2. Academic Validation
  3. DPP8 Selective Inhibitor Tominostat as a Novel and Broad-Spectrum Anticancer Agent against Hematological Malignancies

DPP8 Selective Inhibitor Tominostat as a Novel and Broad-Spectrum Anticancer Agent against Hematological Malignancies

  • Cells. 2023 Apr 6;12(7):1100. doi: 10.3390/cells12071100.
Shohei Kikuchi 1,  Akinori Wada 1,  Yusuke Kamihara 1,  Kosuke Okazaki 2,  Paras Jawaid 1,  Mati Ur Rehman 3,  Eiji Kobayashi 4,  Takeshi Susukida 5,  Tomoki Minemura 1,  Yoshimi Nabe 1,  Noriaki Iwao 6,  Tatsuhiko Ozawa 4,  Ryo Hatano 7,  Mitsugu Yamada 8,  Hiroyuki Kishi 4,  Yuji Matsuya 9,  Mineyuki Mizuguchi 9,  Yoshihiro Hayakawa 5,  Nam H Dang 10,  Yasumitsu Sakamoto 11,  Chikao Morimoto 7,  Tsutomu Sato 1
Affiliations

Affiliations

  • 1 Department of Hematology, Faculty of Medicine, Academic Assembly, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
  • 2 Center for Clinical Research, Toyama University Hospital, 2630 Sugitani, Toyama 930-0194, Japan.
  • 3 Department of Biological and Biomedical Sciences, The Aga Khan University, Karachi 74800, Pakistan.
  • 4 Department of Immunology, Faculty of Medicine, Academic Assembly, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
  • 5 Section of Host Defences, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
  • 6 Department of Hematology, Juntendo University Shizuoka Hospital, 1129 Nagaoka, Izunokuni City, Shizuoka 410-2295, Japan.
  • 7 Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo Bunkyo-ku, Tokyo 113-8421, Japan.
  • 8 JEM Utilization Center Human Spaceflight Technology Directorate, Japan Aerospace Exploration Agency (JAXA), 2-1-1 Sengen, Tsukuba-shi 305-8505, Japan.
  • 9 Faculty of Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
  • 10 Division of Hematology/Oncology, University of Florida, Gainesville, FL 32610, USA.
  • 11 School of Pharmacy, Iwate Medical University, 1-1-1 Idaidori, Yahaba 028-3694, Japan.
PMID: 37048172 DOI: 10.3390/cells12071100
Abstract

DPP8/9 inhibition induces either pyroptotic or apoptotic cell death in hematological malignancies. We previously reported that treatment with the DPP8/9 inhibitor 1G244 resulted in apoptotic cell death in myeloma, and our current study further evaluates the mechanism of action of 1G244 in different blood Cancer cell lines. Specifically, 1G244 inhibited DPP9 to induce GSDMD-mediated-pyroptosis at low concentrations and inhibited DPP8 to cause caspase-3-mediated-apoptosis at high concentrations. Hck expression is necessary to induce susceptibility to Pyroptosis but does not participate in the induction of Apoptosis. To further characterize this DPP8-dependent broad-spectrum Apoptosis induction effect, we evaluated the potential antineoplastic role for an analog of 1G244 with higher DPP8 selectivity, tominostat (also known as 12 m). In vitro studies demonstrated that the cytotoxic effect of 1G244 at high concentrations was enhanced in tominostat. Meanwhile, in vivo work showed tominostat exhibited antitumor activity that was more effective on a cell line sensitive to 1G244, and at higher doses, it was also effective on a cell line resistant to 1G244. Importantly, the weight loss morbidity associated with increasing doses of 1G244 was not observed with tominostat. These results suggest the possible development of novel drugs with antineoplastic activity against selected hematological malignancies by refining and increasing the DPP8 selectivity of tominostat.

Keywords

DPP8; anticancer agent; hematological; inhibitor; malignancies.

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