Preprint Brief Report Version 1 Preserved in Portico This version is not peer-reviewed

Novel Ceramide Mimetics Induce Necroptotic Cell Death in Multiple Cancer Cell Lines

Yuri Ogiso
,
Kentaro Kawai
,
Kazuya Nakayama
,
Ryosei Tokoo
,
Harumi Sakae
,
Shogo Shigeta
,
Masumi Ishibashi
ORCID logo ,
Muneaki Shimada
,
Yukiko Karuo
,
Masaaki Omote
,
Masaya Matsuda
ORCID logo ,
Takeshi Nabe
,
Kazuyuki Kitatani
* ORCID logo
Version 1 : Received: 6 December 2023 / Approved: 6 December 2023 / Online: 6 December 2023 (11:02:23 CET)

How to cite: Ogiso, Y.; Kawai, K.; Nakayama, K.; Tokoo, R.; Sakae, H.; Shigeta, S.; Ishibashi, M.; Shimada, M.; Karuo, Y.; Omote, M.; Matsuda, M.; Nabe, T.; Kitatani, K. Novel Ceramide Mimetics Induce Necroptotic Cell Death in Multiple Cancer Cell Lines. Preprints 2023, 2023120414. https://doi.org/10.20944/preprints202312.0414.v1 Ogiso, Y.; Kawai, K.; Nakayama, K.; Tokoo, R.; Sakae, H.; Shigeta, S.; Ishibashi, M.; Shimada, M.; Karuo, Y.; Omote, M.; Matsuda, M.; Nabe, T.; Kitatani, K. Novel Ceramide Mimetics Induce Necroptotic Cell Death in Multiple Cancer Cell Lines. Preprints 2023, 2023120414. https://doi.org/10.20944/preprints202312.0414.v1

Abstract

Ceramide is a lipid that regulates cell death including apoptosis and necroptosis and acts as a powerful tumor suppressor. These characteristics have supported the development of ceramide-based cancer therapeutics. In the present study, ceramide mimetics (RT-25, RT-71 and YM-07) were designed and chemically synthesized, and their potential as necroptosis-inducing chemotherapeutic reagents was examined. RT-71 and YM-07, but not RT-25, potently decreased cell viability in multiple cancer cell lines. The ranges of IC50 values for RT-71 and YM-07 were 8.4–40.8 µM and 4.4–23.7 µM, respectively. Cleavage of PARP, an apoptosis marker, was not observed in MCF-7 cells treated with the mimetics. To determine the effects on necroptotic cell death, we used siRNAs specific to mixed lineage kinase domain-like protein (MLKL). MLKL knockdown significantly suppressed the cell death induced by YM-07 but not RT-71. These results suggest that YM-07 exhibits pro-necroptotic activity. Taken together, these findings indicate ceramide mimetic YM-07 as a lead compound for developing MLKL-activating necroptotic reagents. Our results help establish a foundation for pro-necroptotic therapy for cancer.

Keywords

ceramide mimetics; ceramide; necroptosis

Subject

Medicine and Pharmacology, Oncology and Oncogenics

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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