2. Academic Validation
  3. DPP8 is a novel therapeutic target for multiple myeloma

DPP8 is a novel therapeutic target for multiple myeloma

  • Sci Rep. 2019 Dec 2;9(1):18094. doi: 10.1038/s41598-019-54695-w.
Tsutomu Sato 1,  Ayumi Tatekoshi 2,  Kohichi Takada 2,  Satoshi Iyama 2,  Yusuke Kamihara 3,  Paras Jawaid 4,  Mati Ur Rehman 4,  Kyo Noguchi 4,  Takashi Kondo 4,  Sayaka Kajikawa 5,  Kotaro Arita 5,  Akinori Wada 5,  Jun Murakami 5,  Miho Arai 6,  Ichiro Yasuda 7,  Nam H Dang 8,  Ryo Hatano 9,  Noriaki Iwao 9,  Kei Ohnuma 9,  Chikao Morimoto 9
Affiliations

Affiliations

  • 1 Department of Hematology, Toyama University Hospital, Toyama, Japan. [email protected].
  • 2 Department of Medical Oncology and Hematology, Sapporo Medical University, Sapporo, Japan.
  • 3 Department of Hematology, National Cancer Center Hospital East, Kashiwa, Japan.
  • 4 Department of Radiology, University of Toyama, Toyama, Japan.
  • 5 Department of Hematology, Toyama University Hospital, Toyama, Japan.
  • 6 Department of Pediatrics, University of Toyama, Toyama, Japan.
  • 7 Department of Gastroenterology and Hematology, University of Toyama, Toyama, Japan.
  • 8 Division of Hematology/Oncology, University of Florida, Gainesville, Florida, USA.
  • 9 Department of Therapy Development and Innovation for Immune Disorders and Cancers, Juntendo University, Tokyo, Japan.
PMID: 31792328 DOI: 10.1038/s41598-019-54695-w
Abstract

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.

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