New Strategies to Overcome Drug Resistance on Infectious Disease and Cancer

• Main Authors: Lan-Hui Li, 李蘭蕙
• Other Authors: 陳惠文
• Format: Others
• Language: en_US
• Published: 2014
• Online Access: http://ndltd.ncl.edu.tw/handle/66105616838946579542

博士 === 國立臺灣大學 === 毒理學研究所 === 102 === Non-cytotoxic Nanomaterials Enhance Antimicrobial Activities of Cefmetazole against Multidrug-Resistant Neisseria Gonorrhoeae The emergence and spread of antibiotic-resistant Neisseria gonorrhoeae has led to difficulties in treating patients, and novel strategies to prevent and treat this infection are urgently needed. Here, we examined 21 different nanomaterials including Si, carbons, metals and metal oxides for their potential activity against N. gonorrhoeae (ATCC 49226). The data showed good antibacterial activity among most nanomaterials. Specifically, silver nanoparticles (Ag NPs, 120 nm) showed the greatest potency for reducing N. gonorrhoeae colony formation (MIC: 12.5 μg/ml). We further test the size effects of silver nanoparticles and found 120 nm and 20 nm (MIC: 12.5 μg/ml) had better activity than 1 μm (MIC: 500 μg/ml) against N. gonorrhoeae. Ag NPs in 120 nm within a concentration range that did not induce cytotoxicity in human fibroblasts or epithelial cells compared with smaller size of 20 nm. Thus we focused on the antibacterial mechanisms of Ag NPs in 120 nm in the following experiments. Scanning electron microscopy revealed that the Ag NPs significantly reduced bacterial size and cell membrane integrity; transmission electron microscopy revealed that Ag NPs significantly reduced bacterial cell wall/ membrane thickness and simulated cytoplasm disorganization. Besides ATCC N. gonorrhoeae, Ag NPs possessed similar effects against multidrug-resistant N. gonorrhoeae in clinical isolates. Furthermore, combined treatment with 120 nm Ag NPs and cefmetazole produced additive effects. The modes of action probably due to the zeta potential of Ag NPs that might form complex with cefmetazole to enhance the susceptibility. Based on the ICP-MASS analysis, Ag NPs possessed the dominant influence on the antibacterial activity with their properties of the nanoparticles. This is the first report to screen the effectiveness of nanomaterials against N. gonorrhoeae, and our results indicate that 120 nm Ag NPs deliver low levels of toxicity to human epithelial cells and could be used as an adjuvant with antibiotic therapy, either for topical use or as a coating for biomaterials, to prevent or treat multidrug-resistant N. gonorrhoeae.. Hinokitiol Induces DNA Damage and Autophagy Followed by Cell Cycle Arrest and Senescence in Gefitinib-Resistant Lung Adenocarcinoma Cells According to the cancer statistics in 2013, lung cancer remains the top one leading cause of cancer death in USA and also in Taiwan. Despite of the good response initially following standard treatment options, most of the lung adenocarcinoma patients with EGFR mutations took EGFR-tyrosine kinase inhibitors (TKIs) might develop resistance within 9 months. To explore the new anti-cancer strategy is urgent. In this study, we investigated 40 Taiwan indigenous essential oils, these essential oils from plants were used as alternative treatments for a wide range of illnesses; however its’ anti-cancer effects and underlying mechanisms are less evaluated. In this study, we found hinokitiol, a natural monoterpenoid from the heartwood of Calocedrus formosana, exhibited potent anticancer effects. Here, we demonstrated that hinokitiol inhibited a series of lung adenocarcinoma cells proliferation and colony formation as well as corresponding EGFR-TKI resistant cell lines (PC9-IR and H1975). The transcriptomic analysis and pathway prediction indicated that DNA damage, autophagy, and cell cycle pathways were majorly affected. Further validations confirmed that hinokitiol could inhibit cell proliferation without inducing apoptosis but autophagy; induced p53-independent DNA damage, arrested cell cycle in S phase and senescence, whereas had less effects in lung stromal fibroblasts. Furthermore, hinokitiol inhibited the growth of xenograft tumors and increaseed DNA damage and autophagy evidenced by IHC staining. Taken together, we first demonstrated the novel mechanisms of hinokitiol from essential oils as a promising anticancer agent to overcome the EGFR-TKI resistant lung cancer.