Design, Synthesis, and Biological Evaluation of Novel Biotinylated Podophyllotoxin Derivatives as Potential Antitumor Agents.

Podophyllotoxin has long been used as an active substance for cytotoxic activity. Fourteen novel biotinylated podophyllotoxin derivatives were designed, synthesized, and evaluated for cytotoxic activity for this study. The synthesized compounds were evaluated for cytotoxic activity in the following human cancer cell lines, SW480, MCF-7, A-549, SMMC-7721, and HL-60 by MTT assay. Most of them exhibited potent cytotoxic effects and compound 15 showed the highest cytotoxic activity among the five cancer cell lines tested, having its IC50 values in the range of 0.13 to 0.84 µM. Apoptosis analysis revealed that compound 15 caused obvious induction of cell apoptosis. Compound 15 significantly down-regulated the expression level of the marker proteins (caspase-3 and PARP) in H1299 and H1975 cells, activated the transcription of IRE1α, increased the expression of GRP78 and XBP-1s, and finally induced apoptosis of H1299 cells. In vivo studies showed that 15 at a dose of 20 mg/kg suppressed tumor growth of S180 cell xenografts in icr mice significantly. Further molecular docking studies suggested that compound 15 could bind well with the ATPase domain of Topoisomerase-II. These data suggest that compound 15 is a promising agent for cancer therapy deserving further research.

Synergistic combination of DT-13 and topotecan inhibits human gastric cancer via myosin IIA-induced endocytosis of EGF receptor in vitro and in vivo.

Combination therapy has a higher success rate for many cancers compared to mono-therapy. The treatment of Topotecan (TPT) on gastric cancer (GC) is limited by its toxicity and the potential drug resistance. We found that the combination of the saponin monomer 13 from the dwarf lilyturf tuber (DT-13), performing anti-metastasis and anti-angiogenesis effects, with TPT synergistically induced apoptotic cytotoxicity in GCs with high EGF receptor (EGFR) expression, which was dependent on DT-13-induced endocytosis of EGFR. With TPT, DT-13 promoted EGFR ubiquitin--mediated degradation through myosin IIA-induced and Src/ caveolin-1 (Cav-1)-induced endocytosis of EGFR; inhibited EGFR downstream signalling and then increased the pro-apoptotic effects. Moreover, the synergistic pro-apoptotic efficacy of DT-13 and TPT in GCs with high EGFR expression was eliminated by both the NM II inhibitor (-)-blebbistatin and MYH-9 shRNA. The combination therapy of DT-13 with TPT showed stronger anti-tumour effects in vivo compared with their individual effects. Moreover, the results of combination therapy revealed selective upregulation of pro-apoptotic activity in TUNEL assays and cleaved caspase-3 and NM IIA in immunohischemical analysis; while specific downregulation of p-extracellular regulated kinase 1/2 (p-ERK1/2), EGFR and Cav-1 in immunohischemical analysis. Collectively, these findings have significant clinical implications for patients with tumours harbouring high EGFR expression due to the possible high sensitivity of this regimen.

Using fuzzy gap analysis to measure service quality of medical tourism in Taiwan.

PURPOSE: The purpose of this paper is intended to create a model to measure quality of service, using fuzzy linguistics to analyze the quality of service of medical tourism in Taiwan so as to find the direction for improvement of service quality in medical tourism. DESIGN/METHODOLOGY/APPROACH: The study developed fuzzy questionnaires based on the characteristics of medical tourism quality of service in Taiwan. Questionnaires were delivered and recovered from February to April 2014, using random sampling according to the proportion of medical tourism companies in each region, and 150 effective samples were obtained. The critical quality of service level is found through the fuzzy gap analysis using questionnaires examining expectations and perceptions of customers, as the direction for continuous improvement. FINDINGS: From the study, the primary five critical service items that improve the quality of service for medical tourism in Taiwan include, in order: the capability of the service provider to provide committed medical tourism services reliably and accurately, facility service providers in conjunction with the services provided, the cordial and polite attitude of the service provider eliciting a sense of trust from the customer, professional ability of medical (nursing) personnel in hospital and reliability of service provider. ORIGINALITY/VALUE: The contribution of this study is to create a fuzzy gap analysis to assess the performance of medical tourism service quality, identify key quality characteristics and provide a direction for improvement and development for medical tourism service quality in Taiwan.