著者

Zhiwei Qiao Tadashi Kondo

出版者

Japanese Electrophoresis Society

雑誌

Journal of Electrophoresis (ISSN:13499394)

巻号頁・発行日

vol.63, no.1, pp.1-7, 2019 (Released:2019-02-06)

参考文献数

34

被引用文献数

2

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There is a need for novel drugs for sarcoma treatment. In the present study, to identify inhibitors with potential therapeutic utility in sarcomas, we screened the growth inhibitory effects of 361 inhibitors, including experimental reagents and anti-cancer drugs approved for use in non-sarcoma malignancies and those under clinical trials. The inhibitors were initially tested using 10 osteosarcoma cell lines. The half-maximal inhibitory concentration (IC50) of leptomycin B, actinomycin D, chetomin, and staurosporine was <100 nM in all the cell lines. As the promiscuous effects of staurosporine on kinases make it unsuitable for clinical applications, the other three inhibitors were tested in an additional 15 sarcoma cell lines derived from synovial sarcoma, fibrosarcoma, liposarcoma, rhabdomyosarcoma, malignant peripheral nerve sheath tumor, leiomyosarcoma, and Ewing’s sarcoma. The IC50 of leptomycin B and actinomycin D was <100 nM in all cell lines and that of chetomin was <100 nM in all but three synovial sarcoma cell lines. Although the clinical development of leptomycin B, a chromosomal region maintenance (CRM)1/exportin (XPO)1 inhibitor, was discontinued because of toxicity, a previous clinical trial revealed that other CRM1/XPO1 inhibitors, such as selinexor, have anti-tumor effects in sarcomas. Actinomycin D has proven clinical utility in the treatment of sarcomas. Chetomin disrupts the interaction of hypoxia-inducible factor-1 with the transcriptional coactivator p300 and its clinical utility has not been established in sarcomas. Chetomin exhibited growth inhibitory effects on sarcoma cells with different histological subtypes. Library screening is a powerful approach to detect the potential utility of anti-cancer drugs in sarcoma treatment.

著者

Rieko OYAMA Mami TAKAHASHI Fusako KITO Marimu SAKUMOTO Yoko TAKAI Kumiko SHIOZAWA Zhiwei QIAO Shunichi TOKI Yoshikazu TANZAWA Akihiko YOSHIDA Akira KAWAI Tadashi KONDO

出版者

The Japanese Tissue Culture Association

雑誌

組織培養研究 (ISSN:09123636)

巻号頁・発行日

vol.38, no.1, pp.1-12, 2019 (Released:2019-02-15)

参考文献数

57

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Background: Pleomorphic rhabdomyosarcoma (pRMS) is an aggressive mesenchymal malignancy affecting adults, and its characteristics and clinical behaviors differ considerably from those of embryonal and alveolar RMS subtypes. A therapeutic strategy for pRMS has not been established, and its prognosis remains poor. Further investigations are therefore required to improve the clinical outcomes associated with this disease. Patient-derived cancer models are essential tools for basic and translational research, and numerous models of different RMS subtypes have been established. However, only two pRMS cell lines are available, and no xenograft model of this disease has been developed. Hence, the objective of this study was to establish patient-derived pRMS models.Methods: We obtained tumor tissues from a 73-year-old pRMS patient who had not received chemotherapy or radiotherapy. We prepared patient-derived xenografts (PDXs) from these tumor tissues and stable patient-derived cell lines from both the original tumor and a PDX. The established models were then characterized, and their novelty was confirmed by short tandem repeat analysis.Results: The PDX tumors were histologically similar to the original source tumor. Moreover, the established cell lines exhibited morphological features resembling those of RMS, the ability to form spheroids, constant growth, and invasive behavior. By screening an anti-cancer drug library, we identified mitoxantrone, ponatinib, romidepsin, vandetanib, belinostat, bortezomib, and vorinostat as potential drugs for pRMS treatment.Conclusions: Our novel pRMS models will be useful research resources, providing an opportunity for in-depth investigations of the molecular basis and treatment of this disease. Clinical trials for the drugs showing anti-proliferative effects on pRMS cells may be worth considering in further studies.