DPP8 selective inhibitor tominostat as a novel and broad-spectrum anticancer agent against hematological malignancies

Authors

Shohei Kikuchi, University of Toyama, Japan
Akinori Wada, University of Toyama, Japan
Yusuke Kamihara, University of Toyama, Japan
Kosuke Okazaki, Toyama University Hospital, Japan
Paras Jawaid, University of Toyama, Japan
Mati Ur Rehman, Aga Khan UniversityFollow
Eiji Kobayashi, University of Toyama, Japan
Takeshi Susukida, University of Toyama, Japan
Tomoki Minemura, University of Toyama, Japan
Yoshimi Nabe, University of Toyama, Japan

Document Type

Article

Department

Biological and Biomedical Sciences

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.

Comments

Pagination are not provided by the author/publisher.

Publication (Name of Journal)

Cells

Recommended Citation

Kikuchi, S., Wada, A., Kamihara, Y., Okazaki, K., Jawaid, P., Rehman, M. U., Kobayashi, E., Susukida, T., Minemura, T., Nabe, Y. (2023). DPP8 selective inhibitor tominostat as a novel and broad-spectrum anticancer agent against hematological malignancies. Cells, 12(7).
Available at: https://ecommons.aku.edu/pakistan_fhs_mc_bbs/1012