Development of a Novel Quinoline Derivative as a P-Glycoprotein Inhibitor to Reverse Multidrug Resistance in Cancer Cells.

Multidrug resistance (MDR) is one of conventional cancer chemotherapy's limitations. Our group previously synthesized a series of quinoline-based compounds in an attempt to identify novel anticancer agents. With a molecular docking analysis, the novel compound 160a was predicted to target p-glycoprotein, an MDR candidate. The purpose of this study is to evaluate 160a's MDR reversal effect and investigate the underlying mechanism at the molecular level. To investigate 160a's inhibitory effect, we used a series of parental cancer cell lines (A549, LCC6, KYSE150, and MCF-7), the corresponding doxorubicin-resistant cell lines, an MTS cytotoxicity assay, an intracellular doxorubicin accumulation test, and multidrug resistance assays. The Compusyn program confirmed, with a combination index (CI) value greater than 1, that 160a combined with doxorubicin exerts a synergistic effect. Intracellular doxorubicin accumulation and transported calcein acetoxymethyl (AM) (a substrate for p-glycoprotein) were both increased when cancer cells with MDR were treated with compound 160a. We also showed that compound 160a's MDR reversal effect can persist for at least 1 h. Taken together, these results suggest that the quinoline compound 160a possesses high potential to reverse MDR by inhibiting p-glycoprotein-mediated drug efflux in cancer cells with MDR.

Targeting DNA Binding for NF-κB as an Anticancer Approach in Hepatocellular Carcinoma.

Quinoline core has been shown to possess a promising role in the development of anticancer agents. However, the correlation between its broad spectrum of bioactivity and the underlying mechanism of actions is poorly understood. The present study, with the use of bioinformatics approaches, reported a series of designed molecules which integrated quinoline core and sulfonyl moiety, with the objective of evaluating the substituent and linker effects on anticancer activities and associated mechanistic targets. We identified potent compounds (1h, 2h, 5 and 8) exhibiting significant anticancer effects towards liver cancer cells (Hep3B) with the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) relative values of cytotoxicity below 0.40, a value in the range of doxorubicin positive control with the value of 0.12. Bulky substituents and the presence of bromine atom, as well as the presence of sulfonamide linkage, are likely the favorable structural components for molecules exerting a strong anticancer effect. To the best of our knowledge, our findings obtained from chemical synthesis, in vitro cytotoxicity, bioinformatics-based molecular docking analysis (similarity ensemble approach, SEA),and electrophoretic mobility shift assay provided the first evidence in correlation to the anticancer activities of the selected compound 5 with the modulation on the binding of transcription factor NF-κB to its target DNA. Accordingly, compound 5 represented a lead structure for the development of quinoline-based NF-κB inhibitors and this work added novel information on the understanding of the mechanism of action for bioactive sulfonyl-containing quinoline compounds against hepatocellular carcinoma.

Expression of Insulin-Like Growth Factor Binding Protein-5 (IGFBP5) Reverses Cisplatin-Resistance in Esophageal Carcinoma.

Cisplatin (CDDP) is one of the front-line chemotherapeutic drugs used in the treatment of esophageal squamous cell carcinoma (ESCC). Occurrence of resistance to CDDP has become one of the main challenges in cancer therapy. In this study, the gene expression profile of CDDP-resistant ESCC cells was investigated and molecular approaches were explored in an attempt to reverse the CDDP resistance. A CDDP-resistant SLMT-1/CDDP1R cell line was established from SLMT-1 cells by subculturing in the medium containing an increasing concentration of CDDP (0.1⁻1µg/mL). Mitochondrial (MTS) cytotoxicity assay, cell proliferation assay and cell morphology were used to assess the acquisition of cisplatin-resistance. The most differentially expressed gene in SLMT-1/CDDP1R cells was identified by cDNA microarray analysis compared with the parental SLMT-1 cells and validated by quantitative real-time polymerase chain reaction (qPCR). Association between expression of the most differentially expressed target gene to cisplatin-resistance was verified by RNA interference. An attempt to reversecisplatin-resistance phenotypes was made by using the vector expressing the most downregulated target gene in the CDDP-resistant cells. A CDDP-resistant ESCC cell line, SLMT-1/CDDP1R, was established with 2.8-fold increase CDDP-resistance (MTS50 = 25.8 µg/mL) compared with the parental SLMT-1 cells. cDNA microarray analysis revealed that IGFBP5 showed the highest level of downregulation in SLMT-1/CDDP1R cells compared with the parental SLMT-1 cells. Suppression of IGFBP5 mediated by IGFBP5-targeting siRNA in parental SLMT-1 cells confirmed that IGFBP5 suppression in ESCC cells would induce CDDP-resistance. More importantly, upregulation of IGFBP5 using IGFBP5 expression vector reduced cisplatin-resistance in SLMT-1/CDDP1R cells by 41%. Thus, our results demonstrated that IGFBP5 suppression is one of the mechanisms for the acquisition of cisplatin-resistance in ESCC cells. Cisplatin-resistance phenotype can be reversed by increasing the expression level of IGFBP5. The overall findings of this study thus offered a new direction for reversing the CDDP resistance in ESCC and possibly in other cancer types with further investigations in future.

Corilagin Induces High Levels of Apoptosis in the Temozolomide-Resistant T98G Glioma Cell Line.

Glioblastoma multiforme (GBM), a malignant tumor of the central nervous system, has a high mortality rate. No curative treatment is presently available, and the most commonly used chemotherapeutic drug, the alkylating agent temozolomide (TMZ), is only able to increase life expectancy and is often associated with drug resistance. Therefore, an urgent need does exist for novel drugs aimed at treating gliomas. In the present study, we obtained three major results using corilagin: (a) demonstrated that it inhibits the growth of U251 glioma cells through activation of the apoptotic pathway; (b) demonstrated that it is also active on TMZ-resistant T98G glioma cells; and (c) demonstrated that when used in combination with TMZ on T98G glioma cells, a higher level of proapototic and antiproliferative effects is observed. Our study indicates that corilagin should be investigated in more detail to determine whether it can be developed as a potential therapeutic agent. In addition, our results suggest that corilagin could be used in combination with low doses of other standard anticancer chemotherapeutic drugs against gliomas (such as TMZ) with the aim of obtaining enhanced anticancer effects.

Recent advances in green nanoparticulate systems for drug delivery: efficient delivery and safety concern.

Nanotechnology manipulates therapeutic agents at the nanoscale for the development of nanomedicines. However, there are current concerns over nanomedicines, mainly related to the possible toxicity of nanomaterials used for health medications. Due to their small size, they can enter the human body more readily than larger sized particles. Green chemistry encompasses the green synthesis of drug-loaded nanoparticles by reducing the use of hazardous materials in the synthesis process, thus reducing the adverse health impacts of pharmaceutics. This would greatly expand their potential in biomedical treatments. This review highlights the potential risks of nanomedicine formulations to health, delivery routes of green nanomedicines, recent advances in the development of green nanoscale systems for biomedical applications and future perspectives for the green development of nanomedicines.

Anti-cancer Effects of a Novel Quinoline Derivative 83b1 on Human Esophageal Squamous Cell Carcinoma through Down-Regulation of COX-2 mRNA and PGE2.

PURPOSE: 83b1 is a novel quinoline derivative that has been shown to inhibit cancer growth in human esophageal squamous cell carcinoma (ESCC). This study was conducted to comprehensively evaluate the cytotoxic effects of 83b1 on a series of ESCC cell lines and investigate the mechanisms by which 83b1 suppresses cancer growth based on molecular docking analysis. MATERIALS AND METHODS: A series of ESCC and nontumor immortalized cell lines were exposed to 83b1 and cisplatin (CDDP) in a dose-dependent manner, and the cytotoxicity was examined by a MTS assay kit. Prediction of the molecular targets of 83b1 was conducted by molecular docking analysis. Expression of cyclooxygenase 2 (COX-2) mRNA and COX-2-derived prostaglandin E2 (PGE2) were measured by quantitative real-time polymerase chain reaction and enzymelinked immuno-sorbent assay, respectively. In vivo anti-tumor effect was determined using a nude mice xenografted model transplanted with an ESCC cell line, KYSE-450. RESULTS: 83b1 showed the significant anti-cancer effects on all ESCC cell lines compared to CDDP; however, 83b1 revealed much lower toxic effects on non-tumor cell lines than CDDP. The predicted molecular target of 83b1 is peroxisome proliferator-activated receptor delta (PPARδ), which is a widely known oncoprotein. Additionally the expression of COX-2 mRNA and COX-2-derived PGE2 were down-regulated by 83b1 in a dose-dependent manner in ESCC cell lines. Furthermore, 83b1 was shown to significantly reduce the tumor size in nude mice xenograft. CONCLUSION: The results of this study suggest that the potential anti-cancer effects of 83b1 on human esophageal cancers occur through the possible oncotarget, PPARδ, and down-regulation of the cancer related genes and molecules.

Sensitization of Candida albicans to terbinafine by berberine and berberrubine.

Candida albicans (C. albicans) is an opportunistic fungal pathogen, particularly observed in immunocompromised patients. C. albicans accounts for 50-70% of cases of invasive candidiasis in the majority of clinical settings. Terbinafine, an allylamine antifungal drug, has been used to treat fungal infections previously. It has fungistatic activity against C. albicans. Traditional Chinese medicines can be used as complementary medicines to conventional drugs to treat a variety of ailments and diseases. Berberine is a quaternary alkaloid isolated from the traditional Chinese herb, Coptidis Rhizoma, while berberrubine is isolated from the medicinal plant Berberis vulgaris, but is also readily derived from berberine by pyrolysis. The present study demonstrates the possible complementary use of berberine and berberrubine with terbinafine against C. albicans. The experimental findings assume that the potential application of these alkaloids together with reduced dosage of the standard drug would enhance the resulting antifungal potency.

Recent advances in research of natural and synthetic bioactive quinolines.

Many natural products that consist of quinoline core are found to be bioactive and the versatility of quinoline and its derivatives have attracted great attention in the field of drug development. As a result, in recent years, many green and sustainable synthetic approaches for the synthesis of structurally diverse quinolines have been developed. This review covers four main aspects, namely bioactive quinoline alkaloids, the biological activity and mechanism of action of quinoline-based compounds as well as various quinoline syntheses.

The loss of cellular junctions in epithelial lung cells induced by cigarette smoke is attenuated by corilagin.

Cigarette smoke (CS) contains over 4700 compounds, many of which can affect cellular redox balance through free radicals production or through the modulation of antioxidant enzymes. The respiratory tract is one of the organs directly exposed to CS and it is known that CS can damage the integrity of lung epithelium by affecting cell junctions and increasing epithelium permeability. In this study, we have used a human lung epithelial cell line, Calu-3, to evaluate the effect of CS on lung epithelial cell junctions levels, with special focus on the expression of two proteins involved in intercellular communication: connexins (Cx) 40 and 43. CS exposure increased Cx40 gene expression but not of Cx43. CS also induced NFκB activation and the formation of 4HNE-Cxs adducts. Since corilagin, a natural polyphenol, is able to inhibit NFκB activation, we have determined whether corilagin could counteract the effect of CS on Cxs expression. Corilagin was able to diminish CS induced Cx40 gene expression, 4HNE-Cx40 adducts formation, and NFκB activation. The results of this study demonstrated that CS induced the loss of cellular junctions in lung epithelium, possibly as a consequence of Cx-4HNE adducts formation, and corilagin seems to be able to abolish these CS induced alterations.

Anti-tumour and pharmacokinetics study of 2-Formyl-8-hydroxy-quinolinium chloride as Galipea longiflora alkaloid analogue.

The quinolinium chloride salt of 8-hydroxyqinolinecarbaldehyde (2-Formyl-8-hydroxy-quinolinium chloride) was prepared as Galipea longiflora alkaloid analogue and its anticancer activity was evaluated both in vitro and in vivo. This chloride salt was found to show certain degree of selectivity between hepatoma cells and normal hepatocytes in vitro. Athymic nude mice Hep3B xenograft model further demonstrated that this 2-Formyl-8-hydroxy-quinolinium chloride could execute strong anti-tumour activity with the identification of extensive necrotic feature from the tumour xenograft and limited adverse toxicological effect.

The puzzling issue of 'vehicle-treated control' when using ethanol as drug carrier for MCF-7 cells.

Ethanol has been commonly used as a vehicle for drug discovery purpose in vitro. The human breast cancer MCF-7 estrogen dependent cell line is a common in vitro model used for hormonal therapy study. However, special precaution is suggested when ethanol is used in pharmacological tests as solvent in order to evaluate the biological activity of potential drugs especially concerning about the MCF-7. Ethanol was shown to stimulate the proliferation of this estrogen receptor positive cell line. Here, we have further demonstrated that the dose responsive stimulatory effect of ethanol on the MCF-7 cells after pre-incubating the breast carcinoma cells with phenol red-free medium and stripped fetal bovine serum. Our findings open a discussion for the evaluation of ethanol as solvent for drug discovery and screening when using MCF-7 cells as a testing model.

Sensitization of Hep3B hepatoma cells to cisplatin and doxorubicin by corilagin.

The anticancer action of gallotannins is a well-developed topic. We have demonstrated the in vivo antitumour activity of corilagin on Hep3B hepatoma using the xenograft athymic nude mice model. Here, we further report the potential sensitization of Hep3B hepatoma cells to cisplatin and doxorubicin by corilagin. Our results showed that corilagin is able to enhance the cytotoxicity of both cisplatin and doxorubicin on the Hep3B hepatoma cells. We speculate the possible use of corilagin in combination with low dosages of the anticancer chemotherapeutic standard drugs like cisplatin and doxorubicin, with the aim of obtaining an increment in the anticancer effect.

Preparation of 8-hydroxyquinoline derivatives as potential antibiotics against Staphylococcus aureus.

This work describes the preparation of quinoline compounds as possible anti-bacterial agents. The synthesized quinoline derivatives show anti-bacterial activity towards Staphylococcus aureus. It is interesting to observe that the synthetic 5,7-dibromo-2-methylquinolin-8-ol (4) shows a similar minimum inhibitory concentration of 6.25µg/mL as compared to that of methicillin (3.125µg/mL) against Staphylococcus aureus.

In vivo antitumour activity of amphiphilic silicon(IV) phthalocyanine with axially ligated rhodamine B.

We explore the possible cellular cytotoxic activity of an amphiphilic silicon(IV) phthalocyanine with axially ligated rhodamine B under ambient light experimental environment as well as its in vivo antitumour potential using Hep3B hepatoma cell model. After loading into the Hep3B hepatoma cells, induction of cellular cytotoxicity and cell cycle arrest were detected. Strong growth inhibition of tumour xenograft together with significant tumour necrosis and limited toxicological effects exerted on the nude mice could be identified.

Preparation of Galipea officinalis Hancock type tetrahydroquinoline alkaloid analogues as anti-tumour agents.

The preparation of chiral tetrahydroquinolines using Ir-catalysed asymmetric hydrogenation and their possible cytotoxic potential anti-cancer activity were reported. Both of the in vitro cytotoxicity assay on a series of human cancer cell lines including A549 small cell lung cancer, MDA-MB-231 breast cancer, SaoS2 sacroma, SKHep-1 hepatoma and Hep3B hepatocellular carcinoma as well as in vivo animal model using Hep3B hepatocellular tumour xenograft on athymic nude mice suggest that 1,2,3,4-tetrahydroquin-8-ol is a potential anti-tumour alkaloid which may be further developed as a novel cancer chemotherapeutic agent.

A novel green gelatin-agar microencapsulation system with P. urinaria as an improved anti-A. niger model.

In this study, a novel green microencapsulation system was used to develop Phyllanthus urinaria (PU) extract containing microcapsules. Agar was used with gelatin as the wall matrix materials of microcapsules to prevent the use of toxic crosslinker formaldehyde. Microencapsulated PU extract was developed to improve the potential antifungal activities of PU water extracts. The active components and surface morphology of PU extract containing microcapsules were analyzed by liquid chromatography/mass spectrometry and scanning electron microscopy, respectively. The in vitro release study demonstrated that approximately 80% of drug was released after 120 h. PU loaded microcapsules were shown to have a stronger anti-Aspergillus niger activity than the free drug.

Synthesis of 8-hydroxyquinoline derivatives as novel antitumor agents.

This letter describes the preparation of quinoline derivatives and their cytotoxic potentials toward human carcinoma cell lines. Among the selected compounds, 8-hydroxy-2-quinolinecarbaldehyde (3) showed the best in vitro cytotoxicity against the human cancer cell lines, including MDA231, T-47D, Hs578t, SaoS2, K562, SKHep1 (with a MTS50 range of 12.5-25 µg/mL) and Hep3B (with a MTS50 range of 6.25±0.034 µg/mL). The in vivo antitumor activity of compound 3 on subcutenaous Hep3B hepatocellular carcinoma xenograft in athymic nude mice was then studied. The results showed that the dose of 10 mg/kg/day of compound 3 with intraperitoneal injection for 9 days totally abolished the growth of the xenograft tumor of Hep3B with no histological damage on vital organs as compared with the control. The experimental results suggested that compound 3 has a good potential as an antitumor agent.

Corilagin is a potent inhibitor of NF-kappaB activity and downregulates TNF-alpha induced expression of IL-8 gene in cystic fibrosis IB3-1 cells.

Corilagin (beta-1-O-galloyl-3,6-(R)-hexahydroxydiphenoyl-d-glucose), a gallotannin identified in several plants, including Phyllanthus urinaria, has been shown to exhibit versatile medicinal activities. As far as possible anti-inflammatory effects of corilagin, only few reports are available, and the potential use of corilagin as possible therapeutic molecule for cystic fibrosis has not been evaluated. In the present paper we report experiments aimed at determining the activity of corilagin on nuclear factor kappaB (NF-kappaB) binding to DNA target and on the expression of the major pro-inflammatory gene involved in cystic fibrosis, interleukin-8 (IL-8). Both IL-8 mRNA content and IL-8 protein secretion were analyzed in cystic fibrosis bronchial IB3-1 cells stimulated by tumor necrosis factor-alpha (TNF-alpha), one of the most potent pro-inflammatory agents. The data obtained demonstrate that corilagin binds to NF-kappaB, inhibits NF-kappaB/DNA interactions and affects IL-8 gene expression in TNF-alpha treated IB3-1 cells. In addition, corilagin inhibits TNF-alpha induced secretion of MCP-1 and RANTES, exhibiting low or no effect on the release of G-CSF, IL-6 and VEGF. Therefore, corilagin might be of interest for experimental anti-inflammatory therapy of cystic fibrosis.

Development of hydrocortisone succinic acid/and 5-fluorouracil/chitosan microcapsules for oral and topical drug deliveries.

Recently, we demonstrated the safety use of calendula oil/chitosan microcapsules as a carrier for both oral and topical deliveries. We also reported the improved biological activity towards skin cells and Staphylococcus aureus of phyllanthin containing chitosan microcapsules. However, the possibility of both oral and topical applications was still necessary to be further studied. Here we investigated that both oral and topical applications of chitosan-based microcapsules were tested using hydrocortisone succinic acid (HSA) and 5-fluorouracil (5-FU), respectively. The drug loading efficiency, particle size, surface morphology and chemical compositions of both drug loaded microcapsules were confirmed by UV-vis spectrophotometer, particle size analyzer, scanning electron microscope and Fourier transform infrared spectroscopy. The in vitro release studies revealed that both HSA and 5-FU could be released form chitosan microcapsules. The mean adrenocorticotropic hormone concentration in HSA loaded microcapsule mice plasma was detected to be lower than that of water control. One hundred micrograms per milliliter of 5-FU containing microcapsules exhibited a stronger growth inhibition towards skin keratinocytes than that of free 5-FU. In vitro drug delivery model demonstrated the delivery of 5-FU from microcapsule treated textiles into nude mice skin. Further uses of the drug loaded microcapsules may provide an efficiency deliverable tool for both oral and topical applications.