TP-0903 Suppresses Aurora A-PLK1 Signaling to Inhibit Proliferation of a Myelodysplastic Syndrome-Derived Cell Line

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• TP-0903 is a low molecular compound initially developed as an anexelekto inhibitor.
• It shows promise as a therapeutic agent for chronic lymphocytic leukemia, solid tumors, and drug-resistant acute myeloid leukemia (AML).

Purpose of the Study:

• To investigate the in vitro effects of TP-0903 on myelodysplastic syndrome (MDS)-derived cell line (MDS-L) and two myeloid leukemia cell lines.
• To elucidate the molecular mechanisms underlying TP-0903's anti-cancer activity.

Main Methods:

• Treatment of MDS-L and myeloid leukemia cell lines with TP-0903.
• Analysis of cell proliferation, apoptosis, cell cycle progression, and key signaling pathways (PI3K/AKT, JAK/STAT3, MET, Aurora kinases, TGF-β1/SMAD3).
• Gene expression profiling focusing on ferroptosis-related genes and assessment of reactive oxygen species and intracellular iron levels.

Main Results:

• TP-0903 inhibited cell proliferation and induced apoptosis in all tested cell lines.
• Inhibition of PI3K/AKT and JAK/STAT3 pathways was observed, potentially linked to reduced MET interactions.
• TP-0903 induced G2/M cell cycle arrest by affecting DNA damage response and Aurora kinase activity, leading to mitotic disruption.
• Gene expression changes and increased reactive oxygen species/iron accumulation suggested activation of an atypical ferroptosis pathway via TGF-β1/SMAD3 signaling.

Conclusions:

• TP-0903 demonstrates potent anti-leukemic effects in vitro against MDS and myeloid leukemia cells.
• The compound exerts its effects through multiple mechanisms, including cell cycle arrest and ferroptosis induction.
• TP-0903 represents a potential novel therapeutic strategy for refractory hematological malignancies.