated steroid metabolites

Yi Rong, Biyun Huang, Junjun Huang, Liu Zhu, Xiawen Liu

2016, 25(4): 291-301. DOI: 10.5246/jcps.2016.04.033

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In the present study, we effectively detected 10 steroids and glucuronic acid-conjugated steroid metabolites in 12 min by ultraperformance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS). Steroids testosterone (T), 5α-dihydrotestosterone (DHT), androsterone (ADT), etiocholanolone (ETIO), estradiol (E₂) and their glucuronide conjugates were well-separated on an Eclipse Plus C₁₈ column (2.1 mm×50 mm, RRHD 1.8 µm). The mobile phase consisted of a mixture of methanol and ultrapure water (containing 1 mM ammonium formate) at a ratio of 60:40 (v/v), and the flow rate was set at 0.25 mL/min. The LC eluate was detected by electrospray ionization (ESI) source in both positive and negative ion modes. Neutral loss (NL of 176, 194, 211 and 229 Da in positive mode) and precursor ion (PI of m/z 141, 159 and 177 in positive mode and 75, 85 and 133 in negative mode) methods were applied for the detection of steroid glucuronides. The multiple reaction monitoring (MRM) transitions were m/z 289.3→97.1, 291.3→105, 291.3→199.2, 273.2→145.4 and 255.2→159.1 for T, DHT, ADT, ETIO and E₂in positive mode, respectively; as well as m/z 463.3→85 for T glucuronide (T-G), m/z 465.3→75 for DHT glucuronide (DHT-G), ADT glucuronide (ADT-G), ETIO glucuronide (ETIO-G) and m/z 447.3→271 for E₂ glucuronide (E₂-G) in negative mode. In addition, the analytical method was also applied for the detection of steroid glucuronides in pooled human liver microsomes (HLM), which might serve as a basis for further investigation of steroid metabolism in vivo and in vitro.

Different responses of HepG2 subclones to low dose ethaselen

Guozhou Zhang, Kun Xiong, Weiwei Ma, Wei Xu, Huihui Zeng

2016, 25(4): 302-309. DOI: 10.5246/jcps.2016.04.034

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As a synthesized antineoplastic organoselenium compound, ethaselen is known to induce apoptosis in tumor cells via dose-dependent thioredoxin reductase (TrxR) inhibition. Thioredoxin, the multifunctional biological substrate of TrxR, is then left in the oxidized state, which subsequently leads to intracellular accumulation of reactive oxygen species (ROS), cell cycle arrest and/or apoptosis. However, the low dose effect of ethaselen remains largely unknown. Several subclones have been derived from HepG2 cells by using single cell or colony isolation. The low dose of ethaselen was defined as the drug concentration of retaining >90% HepG2 cells alive. The HepG2 cells were used as reference of its subclones (SM01, SM02 and SM03), and the cell cycle transition, intracellular proteins change, colony formation and sphere growth were assayed in treatment of low dose ethaselen. HepG2 and its subclones differently responded to lethal dose of cisplatin or 5-fluorouracil. Low dose of ethaselen (1 µm) modulated the cell cycle transition at 12 h of treatment, but cells were partially recovered at 24 h of treatment though some proteins were still affected. Low dose of ethaselen did not inhibit the small colony (diameter >100 µm) formation and sphere growth of HepG2 and SM01. However, low dose of ethaselen could specifically inhibit the survival, large colony (diameter >500 µm) formation and sphere growth of SM03, although SM03 could be rapidly recovered from ethaselen-induced cell cycle check. HepG2 and its subclone cells could survive but respond differently to treatment of low dose ethaselen (1 µM). Low dose of ethaselen could significantly inhibit a HepG2 subclone (SM03) in cell survival and colony growth.

KL-0153, a novel inhibitor of Pseudomonas aeruginosa MexAB-OprM efflux pump

Yishuang Liu, Ying Wang, Jiayin Zheng, Xinghua Li, Yan Guan, Shuchao Huang, Chunling Xiao

2016, 25(4): 310-315. DOI: 10.5246/jcps.2016.04.035

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Pseudomonas aeruginosa is an opportunistic pathogen that contributes to high morbidity and mortality. MexAB-OprM is the main efflux pump among the Resistance-Nodulation-Division family multi-drug efflux systems, which contribute greatly to the multidrug resistance of P. aeruginosa. Efflux pump inhibitors (EPIs) of MexAB-OprM could enhance the activity of the antibiotics effluxed by MexAB-OprM, and thus they might be useful in the clinic as antibacterial synergistic agents. In this work, a new EPI of MexAB-OprM, KL-0153, was discovered by screening of a small molecular library. Its inhibition of MexAB-OprM was conﬁrmed by assays of synergistic activity and EB accumulation. The activity of KL-0153 was shown to be synergistic with antibiotics effluxed by MexAB-OprM when they were tested against strains expressing MexAB-OprM, especially so for the strains that express MexAB-OprM at high levels. KL-0153 showed more activity than the positive drug carbonyl cyanide m-chlorophenylhydrazone in the EB accumulation assay. It cannot be neglected that KL-0153 has significant liver and kidney toxicity. However, KL-0153 may be a lead compound for the research and development of new types of EPIs.

The 2015 Annual Conference of the State Key Laboratory of Natural and Biomimetic Drugs was held in Peking University Health Science Center

The State Key Laboratory of Natural and Biomimetic Drugs

2016, 25(4): 316-317.

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