Discovery of a drug targeting microenvironmental support for lymphoma cells by screening using patient-derived xenograft cells.
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.
1] Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan [2] Fujii Memorial Research Institute, Otsuka Pharmaceutical Co., Ltd., Otsu, Japan.
Keiki
K
Sugimoto
Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Fumihiko
F
Hayakawa
Department of Pathology and Clinical Laboratories, Nagoya University Hospital, Nagoya, Japan.
Satoko
S
Shimada
Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Takanobu
T
Morishita
Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Kazuyuki
K
Shimada
Department of Immunology, Niigata University Graduate Scholl of Medical and Dental Sciences.
Tomoya
T
Katakai
Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Akihiro
A
Tomita
Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Hitoshi
H
Kiyoi
1] Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan [2] National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
Tomoki
T
Naoe
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D055808:Drug Discovery; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D008223:Lymphoma / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D018384:Oxidative Stress / Q000187:drug effects; D011774:Pyrvinium Compounds / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
D000970:Antineoplastic Agents; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D011774:Pyrvinium Compounds; D017382:Reactive Oxygen Species; C024631:pyrvinium; D005978:Glutathione