@article{1fbb69637ae44492b8ace02a810d84c5,
title = "Discovery of a drug targeting microenvironmental support for lymphoma cells by screening using patient-derived xenograft cells",
abstract = "Cell lines have been used for drug discovery as useful models of cancers; however, they do not recapitulate cancers faithfully, especially in the points of rapid growth rate and microenvironment independency. Consequently, the majority of conventional anti-cancer drugs are less sensitive to slow growing cells and do not target microenvironmental support, although most primary cancer cells grow slower than cell lines and depend on microenvironmental support. Here, we developed a novel high throughput drug screening system using patient-derived xenograft (PDX) cells of lymphoma that maintained primary cancer cell phenotype more than cell lines. The library containing 2613 known pharmacologically active substance and off-patent drugs were screened by this system. We could find many compounds showing higher cytotoxicity than conventional anti-tumor drugs. Especially, pyruvinium pamoate showed the highest activity and its strong anti-tumor effect was confirmed also in vivo. We extensively investigated its mechanism of action and found that it inhibited glutathione supply from stromal cells to lymphoma cells, implying the importance of the stromal protection from oxidative stress for lymphoma cell survival and a new therapeutic strategy for lymphoma. Our system introduces a primary cancer cell phenotype into cell-based phenotype screening and sheds new light on anti-cancer drug development.",
author = "Keiki Sugimoto and Fumihiko Hayakawa and Satoko Shimada and Takanobu Morishita and Kazuyuki Shimada and Tomoya Katakai and Akihiro Tomita and Hitoshi Kiyoi and Tomoki Naoe",
note = "Funding Information: We thank the Open Innovation Center for Drug Discovery (The Tokyo University, Tokyo, Japan) for providing the Prestwick and Lopack chemical library. We are very grateful to Yoko Matsuyama and Chika Wakamatsu for their technical assistance. This work was supported by MHLW KAKENHI Grant Number H22-3jigan-Ippan-010 and H26-Kakushintekigan-Ippan-133 and JSPS KAKENHI Grant Numbers 23591381, 25118711, 25293218 and 25670449. This work was also supported by the Program to Disseminate Tenure Tracking System, MEXT, Japan and the Platform for Drug Discovery, Informatics and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology, Japan. Funding Information: Competing financial interests: T.N. received research funding from Otsuka Pharmaceutical Co. LTD., Bristol-Myers Squibb, Novartis Pharma, Chugai Pharmaceutical Co. LTD., Kyowa Hakko Kirin Co. LTD., Dainippon Sumitomo Pharma, Zenyaku Kogyo and FUJIFILM Corporation. K. Sugimoto is an employee of Otsuka Pharmaceutical Co., Ltd. H.K. received research funding from Bristol-Myers Squibb, Chugai Pharmaceutical Co. LTD., Kyowa Hakko Kirin Co. LTD., Dainippon Sumitomo Pharma, Zenyaku Kogyo and FUJIFILM Corporation. The other authors have no potential conflicts of interest.",
year = "2015",
month = aug,
day = "17",
doi = "10.1038/srep13054",
language = "English",
volume = "5",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
}