DPP8 is a novel therapeutic target for multiple myeloma
| Autor: | Ayumi Tatekoshi, Kotaro Arita, Paras Jawaid, Nam H. Dang, Noriaki Iwao, Takashi Kondo, Satoshi Iyama, Chikao Morimoto, Yusuke Kamihara, Miho Arai, Ryo Hatano, Mati Ur Rehman, Jun Murakami, Kohichi Takada, Akinori Wada, Kyo Noguchi, Tsutomu Sato, Kei Ohnuma, Ichiro Yasuda, Sayaka Kajikawa |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Programmed cell death Dipeptidases lcsh:Medicine Myeloma Apoptosis Antineoplastic Agents CD38 Article 03 medical and health sciences Mice 0302 clinical medicine Mice Inbred NOD Cell Line Tumor Drug Discovery medicine Cytotoxic T cell Animals Humans Vildagliptin Protease Inhibitors lcsh:Science Multiple myeloma Multidisciplinary Chemistry lcsh:R Proteolytic enzymes medicine.disease 030104 developmental biology Cell culture 030220 oncology & carcinogenesis Cancer research lcsh:Q Female Multiple Myeloma medicine.drug |
| Zdroj: | Scientific Reports Scientific Reports, Vol 9, Iss 1, Pp 1-8 (2019) |
| ISSN: | 2045-2322 |
| Popis: | Dipeptidyl peptidases (DPPs) are proteolytic enzymes that are ideal therapeutic targets in human diseases. Indeed, DPP4 inhibitors are widely used in clinical practice as anti-diabetic agents. In this paper, we show that DPP4 inhibitors also induced cell death in multiple human myeloma cells. Among five DPP4 inhibitors, only two of them, vildagliptin and saxagliptin, exhibited apparent cytotoxic effects on myeloma cell lines, without any difference in suppression of DPP4 activity. As these two DPP4 inhibitors are known to have off-target effects against DPP8/9, we employed the specific DPP8/9 inhibitor 1G244. 1G244 demonstrated anti-myeloma effects on several cell lines and CD138+ cells from patients as well as in murine xenograft model. Through siRNA silencing approach, we further confirmed that DPP8 but not DPP9 is a key molecule in inducing cell death induced by DPP8/9 inhibition. In fact, the expression of DPP8 in CD38+ cells from myeloma patients was higher than that of healthy volunteers. DPP8/9 inhibition induced apoptosis, as evidenced by activated form of PARP, caspases-3 and was suppressed by the pan-caspase inhibitor Z-VAD-FMK. Taken together, these results indicate that DPP8 is a novel therapeutic target for myeloma treatment. |
| Databáze: | OpenAIRE |
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