ISSN 1881-7831 Online ISSN 1881-784X DD&T Drug Discoveries & Therapeutics Volume 8, Number 4 August, 2014 www.ddtjournal.com ISSN: 1881-7831 Online ISSN: 1881-784X CODEN: DDTRBX Issues/Year: 6 Language: English Publisher: IACMHR Co., Ltd. Drug Discoveries & Therapeutics is one of a series of peer-reviewed journals of the International Research and Cooperation Association for Bio & Socio-Sciences Advancement (IRCA-BSSA) Group and is published bimonthly by the International Advancement Center for Medicine & Health Research Co., Ltd. (IACMHR Co., Ltd.) and supported by the IRCA-BSSA and Shandong University China-Japan Cooperation Center for Drug Discovery & Screening (SDU-DDSC). Drug Discoveries & Therapeutics publishes contributions in all fields of pharmaceutical and therapeutic research such as medicinal chemistry, pharmacology, pharmaceutical analysis, pharmaceutics, pharmaceutical administration, and experimental and clinical studies of effects, mechanisms, or uses of various treatments. Studies in drug-related fields such as biology, biochemistry, physiology, microbiology, and immunology are also within the scope of this journal. Drug Discoveries & Therapeutics publishes Original Articles, Brief Reports, Reviews, Policy Forum articles, Case Reports, News, and Letters on all aspects of the field of pharmaceutical research. All contributions should seek to promote international collaboration in pharmaceutical science. Editorial Board Editor-in-Chief: Xiao-Kang LI National Research Institute for Child Health and Development, Kazuhisa SEKIMIZU Tokyo, Japan The University of Tokyo, Tokyo, Japan Masahiro MURAKAMI Osaka Ohtani University, Osaka, Japan Co-Editors-in-Chief: Yutaka ORIHARA The University of Tokyo, Tokyo, Japan Xishan HAO Tomofumi SANTA Tianjin Medical University, Tianjin, China The University of Tokyo, Tokyo, Japan Norihiro KOKUDO Wenfang XU The University of Tokyo, Tokyo, Japan Shandong University, Ji'nan, China Hongxiang LOU Shandong University, Ji'nan, China Web Editor: Yun YEN City of Hope National Medical Center, Duarte, CA, USA Yu CHEN The University of Tokyo, Tokyo, Japan Chief Director & Executive Editor: Proofreaders: Wei TANG The University of Tokyo, Tokyo, Japan Curtis BENTLEY Roswell, GA, USA Managing Editor: Thomas R. LEBON Los Angeles, CA, USA Hiroshi HAMAMOTO The University of Tokyo, Tokyo, Japan Munehiro NAKATA Editorial and Head Office: Tokai University, Hiratsuka, Japan Pearl City Koishikawa 603, Senior Editors: 2-4-5 Kasuga, Bunkyo-ku, Tokyo 112-0003, Japan Guanhua DU Tel.: +81-3-5840-9697 Chinese Academy of Medical Science and Peking Union Medical Fax: +81-3-5840-9698 College, Beijing, China E-mail: [email protected] www.ddtjournal.com i Drug Discoveries & Therapeutics Editorial and Head Office Tel: +81-3-5840-9697, Fax: +81-3-5840-9698 Pearl City Koishikawa 603, 2-4-5 Kasuga, Bunkyo-ku, E-mail: [email protected] Tokyo 112-0003, Japan URL: www.ddtjournal.com Editorial Board Members Alex ALMASAN Rodney J. Y. HO Sridhar MANI Yuhong XU (Cleveland, OH) (Seattle, WA) (Bronx, NY) (Shanghai) John K. BUOLAMWINI Hsing-Pang HSIEH Tohru MIZUSHIMA Bing YAN (Memphis, TN) (Zhunan, Miaoli) (Tokyo) (Ji'nan, Shandong) Jianping CAO Yongzhou HU Abdulla M. MOLOKHIA Yasuko YOKOTA (Shanghai) (Hangzhou, Zhejiang) (Alexandria) (Tokyo) Shousong CAO Yu HUANG Yoshinobu NAKANISHI Takako YOKOZAWA (Buffalo, NY) (Hong Kong) (Kanazawa, Ishikawa) (Toyama, Toyama) Jang-Yang CHANG Hans E. JUNGINGER Weisan PAN Rongmin YU (Tainan) (Marburg, Hesse) (Shenyang, Liaoning) (Guangzhou, Guangdong) Fen-Er CHEN Amrit B. KARMARKAR Rakesh P. PATEL Guangxi ZHAI (Shanghai) (Karad, Maharashra) (Mehsana, Gujarat) (Ji'nan, Shandong) Zhe-Sheng CHEN Toshiaki KATADA Shivanand P. PUTHLI Liangren ZHANG (Queens, NY) (Tokyo) (Mumbai, Maharashtra) (Beijing) Zilin CHEN Gagan KAUSHAL Shafi qur RAHMAN Lining ZHANG (Wuhan, Hubei) (Philadelphia, PA) (Brookings, SD) (Ji'nan, Shandong) Shaofeng DUAN Ibrahim S. KHATTAB Adel SAKR Na ZHANG (Lawrence, KS) (Kuwait) (Cairo) (Ji'nan, Shandong) Chandradhar DWIVEDI Shiroh KISHIOKA Gary K. SCHWARTZ Ruiwen ZHANG (Brookings, SD) (Wakayama, Wakayama) (New York, NY) (Amarillo, TX) Mohamed F. EL-MILIGI Robert Kam-Ming KO Yuemao SHEN Xiu-Mei ZHANG (6th of October City) (Hong Kong) (Ji'nan, Shandong) (Ji'nan, Shandong) Hao FANG Nobuyuki KOBAYASHI Brahma N. SINGH Yongxiang ZHANG (Ji'nan, Shandong) (Nagasaki, Nagasaki) (New York, NY) (Beijing) Marcus L. FORREST Toshiro KONISHI Tianqiang SONG (Lawrence, KS) (Tokyo) (Tianjin) (As of August 2014) Takeshi FUKUSHIMA Chun-Guang LI Sanjay K. SRIVASTAVA (Funabashi, Chiba) (Melbourne) (Amarillo, TX) Harald HAMACHER Minyong LI Hongbin SUN (Tübingen, Baden-Württemberg) (Ji'nan, Shandong) (Nanjing, Jiangsu) Kenji HAMASE Xun LI Chandan M. THOMAS (Fukuoka, Fukuoka) (Ji'nan, Shandong) (Bradenton, FL) Junqing HAN Jikai LIU Murat TURKOGLU (Ji'nan, Shandong) (Kunming, Yunnan) (Istanbul) Xiaojiang HAO Xinyong LIU Fengshan WANG (Kunming, Yunnan) (Ji'nan, Shandong) (Ji'nan, Shandong) Kiyoshi HASEGAWA Yuxiu LIU Hui WANG (Tokyo) (Nanjing, Jiangsu) (Shanghai) Waseem HASSAN Xingyuan MA Quanxing WANG (Rio de Janeiro) (Shanghai) (Shanghai) Langchong HE Ken-ichi MAFUNE Stephen G. WARD (Xi'an, Shaanxi) (Tokyo) (Bath) ii www.ddtjournal.com CONTENTS Volume 8, Number 4, 2014 Reviews 139 - 153 A map describing the association between effective components of traditional Chinese medicine and signaling pathways in cancer cells in vitro and in vivo. Jufeng Xia, Jialu Chen, Zhongmin Zhang, Peipei Song, Wei Tang, Norihiro Kokudo 154 - 164 Advances in the study of molecularly targeted agents to treat hepatocellular carcinoma. Jialu Chen, Jianjun Gao Original Articles 165 - 172 Design of amphiphilic oligopeptides as models for fine tuning peptide assembly with plasmid DNA. Geetha N. Goparaju, Pardeep K. Gupta 173 - 177 Subcellular localization of KL-6 mucin in intraductal papillary mucinous neoplasm of the pancreas. Yoshinori Inagaki, Yasuji Seyama, Kiyoshi Hasegawa, Wei Tang, Norihiro Kokudo 178 - 184 Enhancement of solubility of dexibuprofen applying mixed hydrotropic solubilization technique. Boushra Mohamed El-Houssieny, Esmat Zein El-Dein, Hussien Mohamed El-Messiry 185 - 193 Formulation, optimization, and evaluation of a transdermal patch of heparin sodium. Rakesh P. Patel, Dipika R. Gaiakwad, Nikunjana A. Patel www.ddtjournal.com iii CONTENTS (Continued ) Guide for Authors Copyright iv www.ddtjournal.com Drug Discoveries & Therapeutics. 2014; 8(4):139-153. 139 Review DOI: 10.5582/ddt.2014.01032 A map describing the association between effective components of traditional Chinese medicine and signaling pathways in cancer cells in vitro and in vivo Jufeng Xia1, Jialu Chen2, Zhongmin Zhang2, Peipei Song1, Wei Tang1,*, Norihiro Kokudo1 1 Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; 2 Department of Chemistry, Fudan University, Shanghai, China. Summary Cancer is the second leading cause of death by disease in the world. Chemotherapy is one of three major therapeutic methods for cancer treatment, but cancer cells gradually evolve resistance to chemotherapeutic reagents. For centuries, traditional Chinese medicine (TCM) was used to fight against cancer. In recent years, a number of effective component mechanisms of TCM have been increasingly illuminated. As we know, chemical structures of reagents decide or affect their activities on target pathways. Thus, we classified some antitumor-related TCM components reported in the last five years into thirteen groups by their chemical structures, such as, alkaloids, diterpenoids, triterpenes, sesquiterpenes, anthraquinones, benzoquinones, flavonoids, berbamines, xanthones, saponins, steroids, polysaccharides, and glycosides. In various cancer cell lines, these constituents target dozens of signaling pathways in vitro and in vivo. Among these components, there are three sets: i) mainly apoptosis-related groups, such as, alkaloids, diterpenoids, anthraquinones, berbamines, and xanthones, target pathways like the mitochondrial pathway, NF-κB pathway, p53 pathway and so on; ii) mainly proliferation, invasion and metastasis-related groups, such as, triterpenes, sesquiterpenes, polysaccharides, and glycosides, target pathways like the mTOR pathway, β-catenin pathway, ERK pathway and so on; iii) both apoptosis and proliferation, invasion and metastasis-related groups, such as benzoquinones, flavonoids, saponins, and steroids, target the pathways in i) and ii) synchronously. These will provide association information between TCM components and signaling pathways to promote studies on mechanisms of effective constituents, target drug development, and combinational chemotherapy. TCM could be alternative medicine for cancer treatment in the future. Keywords: Traditional Chinese medicine, signaling pathway, chemical structure, alternative medicine, combination therapy 1. Introduction for approximately 13% of all deaths each year with the most common being: lung cancer (1.4 million deaths), In 2008, approximately 12.7 million cancers were stomach cancer (740,000 deaths), liver cancer (700,000 diagnosed (excluding non-melanoma skin cancers and deaths), colorectal cancer (610,000 deaths), and breast other non-invasive cancers) (1), and in 2010 nearly cancer (460,000 deaths) (2). This makes invasive cancer 7.98 million people died. Cancers as a group account the leading cause of death in the developed world and the second leading cause of death in the developing world. Over half of the cases occur