SphK Inhibitor ZFP-B34 Suppresses the Growth of TNBC Cells

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Sphingosine kinase 1/2 (SphK1/2) are key drivers in breast cancer initiation and progression.
• Triple-negative breast cancer (TNBC) remains a challenging subtype with limited targeted therapies.

Purpose of the Study:

• To identify and evaluate a novel SphK inhibitor, ZFP-B34, for its antitumor potential in TNBC.
• To elucidate the molecular mechanisms underlying ZFP-B34's efficacy against TNBC.

Main Methods:

• Computer molecular docking was used to screen SphK inhibitors.
• In vitro assays assessed ZFP-B34's effects on SphK1/2 activity, cell proliferation, cell cycle, migration, ROS production, mitochondrial function, and DNA damage in TNBC cell lines.
• In vivo studies evaluated ZFP-B34's efficacy in a murine TNBC allograft model.

Main Results:

• ZFP-B34 demonstrated potent dual inhibition of SphK1/2, leading to ceramide accumulation and Sphingosine 1 phosphate (S1P) depletion in TNBC cells.
• The compound effectively inhibited TNBC cell proliferation, migration, and induced cell cycle arrest.
• ZFP-B34 triggered apoptosis via ROS production, mitochondrial dysfunction, and DNA damage, while modulating Akt-mTOR and JNK signaling pathways.
• In vivo, ZFP-B34 significantly inhibited tumor growth in a 4T1 allograft mouse model.

Conclusions:

• ZFP-B34 is a promising dual inhibitor of SphK1/2 with significant in vitro and in vivo antitumor activity against TNBC.
• Targeting SphK1/2 with ZFP-B34 represents a viable therapeutic strategy for managing TNBC progression.