FF-10501 induces caspase-8-mediated apoptotic and endoplasmic reticulum stress-mediated necrotic cell death in...

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Inosine monophosphate dehydrogenase (IMPDH) inhibitors are investigated for hematological malignancies.
• FF-10501 is a novel IMPDH inhibitor with ongoing clinical trials for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).
• The intracellular mechanisms of FF-10501-induced apoptosis in cancer cells remain uncharacterized.

Purpose of the Study:

• To elucidate the intracellular mechanisms of FF-10501-induced cell death in hematological malignant cells.
• To investigate the specific pathways (apoptotic vs. necrotic) activated by FF-10501.

Main Methods:

• In vitro study using 12 hematological malignant cell lines.
• Dose-response assessment of FF-10501.
• Analysis of cell death mechanisms including caspase-8 activation, mitochondrial pathway involvement, and endoplasmic reticulum stress.

Main Results:

• FF-10501 suppressed the growth of all tested cell lines in a dose-dependent manner.
• A clinically relevant dose (40 μM) induced cell death in MOLM-13, OCI-AML3, and MOLT-3 cell lines.
• FF-10501 induced apoptosis via caspase-8 and mitochondrial pathways in MOLM-13 and MOLT-3 cells.
• FF-10501 induced necrotic cell death via endoplasmic reticulum stress in OCI-AML3 cells.

Conclusions:

• FF-10501 induces both apoptotic and necrotic cell death in hematological malignant cell lines.
• The study identifies distinct intracellular pathways mediating FF-10501's cytotoxic effects.
• These findings provide crucial insights into the mechanisms of FF-10501 action for AML and MDS treatment.