FF-10501 induces caspase-8-mediated apoptotic and endoplasmic reticulum stress-mediated necrotic cell death in hematological malignant cells
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FF-10501 is a novel inhibitor of inosine monophosphate dehydrogenase (IMPDH). Clinical trials of FF-10501 for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are currently being conducted in the United States. Although it has been shown that FF-10501 induces apoptosis in hematological malignant cells, the intracellular mechanisms of this effect have not been characterized. We conducted an in vitro study to elucidate the mechanisms of FF-10501-induced cell death using 12 hematological malignant cell lines derived from myeloid and lymphoid malignancies. FF-10501 suppressed the growth of each cell line in a dose-dependent manner. However, the clinically relevant dose (40 μM) of FF-10501 induced cell death in three cell lines (MOLM-13, OCI-AML3, and MOLT-3). Investigation of the cell death mechanism suggested that FF-10501 induces both apoptotic and necrotic cell death. FF-10501-induced apoptosis was mediated by caspase-8 activation followed by activation of the mitochondrial pathway in MOLM-13 and MOLT-3 cells. FF-10501 induced necrotic cell death via endoplasmic reticulum stress in OCI-AML3 cells. The present study is the first to identify intracellular pathways involved in FF-10501-induced cell death.
KeywordsFF-10501 Apoptosis Necrosis Caspase-8 Endoplasmic reticulum stress
The authors would like to thank Miyuki Saisho, Eri Sakai-Nagamatsu, Misato Yagi, Mami Sato, Miku Kamekou, Ayaka Tsuzuki, Takafumi Kuroiwa, Midori Suekane, Kousuke Iwasaki, and Shuntarou Nakamura for their help with the experiments.
TM and SJ designed the research study. TM performed the experiments. TM, SJ, KT, and MM analyzed and interpreted the data. TM drafted the manuscript. SJ, KM, YT, JS, and SH revised the manuscript. SJ provided final approval of the current version for submission.
This research was partially supported by FUJIFILM Corporation.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
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